@article {pmid37261700, year = {2023}, author = {Haridoss, M and Ayyasamy, L and Bagepally, BS}, title = {Is COVID-19 severity associated with telomere length? A systematic review and meta-analysis.}, journal = {Virus genes}, volume = {}, number = {}, pages = {1-10}, pmid = {37261700}, issn = {1572-994X}, abstract = {Telomere shortening, a marker of cellular aging, has been linked to hospitalization and the severity of COVID-19. In this systematic review and meta-analysis, the mean difference in telomere length between non-severe and severe COVID-19 individuals was pooled to determine the association between short telomeres and COVID-19 severity. Relevant studies were retrieved through searches conducted in PubMed-Medline, Scopus, EMBASE, Medrxiv, Biorxiv, EuroPMC, and SSRN databases up to November 2022. Selected studies were systematically reviewed and assessed for risk of bias using AXIS tool. The standardized mean difference in telomere length between non-severe and severe COVID-19 was pooled using random-effects model. A total of thirteen studies were included in the review, out of which seven (1332 patients with the severe COVID-19 disease and 6321 patients with non-severe COVID-19) were eligible for meta-analysis. The estimated pooled mean difference in Leukocyte telomere length between severe COVID-19 and non-severe COVID-19 was 0.39 (95% CI - 0.02 to 0.81, I[2] = 93.5%) with substantial heterogeneity. Our findings do not provide clear evidence for association of shorter telomere length and severe COVID-19 disease. More extensive studies measuring absolute telomere length with age and gender adjustments are needed to draw definitive conclusions on the potential causal association between telomere shortening and COVID-19 severity.}, }
@article {pmid37260287, year = {2023}, author = {Kim, Y and Lin, J and Epel, ES and Carver, CS}, title = {A Lens on Caregiver Stress in Cancer: Longitudinal Investigation of Cancer-Related Stress and Telomere Length Among Family Caregivers of Adult Patients with Cancer.}, journal = {Psychosomatic medicine}, volume = {}, number = {}, pages = {}, doi = {10.1097/PSY.0000000000001220}, pmid = {37260287}, issn = {1534-7796}, abstract = {OBJECTIVE: Family members are typically the primary caregivers of patients with chronic illnesses. Family caregivers of adult relatives with cancer are a fast-growing population yet the physical consequences of their stress due to the cancer in the family have been poorly understood. This study examined the bidirectional relations of the perceived stress of family caregivers of individuals recently diagnosed with cancer and leukocyte cellular aging indexed by telomere length over two years.<br><br>METHODS: Family caregivers (n = 168; mean age = 51 years old, 70% female, 46% Hispanic, 36% spouse to the patient) of patients with colorectal cancer provided psychological data and peripheral blood samples approximately 4 (T1), 12 (T2), and 21 months (T3) post-diagnosis. Time-lagged cross panel modeling was used to test the associations of perceived cancer-related stress and telomere length, controlling for age, gender, and BMI.<br><br>RESULTS: Cancer-related stress was highest at T1 and decreased by one year. Greater cancer-related stress predicted longer telomere length at subsequent assessments over two years (&#x3b2; &#x2265; .911, p &#x2264; .019). However, telomere length did not change significantly over two years overall and did not prospectively predict cancer-related stress over this period.<br><br>CONCLUSIONS: Findings suggest the need to better understand how the perceived stress of colorectal cancer caregivers, which tends to be intense for a relatively short period compared to dementia caregiving, may impact immune cell distributions and telomere length. These findings emphasize the need for further knowledge about psycho-biological mechanisms of how cancer caregiving may impact cellular aging.}, }
@article {pmid37259830, year = {2023}, author = {Nichele, S and Bonfim, C and Junior, LGD and Loth, G and Kuwahara, C and Trennephol, J and Funke, VAM and Marinho, DE and Koliski, A and Rodrigues, AM and Mousquer, RTG and Fasth, A and Lima, ACM and Calado, RT and Pasquini, R}, title = {Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.}, journal = {European journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejh.14023}, pmid = {37259830}, issn = {1600-0609}, abstract = {BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes.<br><br>OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure.<br><br>STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019.<br><br>RESULTS: The median age at transplantation was 14&#x2009;years (range, 3-30&#x2009;years). Most patients received a RIC regimen (n&#x2009;=&#x2009;28) and bone marrow (BM) from an unrelated donor (n&#x2009;=&#x2009;16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20&#x2009;days (13-36&#x2009;days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6&#x2009;years; 1.4-19&#x2009;years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p&#x2009;=&#x2009;.05; CI&#x2009;=&#x2009;95%). Overall, 15 patients died after HCT, most of them (n&#x2009;=&#x2009;11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD.<br><br>CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.}, }
@article {pmid37259606, year = {2023}, author = {Bloom, SI and Liu, Y and Tucker, JR and Islam, MT and Machin, DR and Abdeahad, H and Thomas, TG and Bramwell, RC and Lesniewski, LA and Donato, AJ}, title = {Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e13875}, doi = {10.1111/acel.13875}, pmid = {37259606}, issn = {1474-9726}, support = {R01 AG060395/AG/NIA NIH HHS/United States ; R01 AG048366/AG/NIA NIH HHS/United States ; }, abstract = {In advanced age, increases in oxidative stress and inflammation impair endothelial function, which contributes to the development of cardiovascular disease (CVD). One plausible source of this oxidative stress and inflammation is an increase in the abundance of senescent endothelial cells. To test whether this results in senescence, we selectively reduced the telomere shelterin protein telomere repeat binding factor 2 (Trf2) from endothelial cells of young mice. Trf2 reduction increased endothelial cell telomere dysfunction and resulted in cellular senescence. Furthermore, induction of endothelial cell telomere dysfunction increased inflammatory signaling and oxidative stress, resulting in impairments in endothelial function. Finally, we demonstrate that endothelial cell telomere dysfunction-induced senescence impairs glucose tolerance. This likely occurs through increases in inflammatory signaling in the liver and adipose tissue, as well as reductions in microvascular density and vasodilation to metabolic stimuli. Cumulatively, the findings of the present study identify age-related telomere dysfunction as a mechanism that leads to endothelial cell senescence. Furthermore, these data provide compelling evidence that senescent endothelial cells contribute to age-related increases in oxidative stress and inflammation that impair arterial and metabolic function.}, }
@article {pmid37258936, year = {2023}, author = {Huang, P and Li, Q}, title = {Comments on the effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {37258936}, issn = {1573-7217}, }
@article {pmid37258109, year = {2023}, author = {Ashe, JJ and Evans, MK and Zonderman, AB and Waldstein, SR}, title = {Absent Relations of Religious Coping to Telomere Length in African American and White Women and Men.}, journal = {Experimental aging research}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/0361073X.2023.2219187}, pmid = {37258109}, issn = {1096-4657}, abstract = {OBJECTIVES: This study investigated whether race and sex moderated the relations of religious coping to telomere length (TL), a biomarker of cellular aging implicated in race-related health disparities.<br><br>METHODS: Participant data were drawn from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, which included 252 socioeconomically diverse African American and White men and women aged (30-64&#x2009;years old). Cross-sectional multivariable regression analyses examined interactive associations of religious coping, race, and sex to TL, adjusting for other sociodemographic characteristics.<br><br>RESULTS: Religious coping was unrelated to TL in this sample (p's > .05). There were no notable race or sex differences. Post hoc exploratory analyses similarly found that neither secular social support coping use nor substance use coping was associated with TL.<br><br>CONCLUSION: There was no evidence to support that religious coping use provided protective effects to TL in this sample of African American and White women and men. Nevertheless, future studies should use more comprehensive assessments of religious coping and intersectional identities to provide an in-depth examination of religiosity/spirituality as a potential culturally salient protective factor in cellular aging among African Americans in the context of specific chronic stressors such as discrimination.}, }
@article {pmid37254630, year = {2023}, author = {Liu, R and Xiang, M and Pilling, LC and Melzer, D and Wang, L and Manning, KJ and Steffens, DC and Bowden, J and Fortinsky, RH and Kuchel, GA and Rhee, TG and Diniz, BS and Kuo, CL}, title = {Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e13808}, doi = {10.1111/acel.13808}, pmid = {37254630}, issn = {1474-9726}, support = {P30AG067988/AG/NIA NIH HHS/United States ; R21NR018963-01A1S1/NR/NINR NIH HHS/United States ; }, abstract = {Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90-0.96, p = 3.37 × 10[-7]). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies.}, }
@article {pmid37246640, year = {2023}, author = {Fernandes, RV and Lingner, J}, title = {The THO complex counteracts TERRA R-loop-mediated telomere fragility in telomerase+ cells and telomeric recombination in ALT+ cells.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkad448}, pmid = {37246640}, issn = {1362-4962}, support = {310030_184718/SNSF_/Swiss National Science Foundation/Switzerland ; }, abstract = {Telomeres are the nucleoprotein structures at the ends of linear chromosomes. Telomeres are transcribed into long non-coding Telomeric Repeat-Containing RNA (TERRA), whose functions rely on its ability to associate with telomeric chromatin. The conserved THO complex (THOC) was previously identified at human telomeres. It links transcription with RNA processing, decreasing the accumulation of co-transcriptional DNA:RNA hybrids throughout the genome. Here, we explore the role of THOC at human telomeres, as a regulator of TERRA localization to chromosome ends. We show that THOC counteracts TERRA association with telomeres via R-loops formed co-transcriptionally and also post-transcriptionally, in trans. We demonstrate that THOC binds nucleoplasmic TERRA, and that RNaseH1 loss, which increases telomeric R-loops, promotes THOC occupancy at telomeres. Additionally, we show that THOC counteracts lagging and mainly leading strand telomere fragility, suggesting that TERRA R-loops can interfere with replication fork progression. Finally, we observed that THOC suppresses telomeric sister-chromatid exchange and C-circle accumulation in ALT cancer cells, which maintain telomeres by recombination. Altogether, our findings reveal crucial roles of THOC in telomeric homeostasis through the co- and post-transcriptional regulation of TERRA R-loops.}, }
@article {pmid37245595, year = {2023}, author = {Zhu, X and Li, Z and Wang, Z and Guo, C and Qian, Y and Wang, Z and Li, X and Wei, Y}, title = {Associations between exposure to ambient air pollution and changes in blood telomeres in young people: A repeated-measure study.}, journal = {Chemosphere}, volume = {}, number = {}, pages = {139053}, doi = {10.1016/j.chemosphere.2023.139053}, pmid = {37245595}, issn = {1879-1298}, abstract = {Telomere length (TL) is one of the early biomarkers of aging. Air pollutants play an important role in promoting the aging process. However, few studies have explored how they adversely affect human health by altering telomeres. This study aims to investigate the associations between telomere alterations and exposure to ambient air pollutants, thereby shedding light on the intrinsic and profound link between these pollutants and aging. We recruited 26 healthy young people and conducted 7 repeated measure studies from 2019 to 2021, and TL and telomerase (TA) in the blood samples. We analyzed the associations between air pollutants, including ozone (O3), particulate matter in diameter smaller than 2.5 μm (PM2.5) and 10 μm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) and telomere variability, and explored the lagged effects by linear mixed-effects model. The result showed that short-term exposure to O3 was negatively associated with TL, and this effect in the lag days went up to around 0. In contrast, the associations between O3 and TA presented positive tendency and gradually decreased to around 0 in the lag days. The association between PM2.5 and TL showed positive tendency and gradually decreased to negative. There was no statistically significant association between PM2.5 and TA. Other pollutants (PM10, NO2, SO2, CO) showed similar patterns of variation to that of PM2.5. Our findings suggest that short-term exposure to O3 shortens TL, which can be gradually recovered through activating TA activity, while exposure to PM2.5, PM10, NO2, SO2 and CO lengthens TL and then becomes shorter over time. This implies that the human body has some ability to self-repair telomere changes after exposure to air pollutants, and predictably, when this exposure exceeds a certain threshold, it cannot be repaired, leading to aging of the body.}, }
@article {pmid37239399, year = {2023}, author = {Gouhier, C and Pons-Rejraji, H and Dollet, S and Chaput, L and Bourgne, C and Berger, M and Pereira, B and Tchirkov, A and Brugnon, F}, title = {Freezing Does Not Alter Sperm Telomere Length despite Increasing DNA Oxidation and Fragmentation.}, journal = {Genes}, volume = {14}, number = {5}, pages = {}, pmid = {37239399}, issn = {2073-4425}, mesh = {Male ; Animals ; Freezing ; *Spermatozoa ; *Semen Analysis/methods ; DNA ; Telomere/genetics ; }, abstract = {Correlations were reported between sperm telomere length (STL) and male fertility, sperm DNA fragmentation, and oxidation. Sperm freezing is widely used for assisted reproductive techniques, fertility preservation, and sperm donation. However, its impact on STL remains unknown. For this study, semen surplus from patients who underwent routine semen analysis were used. The impact of slow freezing on STL was analyzed by performing qPCR before and after freezing. Sperm populations with different STL were evaluated using Q-FISH. The relationship between sperm DNA oxidation, DNA fragmentation, and STL was assessed in fresh and frozen sperm samples. No significant impact of slow freezing on STL was observed, neither measured by qPCR nor Q-FISH. However, Q-FISH allowed for the distinguishing of sperm populations with different STLs within individual sperm samples. Slow freezing induced different STL distributions for some of the analyzed sperm samples, but no correlation was found between STL and sperm DNA fragmentation or oxidation. Slow freezing does not alter STL despite increasing sperm DNA oxidation and fragmentation. As STL alterations could be transmitted to offspring, the lack of impact of the slow freezing method on STL ensures the safety of this procedure.}, }
@article {pmid37239390, year = {2023}, author = {Hill, C and Duffy, S and Kettyle, LM and McGlynn, L and Sandholm, N and Salem, RM and Thompson, A and Swan, EJ and Kilner, J and Rossing, P and Shiels, PG and Lajer, M and Groop, PH and Maxwell, AP and McKnight, AJ and On Behalf Of The Genie Consortium, }, title = {Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.}, journal = {Genes}, volume = {14}, number = {5}, pages = {}, pmid = {37239390}, issn = {2073-4425}, support = {MC_PC_20026/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; Aged ; *Diabetes Mellitus, Type 1/complications/genetics ; *Diabetic Nephropathies/genetics/metabolism ; *Kidney Failure, Chronic/genetics ; DNA Methylation/genetics ; Telomere/genetics/metabolism ; }, abstract = {Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10[-6]). Telomere length was also significantly reduced (p = 6.6 × 10[-5]) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10[-8]) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.}, }
@article {pmid37238614, year = {2023}, author = {Chieffi Baccari, G and Iurato, G and Santillo, A and Dale, B}, title = {Male Germ Cell Telomeres and Chemical Pollutants.}, journal = {Biomolecules}, volume = {13}, number = {5}, pages = {}, doi = {10.3390/biom13050745}, pmid = {37238614}, issn = {2218-273X}, abstract = {In recent decades, male infertility has been correlated with the shortening of sperm telomeres. Telomeres regulate the reproductive lifespan by mediating the synapsis and homologous recombination of chromosomes during gametogenesis. They are composed of thousands of hexanucleotide DNA repeats (TTAGGG) that are coupled to specialized shelterin complex proteins and non-coding RNAs. Telomerase activity in male germ cells ensures that the telomere length is maintained at maximum levels during spermatogenesis, despite telomere shortening due to DNA replication or other genotoxic factors such as environmental pollutants. An emerging body of evidence has associated an exposure to pollutants with male infertility. Although telomeric DNA may be one of the important targets of environmental pollutants, only a few authors have considered it as a conventional parameter for sperm function. The aim of this review is to provide comprehensive and up-to-date data on the research carried out so far on the structure/function of telomeres in spermatogenesis and the influence of environmental pollutants on their functionality. The link between pollutant-induced oxidative stress and telomere length in germ cells is discussed.}, }
@article {pmid37236462, year = {2023}, author = {Zhang, Q and Han, XZ and Burraco, P and Hao, X and Teng, LW and Liu, ZS and Zhang, FS and Du, WG}, title = {Telomere length, oxidative stress and their links with growth and survival in a lizard facing climate warming.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {164424}, doi = {10.1016/j.scitotenv.2023.164424}, pmid = {37236462}, issn = {1879-1026}, abstract = {Higher temperatures enhance ectothermic metabolism and development, which can reduce individual health and life expectancy, and therefore increase their vulnerability to climate warming. However, the mechanistic causes and consequences of such a temperature-driven impact remain unclear. Our study aimed to address two questions: (1) does climate warming alter early-life growth and physiology, and, if so, what are the associated carry-over effects in terms of reduced survival, increased oxidative stress and telomere shortening? (2) can oxidative stress and telomere dynamics at early life stages predict the effect of climate warming on individual survival? To answer these questions, we conducted a longitudinal experiment under semi-natural conditions where we exposed multiocellated racerunner (Eremias multiocellata) to warming conditions from juvenile to adult stages. We found that exposure to climate warming enhanced growth rates, induced oxidative stress, and shortened telomere length of juvenile lizards. Warming conditions did not induce carry-over effects in terms of altered growth rate or physiology but resulted in increased mortality risk in the later life. Intriguingly, telomere shortening in young individuals was associated with mortality risk later in life. This study improves our mechanistic understanding of how global warming impacts on ectotherms' life-history traits, which encourages the inclusion of physiological information in assessing species vulnerability to climate change.}, }
@article {pmid37235262, year = {2023}, author = {Zhou, F and Guo, C and Wang, L and Zhang, G and Wang, J and Chen, W and Cui, K and Tan, Y and Zhou, Z}, title = {Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Telomere Structure and Function Disorder Mediates Cell Cycle Dysregulation and Apoptosis via c-Myc and Its Upstream Transcription Factors in a Mouse Spermatogonia-Derived (GC-1) Cell Line.}, journal = {Toxics}, volume = {11}, number = {5}, pages = {}, doi = {10.3390/toxics11050448}, pmid = {37235262}, issn = {2305-6304}, abstract = {As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors.}, }
@article {pmid37232505, year = {2023}, author = {Chen, B and Yan, Y and Wang, H and Xu, J}, title = {Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e13874}, doi = {10.1111/acel.13874}, pmid = {37232505}, issn = {1474-9726}, abstract = {Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.}, }
@article {pmid37232367, year = {2023}, author = {Tsatsakis, A and Oikonomopoulou, T and Nikolouzakis, TK and Vakonaki, E and Tzatzarakis, M and Flamourakis, M and Renieri, E and Fragkiadaki, P and Iliaki, E and Bachlitzanaki, M and Karzi, V and Katsikantami, I and Kakridonis, F and Hatzidaki, E and Tolia, M and Svistunov, AA and Spandidos, DA and Nikitovic, D and Tsiaoussis, J and Berdiaki, A}, title = {Role of telomere length in human carcinogenesis (Review).}, journal = {International journal of oncology}, volume = {63}, number = {1}, pages = {}, doi = {10.3892/ijo.2023.5526}, pmid = {37232367}, issn = {1791-2423}, abstract = {Cancer is considered the most important clinical, social and economic issue regarding cause‑specific disability‑adjusted life years among all human pathologies. Exogenous, endogenous and individual factors, including genetic predisposition, participate in cancer triggering. Telomeres are specific DNA structures positioned at the end of chromosomes and consist of repetitive nucleotide sequences, which, together with shelterin proteins, facilitate the maintenance of chromosome stability, while protecting them from genomic erosion. Even though the connection between telomere status and carcinogenesis has been identified, the absence of a universal or even a cancer‑specific trend renders consent even more complex. It is indicative that both short and long telomere lengths have been associated with a high risk of cancer incidence. When evaluating risk associations between cancer and telomere length, a disparity appears to emerge. Even though shorter telomeres have been adopted as a marker of poorer health status and an older biological age, longer telomeres due to increased cell growth potential are associated with the acquirement of cancer‑initiating somatic mutations. Therefore, the present review aimed to comprehensively present the multifaceted pattern of telomere length and cancer incidence association.}, }
@article {pmid37231745, year = {2023}, author = {Naspolini, NF and Sichieri, R and Cunha Barbosa, D and Pereira, RA and Faerstein, E}, title = {Dietary patterns, obesity markers and leukocyte telomere length among Brazilian civil servants: Cross-sectional results from the Pro-Saude study.}, journal = {Public health nutrition}, volume = {}, number = {}, pages = {1-19}, doi = {10.1017/S1368980023001064}, pmid = {37231745}, issn = {1475-2727}, abstract = {OBJECTIVE: Dietary patterns express the combination and variety of foods in the diet. The Partial Least Squares (PLS) method allows extracting dietary patterns related to a specific health outcome. Few studies have evaluated obesity-related dietary patterns associated with telomeres length. This study aims to identify dietary patterns explaining obesity markers and to assess their association with leucocyte telomere length (LTL), a biological marker of the aging process.<br><br>DESIGN: Cross-sectional study.<br><br>SETTING: University campuses in the state of Rio de Janeiro, Brazil.<br><br>PARTICIPANTS: 478 participants of a civil servants' cohort study with data on food consumption, obesity measurements (total body fat, visceral fat, BMI, leptin, adiponectin), and blood samples.<br><br>RESULTS: Three dietary patterns were extracted: (1) fast food and meat; (2) healthy; and (3) traditional pattern, which included rice and beans, the staple foods most consumed in Brazil. All three dietary patterns explained 23.2% of food consumption variation and 10.7% of the obesity-related variables. The fast food and meat pattern was the first factor extracted, explaining 11-13% variation of the obesity-related response variables (BMI, total body fat and visceral fat), leptin and adiponectin showed the lowest percentage (4.5-0.1%). The healthy pattern mostly explained leptin and adiponectin variations (10.7 and 3.3%, respectively). The traditional pattern was associated with LTL (&#x3b2;= 0.0117; 95% CI 0.0001 - 0.0233) after adjustment for the other patterns, age, sex, exercise practice, income, and energy intake.<br><br>CONCLUSION: Leucocyte telomere length was longer among participants eating a traditional dietary pattern that combines fruit, vegetables, and beans.}, }
@article {pmid37231173, year = {2023}, author = {Jacome Burbano, MS and Robin, JD and Bauwens, S and Martin, M and Donati, E and Martínez, L and Lin, P and Sacconi, S and Magdinier, F and Gilson, E}, title = {Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {561}, pmid = {37231173}, issn = {2399-3642}, abstract = {Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.}, }
@article {pmid37230863, year = {2023}, author = {Liu, Q and Song, L and Fan, G and Wu, M and Bi, J and Xu, L and Xiong, C and Xia, W and Cao, Z and Xu, S and Wang, Y}, title = {Associations of self-reported sleep duration and sleep quality during pregnancy with newborn telomere length.}, journal = {Sleep health}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.sleh.2023.03.001}, pmid = {37230863}, issn = {2352-7226}, abstract = {BACKGROUND: Telomere length (TL) at birth is considered a potential biomarker for lifelong health. Although maternal sleep disturbance has been linked to a series of adverse pregnancy outcomes, evidence on the effect of maternal sleep on newborn TL remains scarce. Therefore, we aim to investigate the association of maternal sleep duration and sleep quality with newborn TL.<br><br>METHODS: A total of 742 mother-newborn pairs were recruited from Wuhan Children's Hospital between November 2013 and March 2015. Cord blood TL was measured using real-time quantitative polymerase chain reaction. Maternal sleep duration and quality during late pregnancy were obtained via questionnaires. Multivariate linear regression models were used to estimate the effects of maternal sleep duration and sleep quality on newborn TL.<br><br>RESULTS: A total of 742 maternal-newborn pairs were included in the analyses. Mothers sleeping &#x2265;10&#xa0;hours had a 9.30% (95% CI: 2.09%, 15.99%) shorter newborn TL than those sleeping 7-<9&#xa0;hours. However, the association in mothers with short sleep duration (<7&#xa0;hours) did not reach statistical significance. Compared to mothers with good sleep quality, those with poor sleep quality had a 9.91% (95% CI: 4.06%, 15.40%) shorter newborn TL. We observed a joint effect of sleep duration and sleep quality on newborn telomere shortening. Women with sleep duration &#x2265;10&#xa0;hours and poor sleep quality were most likely to have newborns with short TL (percent change:-19.66%, 95% CI: -28.42, -9.84%).<br><br>CONCLUSIONS: Long sleep duration and poor sleep quality during late pregnancy were associated with shorter newborn TL.}, }
@article {pmid37230028, year = {2023}, author = {Giunco, S and Padovan, M and Angelini, C and Cavallin, F and Cerretti, G and Morello, M and Caccese, M and Rizzo, B and d'Avella, D and Puppa, AD and Chioffi, F and De Bonis, P and Zagonel, V and De Rossi, A and Lombardi, G}, title = {Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.}, journal = {ESMO open}, volume = {8}, number = {3}, pages = {101570}, doi = {10.1016/j.esmoop.2023.101570}, pmid = {37230028}, issn = {2059-7029}, abstract = {BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients.<br><br>PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and&#xa0;-146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients.<br><br>RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P&#xa0;= 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant.<br><br>CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.}, }
@article {pmid37230009, year = {2023}, author = {Pan, Y and Hu, C and Hou, LJ and Chen, YL and Shi, J and Liu, JC and Zhou, JQ}, title = {Swc4 protects nucleosome-free rDNA, tDNA and telomere loci to inhibit genome instability.}, journal = {DNA repair}, volume = {127}, number = {}, pages = {103512}, doi = {10.1016/j.dnarep.2023.103512}, pmid = {37230009}, issn = {1568-7856}, abstract = {In the baker's yeast Saccharomyces cerevisiae, NuA4 and SWR1-C, two multisubunit complexes, are involved in histone acetylation and chromatin remodeling, respectively. Eaf1 is the assembly platform subunit of NuA4, Swr1 is the assembly platform and catalytic subunit of SWR1-C, while Swc4, Yaf9, Arp4 and Act1 form a functional module, and is present in both NuA4 and SWR1 complexes. ACT1 and ARP4 are essential for cell survival. Deletion of SWC4, but not YAF9, EAF1 or SWR1 results in a severe growth defect, but the underlying mechanism remains largely unknown. Here, we show that swc4Δ, but not yaf9Δ, eaf1Δ, or swr1Δ cells display defects in DNA ploidy and chromosome segregation, suggesting that the defects observed in swc4Δ cells are independent of NuA4 or SWR1-C integrity. Swc4 is enriched in the nucleosome-free regions (NFRs) of the genome, including characteristic regions of RDN5s, tDNAs and telomeres, independently of Yaf9, Eaf1 or Swr1. In particular, rDNA, tDNA and telomere loci are more unstable and prone to recombination in the swc4Δ cells than in wild-type cells. Taken together, we conclude that the chromatin associated Swc4 protects nucleosome-free chromatin of rDNA, tDNA and telomere loci to ensure genome integrity.}, }
@article {pmid37226085, year = {2023}, author = {Raee, P and Shams Mofarahe, Z and Nazarian, H and Abdollahifar, MA and Ghaffari Novin, M and Aghamiri, S and Ghaffari Novin, M}, title = {Male obesity is associated with sperm telomere shortening and aberrant mRNA expression of autophagy-related genes.}, journal = {Basic and clinical andrology}, volume = {33}, number = {1}, pages = {13}, pmid = {37226085}, issn = {2051-4190}, abstract = {BACKGROUND: Obesity is regarded a global public health crisis. It has been implicated in a variety of health problems, but when it comes to male fertility, how and to what extent obesity affects it are poorly understood. Accordingly, semen samples from 32 individuals with obesity (body mass index (BMI) ≥ 30 kg/m[2]) and 32 individuals with normal weight (BMI: 18.5-25 kg/m[2]) were obtained. Here, for the first time, we examined the association between obesity, relative sperm telomere length (STL) and autophagy-related mRNA levels such as Beclin1, AMPKa1, ULK1, BAX, and BCL2. Each group was also evaluated for conventional semen parameters, sperm apoptotic changes, DNA fragmentation index (DFI), sperm chromatin maturation, and reactive oxygen species (ROS) levels.<br><br>RESULTS: Based on our findings, there was a marked reduction in relative STL in individuals with obesity as compared to the normal-weight group. We also found a significant negative correlation between relative STL and age, BMI, DFI, percentage of sperm with immature chromatin, and intracellular ROS levels in patients with obesity. In the normal-weight group, relative STL was only negatively correlated with DFI and intracellular ROS levels. Regarding mRNA expression, there was considerable upregulation of Beclin1, ULK1, and BCL2 in the group with obesity compared to the normal-weight group. Obesity was also found to be associated with a considerable decline in semen volume, total sperm count, progressive motility, and viability in comparison to normal-weight individuals. Furthermore, obesity was associated with considerably higher percentages of DFI, sperm with immature chromatin, late-stage apoptosis, and elevated ROS levels.<br><br>CONCLUSION: According to our findings, obesity is associated with sperm telomere shortening and aberrant autophagy-related mRNA expression. It should be emphasized that telomere shortening in sperm may be an indirect consequence of obesity due to the oxidative stress associated with the condition. Nevertheless, further investigation is required for a more comprehensive understanding.}, }
@article {pmid37216436, year = {2023}, author = {Aix, E and Gallinat, A and Yago-Díez, C and Lucas, J and Gómez, MJ and Benguría, A and Freitag, P and Cortez-Toledo, E and Fernández de Manuel, L and García-Cuasimodo, L and Sánchez-Iranzo, H and Montoya, MC and Dopazo, A and Sánchez-Cabo, F and Mercader, N and López, JE and Fleischmann, BK and Hesse, M and Flores, I}, title = {Telomeres Fuse During Cardiomyocyte Maturation.}, journal = {Circulation}, volume = {147}, number = {21}, pages = {1634-1636}, doi = {10.1161/CIRCULATIONAHA.122.062229}, pmid = {37216436}, issn = {1524-4539}, mesh = {Humans ; *Myocytes, Cardiac ; Cell Proliferation ; *Telomere/genetics ; }, }
@article {pmid37216007, year = {2023}, author = {Allaire, P and He, J and Mayer, J and Moat, L and Gerstenberger, P and Wilhorn, R and Strutz, S and Kim, DSL and Zeng, C and Cox, N and Shay, JW and Denny, J and Bastarache, L and Hebbring, S}, title = {Genetic and clinical determinants of telomere length.}, journal = {HGG advances}, volume = {4}, number = {3}, pages = {100201}, pmid = {37216007}, issn = {2666-2477}, mesh = {Humans ; Aged ; *Leukocytes ; *Telomere/genetics ; Calcium-Binding Proteins/genetics ; Eye Proteins/genetics ; Membrane Proteins/genetics ; }, abstract = {Many epidemiologic studies have identified important relationships between leukocyte telomere length (LTL) with genetics and health. Most of these studies have been significantly limited in scope by focusing predominantly on individual diseases or restricted to GWAS analysis. Using two large patient populations derived from Vanderbilt University and Marshfield Clinic biobanks linked to genomic and phenomic data from medical records, we investigated the inter-relationship between LTL, genomics, and human health. Our GWAS confirmed 11 genetic loci previously associated with LTL and two novel loci in SCNN1D and PITPNM1. PheWAS of LTL identified 67 distinct clinical phenotypes associated with both short and long LTL. We demonstrated that several diseases associated with LTL were related to one another but were largely independent from LTL genetics. Age of death was correlated with LTL independent of age. Those with very short LTL (<-1.5 standard deviation [SD]) died 10.4 years (p < 0.0001) younger than those with average LTL (±0.5 SD; mean age of death = 74.2 years). Likewise, those with very long LTL (>1.5 SD) died 1.9 years (p = 0.0175) younger than those with average LTL. This is consistent with the PheWAS results showing diseases associating with both short and long LTL. Finally, we estimated that the genome (12.8%) and age (8.5%) explain the largest proportion of LTL variance, whereas the phenome (1.5%) and sex (0.9%) explained a smaller fraction. In total, 23.7% of LTL variance was explained. These observations provide the rationale for expanded research to understand the multifaceted correlations between TL biology and human health over time, leading to effective LTL usage in medical applications.}, }
@article {pmid37215005, year = {2023}, author = {Cai, SW and Takai, H and Walz, T and de Lange, T}, title = {Structural basis of CST-Polα/Primase recruitment and regulation by POT1 at telomeres.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.05.08.539880}, pmid = {37215005}, abstract = {UNLABELLED: CST-Polα/Primase maintains telomeres through fill-in synthesis of the C-rich telomeric DNA. We report cryo-EM structures that reveal how human CST is recruited to telomeres by the shelterin subunits POT1 and TPP1. CST-POT1/TPP1 is formed through interactions between POT1 and the Ctc1 subunit of CST. Coats plus syndrome mutations map to the POT1-Ctc1 interface, providing mechanistic insights into this disease. CST-POT1/TPP1 is compatible with the previously reported inactive recruitment complex of CST-Polα/Primase but not with the distinct conformation of active CST-Polα/Primase. We propose that shelterin both recruits and regulates CST-Polα/Primase. Structural and biochemical data indicate that this regulation involves phosphorylation of POT1, which promotes CST-POT1/TPP1 interaction and recruitment, whereas POT1 dephosphorylation releases CST-Polα/Primase for fill-in synthesis.<br><br>ONE-SENTENCE SUMMARY: Cryo-EM structures reveal how telomere maintenance factors are recruited and regulated by the shelterin complex.}, }
@article {pmid37214874, year = {2023}, author = {Granger, SL and Sharma, R and Kaushik, V and Razzaghi, M and Honda, M and Bhat, DS and Wlodarski, M and Antony, E and Spies, M}, title = {Human hnRNPA1 reorganizes telomere-bound Replication Protein A.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.05.09.540056}, pmid = {37214874}, abstract = {UNLABELLED: Human replication protein A (RPA) is a heterotrimeric ssDNA binding protein responsible for many aspects of cellular DNA metabolism. The binding to and dissociation of the four individual DNA binding domains (DBDs) from DNA result in configurational dynamics of the RPA-DNA complexes which are essential for replacement of RPA by downstream proteins in various cellular metabolic pathways. RPA plays several important functions at telomeres where it binds to and melts telomeric G-quadruplexes, non-canonical DNA structures formed at the G-rich telomeric ssDNA overhangs. Here, we combine single-molecule total internal reflection fluorescence microscopy (smTIRFM), mass photometry (MP) with biophysical and biochemical analyses, of a gain-of-function RPA mutant to demonstrate that heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) specifically remodels RPA bound to telomeric ssDNA by dampening the RPA configurational dynamics and forming a stable ternary complex. Uniquely among hnRNPA1 target RNAs, TERRA is capable of releasing hnRNPA1 from the RPA-telomeric DNA complex. We speculate that this telomere specific RPA-DNA-hnRNPA1 complex is an important structure in telomere protection.<br><br>ONE SENTENCE SUMMARY: At the single-stranded ends of human telomeres, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) binds to and modulates conformational dynamics of the ssDNA binding protein RPA forming a ternary complex which is controlled by TERRA RNA.}, }
@article {pmid37213605, year = {2023}, author = {Cai, X and Ning, C and Fan, L and Li, Y and Wang, L and He, H and Dong, T and Cai, Y and Zhang, M and Lu, Z and Chen, C and Shi, K and Ye, T and Zhong, R and Tian, J and Li, H and Li, H and Zhu, Y and Miao, X}, title = {Triclosan is associated with breast cancer via oxidative stress and relative telomere length.}, journal = {Frontiers in public health}, volume = {11}, number = {}, pages = {1163965}, pmid = {37213605}, issn = {2296-2565}, abstract = {INTRODUCTION: Triclosan (TCS), a widely prescribed broad-spectrum antibacterial agent, is an endocrine-disrupting chemical. The relationship and biological mechanisms between TCS exposure and breast cancer (BC) are disputed. We aimed to examine the correlation between urinary TCS exposure and BC risk and estimated the mediating effects of oxidative stress and relative telomere length (RTL) in the above association.<br><br>METHODS: This case-control study included 302 BC patients and 302 healthy individuals in Wuhan, China. We detected urinary TCS, three common oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2&#x3b1; (8-isoPGF2&#x3b1;), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)], and RTL in peripheral blood mononuclear cells.<br><br>RESULTS: Significant associations were observed between log-transformed urinary concentrations of TCS, 8-OHdG, HNE-MA, 8-isoPGF2&#x3b1;, RTL, and BC risk, with the odds ratios (95% confidence intervals) being 1.58 (1.32-1.91), 3.08 (1.55-6.23), 3.39 (2.45-4.77), 3.99 (2.48-6.54), and 1.67 (1.35-2.09), respectively. Continuous TCS exposure was significantly positively correlated with RTL, HNE-MA, and 8-isoPGF2&#x3b1; (all p<0.05) but not with 8-OHdG (p = 0.060) after adjusting for covariates. The mediated proportions of 8-isoPGF22&#x3b1; and RTL in the relationship between TCS and BC risk were 12.84% and 8.95%, respectively (all p<0.001).<br><br>DISCUSSION: In conclusion, our study provides epidemiological evidence to confirmed the deleterious effects of TCS on BC and indicated the mediating effect of oxidative stress and RTL on the correlation between TCS and BC risk. Moreover, exploring the contribution of TCS to BC can clarify the biological mechanisms of TCS exposure, provide new clues for the pathogenesis of BC, which is of great significance to improving public health systems.}, }
@article {pmid37211520, year = {2023}, author = {Ämmälä, AJ and Suvisaari, J and Kananen, L and Lönnqvist, J and Ripatti, S and Pirkola, S and Paunio, T and Hovatta, I}, title = {Corrigendum to Childhood adversities are associated with shorter leukocyte telomere length at adult age in a population-based study [Psychoneuroendocrinology (2021) 130 105276].}, journal = {Psychoneuroendocrinology}, volume = {}, number = {}, pages = {106286}, doi = {10.1016/j.psyneuen.2023.106286}, pmid = {37211520}, issn = {1873-3360}, }
@article {pmid37211230, year = {2023}, author = {Gu, Z and Niu, Z and Yan, Z and Fan, Y and Sun, J and Zhao, X and Duan, X and Yao, W and Yang, Y and Wang, W}, title = {Chain-mediating effect of interaction between telomeres and mitochondria under oxidative stress in coke oven workers.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {}, number = {}, pages = {121855}, doi = {10.1016/j.envpol.2023.121855}, pmid = {37211230}, issn = {1873-6424}, abstract = {Coke oven emissions (COEs) exposure leads to oxidative stress, an imbalance between oxidant production and antioxidant defence in the body, which then leads to shortened relative telomere length (RTL) and reduced mitochondrial DNA copy number (mtDNAcn), ultimately leading to ageing and disease. By analysing the relationship among COEs, oxidative stress, RTL and mtDNAcn, we investigated the chain-mediating effects of oxidative stress and telomeres on mitochondrial damage and mitochondria on telomere damage in coke oven workers. A total of 779 subjects were included in the study. Cumulative COEs exposure concentrations were estimated, and the RTL and mtDNAcn of peripheral blood leukocytes were measured using real-time fluorescence quantitative PCR. Total antioxidant capacity (T-AOC) was measured to reflect the level of oxidative stress. The data were statistically analysed using SPSS 21.0 software and discussed using mediation effect analysis. After adjusting for age, sex, smoking, drinking and BMI, generalised linear model revealed dose-response associations between COEs and T-AOC, RTL and mtDNAcn, respectively. (Ptrend < 0.05). The results of chain-mediating effect showed that the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ RTL→mtDNAcn" was 0.82% (β = -0.0005, 95% CI = [-0.0012, -0.0001]), and the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ mtDNAcn → RTL ″ was 2.64% (β = -0.0013, 95% CI = [-0.0025, -0.0004]). After oxidative stress is induced by COEs, mitochondria and telomeres may interact with each other while leading further to potential bodily damage. This study provides clues to explore the association between mitochondria and telomeres.}, }
@article {pmid37209418, year = {2023}, author = {Wang, W and Huang, N and Zhuang, Z and Song, Z and Li, Y and Dong, X and Xiao, W and Zhao, Y and Jia, J and Liu, Z and Qi, L and Huang, T}, title = {Identifying potential causal effects of telomere length on health outcomes: A phenome-wide investigation and Mendelian randomization study.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glad128}, pmid = {37209418}, issn = {1758-535X}, abstract = {BACKGROUND: Telomere length has been linked to various health outcomes. To comprehensively investigate the causal effects of telomere length throughout the human disease spectrum, we conducted a phenome-wide Mendelian randomization study (MR-PheWAS) and a systematic review for MR studies.<br><br>METHODS: We conducted a PheWAS to screen for associations between telomere length and 1,035 phenotypes in the UK Biobank (n = 408,354). The exposure of interest was the genetic risk score (GRS) of telomere length. Observed associations passing multiple testing corrections were assessed for causality by two-sample MR analysis. A systematic review for MR studies on telomere length was performed to harmonize the published evidence and complement our findings.<br><br>RESULTS: Of the 1,035 phenotypes tested, PheWAS identified 29 and 78 associations of telomere length GRS at a Bonferroni- and false discovery rate-corrected threshold; 24 and 66 distinct health outcomes were causal in the following principal MR analysis. The replication MR using data from the FinnGen study provided evidence of causal effects of genetically instrumented telomere length on 28 out of 66 outcomes, including decreased risks of 5 diseases in respiratory diseases, digestive diseases, and myocardial infarction, and increased risks of 23 diseases, mainly comprised of neoplasms, diseases of the genitourinary system, and essential hypertension. Systematic review of 53 MR studies found evidence to support 16 out of the 66 outcomes.<br><br>CONCLUSION: This large-scale MR-PheWAS identified a wide range of health outcomes that were possibly affected by telomere length, and suggested that susceptibility to telomere length may vary across disease categories.}, }
@article {pmid37204126, year = {2023}, author = {Liao, S and Zhou, Q and Zhang, Y}, title = {Association of ABCA1 R219K polymorphism and telomere length in a Chinese rural population: possible linking to systemic inflammation.}, journal = {Journal of genetics}, volume = {102}, number = {}, pages = {}, pmid = {37204126}, issn = {0973-7731}, abstract = {The ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms have been shown to be associated with various human diseases and pathological conditions such as cardiovascular disease and Alzheimer's disease. However, these associations remain unclear and inconclusive. Interestingly, short telomere length was also observed in these diseases. In the present study, our aims were to investigate the interaction between two selected ABCA1 polymorphisms (-565C/T and R219K) and telomere length in a Chinese rural population including 1629 subjects and explore the underlying mechanisms. Genotyping was conducted using Taqman SNP Genotyping Assays. Mean relative leukocyte telomere length was measured using monochrome multiplex quantitative PCR method. We found that the telomere length of R219K RR genotype was significantly shorter than RK or KK genotypes (1.242 ± 0.198 vs 1.271 ± 0.207, P = 0.027 and 1.242 ± 0.198 vs 1.276 ± 0.209, P = 0.021, respectively). While the neutrophil to lymphocyte ratio (NLR) of R219K RR genotype was significantly higher than KK genotype (1.929 ± 0.826 vs 1.768 ± 0.893, P = 0.019). In the general linear models after adjustments for confounding factors, the KK and RK genotypes were both significantly associated with telomere length and NLR. A significant association was also observed for K allele carrier genotypes when compared with RR genotype for telomere length and NLR. In conclusion, the R219K polymorphism of ABCA1 was independently associated with telomere length. R219K K allele could be protective against shortening of telomeres and inflammation.}, }
@article {pmid37193737, year = {2023}, author = {Carlund, O and Norberg, A and Osterman, P and Landfors, M and Degerman, S and Hultdin, M}, title = {DNA methylation variations and epigenetic aging in telomere biology disorders.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7955}, pmid = {37193737}, issn = {2045-2322}, mesh = {*DNA Methylation ; *DNA ; Epigenesis, Genetic ; Telomere/genetics ; Biology ; }, abstract = {Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.}, }
@article {pmid37191632, year = {2023}, author = {Bhala, S and Savage, SA}, title = {What is the future of telomere length testing in telomere biology disorders?.}, journal = {Expert review of hematology}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/17474086.2023.2215423}, pmid = {37191632}, issn = {1747-4094}, }
@article {pmid37189188, year = {2023}, author = {Byrjalsen, A and Brainin, AE and Lund, TK and Andersen, MK and Jelsig, AM}, title = {Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres.}, journal = {Hereditary cancer in clinical practice}, volume = {21}, number = {1}, pages = {7}, pmid = {37189188}, issn = {1731-2302}, abstract = {The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.}, }
@article {pmid37188431, year = {2023}, author = {Li, S and Liu, Z and Zhang, J and Li, L}, title = {Links between telomere dysfunction and hallmarks of aging.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {888}, number = {}, pages = {503617}, doi = {10.1016/j.mrgentox.2023.503617}, pmid = {37188431}, issn = {1879-3592}, abstract = {Aging is characterized by the gradual loss of physiological integrity, leading to impaired function and increased risk of death. This deterioration is the main risk factor for the great majority of chronic diseases, which account for most of the morbidity, death and medical expenses. The hallmarks of aging comprise diverse molecular mechanisms and cell systems, which are interrelated and coordinated to drive the aging process. This review focuses on telomere to analyze the interrelationships between telomere dysfunction and other aging hallmarks and their relative contributions to the initiation and progression of age-related diseases (such as neurodegeneration, cardiovascular disease, and cancer), which will contribute to determine drug targets, improve human health in the aging process with minimal side effects and provide information for the prevention and treatment of age-related diseases.}, }
@article {pmid37186136, year = {2023}, author = {Kurokochi, H and Tajima, N and Sato, MP and Yoshitake, K and Asakawa, S and Isobe, S and Shirasawa, K}, title = {Telomere-to-telomere genome assembly of matsutake (Tricholoma matsutake).}, journal = {DNA research : an international journal for rapid publication of reports on genes and genomes}, volume = {}, number = {}, pages = {}, doi = {10.1093/dnares/dsad006}, pmid = {37186136}, issn = {1756-1663}, abstract = {Here, we report the first telomere-to-telomere genome assembly of matsutake (Tricholoma matsutake), which consists of 13 sequences (spanning 161.0 Mb) and a 76 kb circular mitochondrial genome. All the 13 sequences were supported with telomeric repeats at the ends. GC-rich regions are located at the middle of the sequences and are enriched with long interspersed nuclear elements (LINEs). Repetitive sequences including long-terminal repeats (LTRs) and LINEs occupy 71.6% of the genome. A total of 21,887 potential protein-coding genes were predicted. The genomic data reported in this study served not only matsutake gene sequences but also genome structures and intergenic sequences. The information gained would be a great reference for exploring the genetics, genomics, and evolutionary study of matsutake in the future, and ultimately facilitate the conservation of this vulnerable genetic resource.}, }
@article {pmid37185424, year = {2023}, author = {Delmonico, L and Bines, J and Nascimento, CMD and Fernandes, PV and Barbosa, IS and Ribeiro, GB and de Paula, BHR and Silvestre, RT and Ornellas, MHF and Alves, G and Lage, C}, title = {Nuclear and Cytoplasmic hTERT, Tumor-Infiltrating Lymphocytes, and Telomere Elongation Leukocytes Are Independent Factors in the Response to Neoadjuvant Treatment in HER2-Enriched Breast Cancer.}, journal = {Current oncology (Toronto, Ont.)}, volume = {30}, number = {4}, pages = {4094-4109}, doi = {10.3390/curroncol30040311}, pmid = {37185424}, issn = {1718-7729}, abstract = {HER2-enriched tumors are responsible for 20% of breast tumors and have high rates of immune infiltrates in the tumor stroma that respond favorably to neoadjuvant chemotherapy. In the context of tumors, telomeres control cell death and prevent tumor cells from replicating discontinuously, leading to their immortalization. This study aimed to evaluate the presence of tumor-infiltrating lymphocytes, hTERT expression, hTERT promoter mutation, and leukocyte telomere length in HER2-enriched breast tumors. A total of 103 cases were evaluated, 19 with pathologic complete response. The TILs percentage was above ≥10 in 44 cases (43%) and significantly present in patients ≥50 years of age. hTERT staining positivity was mostly nuclear, significantly present in the non-pCR group, and associated with a lower survival rate. Leukocyte telomeres were elongated for HER2-enriched tumors, and in multivariate analysis, shortening was associated with an increased risk of death. Overall, our results show that the nuclear and cytoplasmic presence of hTERT may indicate a worse prognosis and that leukocyte telomere elongation is a protective factor.}, }
@article {pmid37184208, year = {2023}, author = {Vittal, A and Niewisch, MR and Bhala, S and Kudaravalli, P and Rahman, F and Hercun, J and Kleiner, DE and Savage, SA and Koh, C and Heller, T and Giri, N}, title = {Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/HEP.0000000000000461}, pmid = {37184208}, issn = {1527-3350}, abstract = {BACKGROUND AIMS: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multi-system organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression.<br><br>APPROACH AND RESULTS: Retrospective review of a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002-2019. The median age at initial assessment was 18 (1.4-67.6) years and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non-TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was precent in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the six-year follow-up, this progression was mainly seen in patients with recessive or TINF2-associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease.<br><br>CONCLUSION: Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC were important predictors of liver disease progression suggesting the need for increased vigilance and monitoring for complications in these patients.}, }
@article {pmid37183325, year = {2023}, author = {Zade, NH and Khattar, E}, title = {POT1 mutations cause differential effects on telomere length leading to opposing disease phenotypes.}, journal = {Journal of cellular physiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcp.31034}, pmid = {37183325}, issn = {1097-4652}, abstract = {The protection of telomere protein (POT1) is a telomere-binding protein and is an essential component of the six-membered shelterin complex, which is associated with the telomeres. POT1 directly binds to the 3' single-stranded telomeric overhang and prevents the activation of DNA damage response at telomeres thus preventing the telomere-telomere fusions and genomic instability. POT1 also plays a pivotal role in maintaining telomere length by regulating telomerase-mediated telomere elongation. Mutations in POT1 proteins result in three different telomere phenotypes, which include long, short, or aberrant telomere length. Long telomeres predispose individuals to cancer, while short or aberrant telomere phenotypes result in pro-aging diseases referred to as telomeropathies. Here, we review the function of POT1 proteins in telomere length hemostasis and how the spectrum of mutations reported in POT1 can be segregated toward developing very distinct disease phenotypes of cancer and telomeropathies.}, }
@article {pmid37179160, year = {2023}, author = {De Rosa, M and Opresko, PL}, title = {Translating the telomeres.}, journal = {Trends in genetics : TIG}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tig.2023.04.009}, pmid = {37179160}, issn = {0168-9525}, abstract = {Telomeres are transcribed into long noncoding telomeric repeat-containing RNA (TERRA). Or so we thought. Recently, Al-Turki and Griffith provided evidence that TERRA can code for valine-arginine (VR) or glycine-leucine (GL) dipeptide repeat proteins by undergoing repeat-associated non-ATG (RAN) translation. This finding uncovers a new mechanism by which telomeres can impact cellular function.}, }
@article {pmid37173827, year = {2023}, author = {Morland, F and Ewen, JG and Simons, MJP and Brekke, P and Hemmings, N}, title = {Early-life telomere length predicts life-history strategy and reproductive senescence in a threatened wild songbird.}, journal = {Molecular ecology}, volume = {}, number = {}, pages = {}, doi = {10.1111/mec.16981}, pmid = {37173827}, issn = {1365-294X}, support = {216405/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Telomeres are well known for their associations with lifespan and ageing across diverse taxa. Early-life telomere length can be influenced by developmental conditions and has been shown positively affect lifetime reproductive success in a limited number of studies. Whether these effects are caused by a change in lifespan, reproductive rate or perhaps most importantly reproductive senescence is unclear. Using long-term data on female breeding success from a threatened songbird (the hihi, Notiomystis cincta), we show that the early-life telomere length of individuals predicts the presence and rate of future senescence of key reproductive traits: clutch size and hatching success. In contrast, senescence of fledging success is not associated with early-life telomere length, which may be due to the added influence of biparental care at this stage. Early-life telomere length does not predict lifespan or lifetime reproductive success in this species. Females may therefore change their reproductive allocation strategy depending on their early developmental conditions, which we hypothesise are reflected in their early-life telomere length. Our results offer new insights on the role that telomeres play in reproductive senescence and individual fitness and suggest telomere length can be used as a predictor for future life history in threatened species.}, }
@article {pmid37172909, year = {2023}, author = {McLester-Davis, LWY and Estrada, P and Hastings, WJ and Kataria, LA and Martin, NA and Siebeneicher, JT and Tristano, RI and Mayne, CV and Horlick, RP and O'Connell, SS and Drury, SS}, title = {A review and meta-analysis: Cross-tissue telomere length correlations in healthy humans.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {101942}, doi = {10.1016/j.arr.2023.101942}, pmid = {37172909}, issn = {1872-9649}, abstract = {BACKGROUND AND AIM: Tissue source has been shown to exert a significant effect on the magnitude of associations between telomere length and various health outcomes and exposures. The purpose of the present qualitative review and meta-analysis is to describe and investigate the impact of study design and methodological features on the correlation between telomere lengths measured in different tissues from the same healthy individual.<br><br>METHODS: This meta-analysis included studies published from 1988 to 2022. Databases searched included PubMed, Embase, and Web of Science and studies were identified using the keywords "telomere length" and "tissues" or "tissue." A total of 220 articles of 7,856 initially identified studies met inclusion criteria for qualitative review, of which 55 met inclusion criteria for meta-analysis in R RESULTS: Studies meeting inclusion criteria for meta-analysis tended to have enhanced demographic and methodological reporting relative to studies only included in the qualitative review. A total of 463 pairwise correlations reported for 4,324 unique individuals and 102 distinct tissues were extracted from the 55 studies and subject to meta-analysis, resulting in a significant effect size z = 0.66 (p < 0.0001) and meta-correlation coefficient of r = 0.58. Meta-correlations were significantly moderated by sample size and telomere length measurement methodology, with studies of smaller size and those using hybridization-based analyses exhibiting the largest meta-correlation. Tissue source also significantly moderated the meta-correlation, wherein correlations between samples of a different lineage (e.g., blood vs. non-blood) or collection method (e.g., peripheral vs. surgical) were lower than correlations between samples of the same lineage or collection method.<br><br>CONCLUSION: These results suggest that telomere lengths measured within individuals are generally correlated, but future research should be intentional in selecting a tissue for telomere length measurement that is most biologically relevant to the exposure or outcome investigated and balance this with the feasibility of obtaining the sample in sufficient numbers of individuals.}, }
@article {pmid37170112, year = {2023}, author = {Wu, W and Li, C and Zhu, X and Liu, X and Li, P and Wan, R and Wu, X and Chen, S}, title = {Genetic association of telomere length, obesity and tobacoo smoking with idiopathic pulmonary fibrosis risk.}, journal = {BMC public health}, volume = {23}, number = {1}, pages = {868}, pmid = {37170112}, issn = {1471-2458}, abstract = {BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease.<br><br>METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1).<br><br>RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR&#x2009;=&#x2009;0.475 per SD increase in TL, 95%CI&#x2009;=&#x2009;0.336&#x2009;~&#x2009;0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR&#x2009;=&#x2009;1.425 per SD increase in BMI level, 95%CI&#x2009;=&#x2009;1.114&#x2009;~&#x2009;1.823, P&#x2009;=&#x2009;0.005; OR&#x2009;=&#x2009;1.702 per SD increase in BFP level, 95%CI&#x2009;=&#x2009;1.202&#x2009;~&#x2009;2.409, P&#x2009;=&#x2009;0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR&#x2009;=&#x2009;13.183 per SD increase in the prevalence of maternal smoking, 95%CI&#x2009;=&#x2009;1.820&#x2009;~&#x2009;95.484, P&#x2009;=&#x2009;0.011).<br><br>CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.}, }
@article {pmid37169669, year = {2023}, author = {Mastrosimini, MG and Manfrin, E and Remo, A and De Bellis, M and Parisi, A and Pedron, S and Luchini, C and Brunelli, M and Ammendola, S and Bernardoni, L and Conti Bellocchi, MC and Gabbrielli, A and Facciorusso, A and Pea, A and Landoni, L and Scarpa, A and Crinò, SF}, title = {Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors.}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pan.2023.05.002}, pmid = {37169669}, issn = {1424-3911}, abstract = {BACKGROUND/OBJECTIVES: Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens.<br><br>METHODS: Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading.<br><br>RESULTS: Forty-one NF-PanNETs (mean diameter 36.1&#xa0;&#xb1;&#xa0;26.5&#xa0;mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (&#x3ba;&#xa0;=&#xa0;0.828; p&#xa0;<&#xa0;0.001), 92.7% (&#x3ba;&#xa0;=&#xa0;0.626; p&#xa0;<&#xa0;0.001), and 100% (&#x3ba;&#xa0;=&#xa0;1; p&#xa0;<&#xa0;0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p&#xa0;<&#xa0;0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss&#xa0;+&#xa0;ALT-positivity&#xa0;+&#xa0;grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k&#xa0;=&#xa0;0.573; p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.}, }
@article {pmid37165507, year = {2023}, author = {Maiese, K}, title = {The Implications of Telomere Length: Advanced Aging, Cell Senescence, MRI Phenotypes, Stem Cells and Alzheimer's Disease.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567202620666230510150337}, pmid = {37165507}, issn = {1875-5739}, }
@article {pmid37165138, year = {2023}, author = {Mannherz, W and Agarwal, S}, title = {Publisher Correction: Thymidine nucleotide metabolism controls human telomere length.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41588-023-01418-7}, pmid = {37165138}, issn = {1546-1718}, }
@article {pmid37163741, year = {2023}, author = {Ida, CM and Jenkins, RB}, title = {SMARCAL1: Expanding the spectrum of genes associated with alternative lengthening of telomeres.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noad084}, pmid = {37163741}, issn = {1523-5866}, }
@article {pmid37160859, year = {2023}, author = {Yang, D and Chen, X and Cao, W and Xu, C and Chang, L and Long, G}, title = {Association between mixed exposure of polycyclic aromatic hydrocarbons and telomere length in general population: NHANES 2001-2002.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {37160859}, issn = {1614-7499}, abstract = {Although an association between single polycyclic aromatic hydrocarbons (PAHs) adult exposure and telomere length has been reported, the evidence of mixed PAHs (1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene, 2-phenanthrene, and 1-pyrene) exposure and telomere length in the adult general population is still not clear. A total of 1460 adults over the age of 20 years provided urine information on 8 PAHs and selected covariates from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). Bayesian nuclear machine regression (BKMR) was conducted to analyze these associations of telomere length in multiple PAH-exposed environments. Linear regression is mainly used for correlation analysis of PAHs with selected covariate adjustments. Restricted cubic spline (RCS) is used to estimate the correlation between selected PAHs and telomere length. After adjusting for potential covariates, PAHs mixed exposure was negatively associated with telomere length. The linear regression results showed that 2-napthol and 2-fluorene were negatively correlated with telomere length. Telomere length decreased by 1.0% in the fully adjusted model per increment of one unit in the base-10-logarithm-transformed 2-napthol and 2-fluorene concentrations (P = 0.030 and 0.049, respectively). However, the other 6 PAH metabolites were not significantly different. In addition, RCS results showed that 2-napthol has a marginal dose effect relationship with telomere length. Our present study suggested that PAHs are negatively associated with telomere length in the general population of the USA. Considering that the low level of PAHs exposure in the general population can also induce reduced telomere length and potential health risks, future research is needed to explore potential mechanisms.}, }
@article {pmid37160312, year = {2023}, author = {Biswas, U and Deb Mallik, T and Pschirer, J and Lesche, M and Sameith, K and Jessberger, R}, title = {Cohesin SMC1β promotes closed chromatin and controls TERRA expression at spermatocyte telomeres.}, journal = {Life science alliance}, volume = {6}, number = {7}, pages = {}, doi = {10.26508/lsa.202201798}, pmid = {37160312}, issn = {2575-1077}, abstract = {Previous data showed that meiotic cohesin SMC1β protects spermatocyte telomeres from damage. The underlying reason, however, remained unknown as the expressions of telomerase and shelterin components were normal in Smc1β [-/-] spermatocytes. Here. we report that SMC1β restricts expression of the long noncoding RNA TERRA (telomeric repeat containing RNA) in spermatocytes. In somatic cell lines increased TERRA was reported to cause telomere damage through altering telomere chromatin structure. In Smc1β [-/-] spermatocytes, we observed strongly increased levels of TERRA which accumulate on damaged chromosomal ends, where enhanced R-loop formation was found. This suggested a more open chromatin configuration near telomeres in Smc1β [-/-] spermatocytes, which was confirmed by ATAC-seq. Telomere-distal regions were not affected by the absence of SMC1β but RNA-seq revealed increased transcriptional activity in telomere-proximal regions. Thus, SMC1β promotes closed chromatin specifically near telomeres and limits TERRA expression in spermatocytes.}, }
@article {pmid37156332, year = {2023}, author = {Hart, M and Conrad, J and Barrett, E and Legg, K and Ivey, G and Lee, PHU and Yung, Y and Shim, JW}, title = {X-linked hydrocephalus genes: Their proximity to telomeres and high a + T content compared to Parkinson's disease.}, journal = {Experimental neurology}, volume = {}, number = {}, pages = {114433}, doi = {10.1016/j.expneurol.2023.114433}, pmid = {37156332}, issn = {1090-2430}, abstract = {Proximity to telomeres (i) and high adenine and thymine (A + T) content (ii) are two factors associated with high mutation rates in human chromosomes. We have previously shown that >100 human genes when mutated to cause congenital hydrocephalus (CH) meet either factor (i) or (ii) at 91% matching, while two factors are poorly satisfied in human genes associated with familial Parkinson's disease (fPD) at 59%. Using the sets of mouse, rat, and human chromosomes, we found that 7 genes associated with CH were located on the X chromosome of mice, rats, and humans. However, genes associated with fPD were in different autosomes depending on species. While the contribution of proximity to telomeres in the autosome was comparable in CH and fPD, high A + T content played a pivotal contribution in X-linked CH (43% in all three species) than in fPD (6% in rodents or 13% in humans). Low A + T content found in fPD cases suggests that PARK family genes harbor roughly 3 times higher chances of methylations in CpG sites or epigenetic changes than X-linked genes.}, }
@article {pmid37154569, year = {2023}, author = {Jain, M and Madeka, S and Khattar, E}, title = {Optimization of Performance Parameters of the TAGGG Telomere Length Assay.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {194}, pages = {}, doi = {10.3791/65288}, pmid = {37154569}, issn = {1940-087X}, mesh = {Humans ; *Aging ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Oxidative Stress ; }, abstract = {Telomeres are repetitive sequences which are present at chromosomal ends; their shortening is a characteristic feature of human somatic cells. Shortening occurs due to a problem with end replication and the absence of the telomerase enzyme, which is responsible for maintaining telomere length. Interestingly, telomeres also shorten in response to various internal physiological processes, like oxidative stress and inflammation, which may be impacted due to extracellular agents like pollutants, infectious agents, nutrients, or radiation. Thus, telomere length serves as an excellent biomarker of aging and various physiological health parameters. The TAGGG telomere length assay kit is used to quantify average telomere lengths using the telomere restriction fragment (TRF) assay and is highly reproducible. However, it is an expensive method, and because of this, it is not employed routinely for large sample numbers. Here, we describe a detailed protocol for an optimized and cost-effective measurement of telomere length using Southern blots or TRF analysis and non-radioactive chemiluminescence-based detection.}, }
@article {pmid37150235, year = {2023}, author = {Gregório, C and Thakur, S and Camara Rivero, R and Márcia Dos Santos Machado, S and Cuenin, C and Carreira, C and White, V and Cree, IA and Vukojevic, K and Glavina Durdov, M and Bersch Osvaldt, A and Ashton-Prolla, P and Herceg, Z and Rahman Talukdar, F}, title = {Telomere length assessment and molecular characterization of TERT gene promoter in periampullary carcinomas.}, journal = {Gene}, volume = {}, number = {}, pages = {147460}, doi = {10.1016/j.gene.2023.147460}, pmid = {37150235}, issn = {1879-0038}, abstract = {Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P=0.01) and lower TERT protein expression (p=0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T>C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δβ 7%; cg02545192 with Δβ 9%; cg03323598 with Δβ 19%; and cg07285213 with Δβ 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.}, }
@article {pmid37149932, year = {2023}, author = {Carson, LM and Flynn, RL}, title = {Highlighting vulnerabilities in the alternative lengthening of telomeres pathway.}, journal = {Current opinion in pharmacology}, volume = {70}, number = {}, pages = {102380}, doi = {10.1016/j.coph.2023.102380}, pmid = {37149932}, issn = {1471-4973}, abstract = {The alternative lengthening of telomeres (ALT) pathway is a telomere elongation mechanism found in a small but often aggressive subset of cancers. Dependent on break-induced replication, telomere extension in ALT-positive cells relies on a baseline level of DNA replication stress to initiate elongation events. This results in an elevated level of DNA damage and presents a possible vulnerability to be exploited in the development of ALT-targeted cancer therapies. Currently, there are no treatment options that target the ALT mechanism or that are specific for ALT-positive tumors. Here, we review recent developments and promising directions in the development of ALT-targeted therapeutics, many of which involve tipping the balance towards inhibition or exacerbation of ALT activity to selectively target these cells.}, }
@article {pmid37149272, year = {2023}, author = {Deregowska, A and Lewinska, A and Warzybok, A and Stoklosa, T and Wnuk, M}, title = {Telomere loss is accompanied by decreased pool of shelterin proteins TRF2 and RAP1, elevated levels of TERRA and enhanced glycolysis in imatinib-resistant CML cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {}, number = {}, pages = {105608}, doi = {10.1016/j.tiv.2023.105608}, pmid = {37149272}, issn = {1879-3177}, abstract = {Telomere length may be maintained by telomerase nucleoprotein complex and shelterin complex, namely TRF1, TRF2, TIN2, TPP1, POT1 and RAP1 proteins and modulated by TERRA expression. Telomere loss is observed during progression of chronic myeloid leukemia (CML) from the chronic phase (CML-CP) to the blastic phase (CML-BP). The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), has changed outcome for majority of patients, however, a number of patients treated with TKIs may develop drug resistance. The molecular mechanisms underlying this phenomenon are not fully understood and require further investigation. In the present study, we demonstrate that IM-resistant BCR::ABL1 gene-positive CML K-562 and MEG-A2 cells are characterized by decreased telomere length, lowered protein levels of TRF2 and RAP1 and increased expression of TERRA in comparison to corresponding IM-sensitive CML cells and BCR::ABL1 gene-negative HL-60 cells. Furthermore, enhanced activity of glycolytic pathway was observed in IM-resistant CML cells. A negative correlation between a telomere length and advanced glycation end products (AGE) was also revealed in CD34[+] cells isolated from CML patients. In conclusion, we suggest that affected expression of shelterin complex proteins, namely TRF2 and RAP1, TERRA levels, and glucose consumption rate may promote telomere dysfunction in IM-resistant CML cells.}, }
@article {pmid37146910, year = {2023}, author = {Thompson, AJ and Henrich, CC}, title = {Maternal depression and child telomere length: The role of genetic sensitivity.}, journal = {Journal of affective disorders}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jad.2023.04.103}, pmid = {37146910}, issn = {1573-2517}, abstract = {BACKGROUND: The stress of a mother's depression may increasingly tax psychobiological systems that help children with self-regulation, increasing children's allostatic load over time. Some evidence supports children exposed to maternal depression tend to have shorter telomeres and tend to have more somatic and psychological problems. Children having one or more A1 alleles of dopamine receptor 2 (DRD2, rs1800497), tend to have greater sensitivity to maternal depression and could experience more adverse child outcomes that contribute to greater allostatic load.<br><br>METHODS: Using the Future Families and Child Wellbeing dataset, secondary-data analyses were used to test the effect of repeated exposure to maternal depression during early childhood on children's telomere length during middle childhood moderated by children's DRD2 genotype (N&#x202f;=&#x202f;2884).<br><br>RESULTS: Greater maternal depression was not significantly associated with shorter child telomere length and this association was not moderated by DRD2 genotypes while controlling for factors associated with child telomere length.<br><br>IMPLICATIONS: The effect of maternal depression on children's TL may not be significant in populations from diverse racial-ethnic and family backgrounds during middle childhood. These findings could help further our current understanding psychobiological systems affected by maternal depression that result in adverse child outcomes.<br><br>LIMITATIONS: Even though this study used a relatively large and diverse sample, replication of DRD2 moderation in even larger samples is an important next step.}, }
@article {pmid37142951, year = {2023}, author = {Mascarenhas Dos Santos, AC and Julian, AT and Liang, P and Juárez, O and Pombert, JF}, title = {Telomere-to-Telomere genome assemblies of human-infecting Encephalitozoon species.}, journal = {BMC genomics}, volume = {24}, number = {1}, pages = {237}, pmid = {37142951}, issn = {1471-2164}, abstract = {BACKGROUND: Microsporidia are diverse spore forming, fungal-related obligate intracellular pathogens infecting a wide range of hosts. This diversity is reflected at the genome level with sizes varying by an order of magnitude, ranging from less than 3 Mb in Encephalitozoon species (the smallest known in eukaryotes) to more than 50 Mb in Edhazardia spp. As a paradigm of genome reduction in eukaryotes, the small Encephalitozoon genomes have attracted much attention with investigations revealing gene dense, repeat- and intron-poor genomes characterized by a thorough pruning of molecular functions no longer relevant to their obligate intracellular lifestyle. However, because no Encephalitozoon genome has been sequenced from telomere-to-telomere and since no methylation data is available for these species, our understanding of their overall genetic and epigenetic architectures is incomplete.<br><br>METHODS: In this study, we sequenced the complete genomes from telomere-to-telomere of three human-infecting Encephalitozoon spp. -E. intestinalis ATCC 50506, E. hellem ATCC 50604 and E. cuniculi ATCC 50602- using short and long read platforms and leveraged the data generated as part of the sequencing process to investigate the presence of epigenetic markers in these genomes. We also used a mixture of sequence- and structure-based computational approaches, including protein structure prediction, to help identify which Encephalitozoon proteins are involved in telomere maintenance, epigenetic regulation, and heterochromatin formation.<br><br>RESULTS: The Encephalitozoon chromosomes were found capped by TTAGG 5-mer telomeric repeats followed by telomere associated repeat elements (TAREs) flanking hypermethylated ribosomal RNA (rRNA) gene loci featuring 5-methylcytosines (5mC) and 5-hemimethylcytosines (5hmC), themselves followed by lesser methylated subtelomeres and hypomethylated chromosome cores. Strong nucleotide biases were identified between the telomeres/subtelomeres and chromosome cores with significant changes in GC/AT, GT/AC and GA/CT contents. The presence of several genes coding for proteins essential to telomere maintenance, epigenetic regulation, and heterochromatin formation was further confirmed in the Encephalitozoon genomes.<br><br>CONCLUSION: Altogether, our results strongly support the subtelomeres as sites of heterochromatin formation in Encephalitozoon genomes and further suggest that these species might shutdown their energy-consuming ribosomal machinery while dormant as spores by silencing of the rRNA genes using both 5mC/5hmC methylation and facultative heterochromatin formation at these loci.}, }
@article {pmid37141574, year = {2023}, author = {Wang, Z and Liu, J and Chen, H and Qiu, X and Xie, L and Kaniskan, H&#xdc; and Chen, X and Jin, J and Wei, W}, title = {Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.3c02783}, pmid = {37141574}, issn = {1520-5126}, abstract = {Telomeres are naturally shortened after each round of cell division in noncancerous normal cells, while the activation of telomerase activity to extend telomere in the cancer cell is essential for cell transformation. Therefore, telomeres are regarded as a potential anticancer target. In this study, we report the development of a nucleotide-based proteolysis-targeting chimera (PROTAC) designed to degrade TRF1/2 (telomeric repeat-binding factor 1/2), which are the key components of the shelterin complex (telosome) that regulates the telomere length by directly interacting with telomere DNA repeats. The prototype telomere-targeting chimeras (TeloTACs) efficiently degrade TRF1/2 in a VHL- and proteosome-dependent manner, resulting in the shortening of telomeres and suppressed cancer cell proliferation. Compared to the traditional receptor-based off-target therapy, TeloTACs have potential application in a broad spectrum of cancer cell lines due to their ability to selectively kill cancer cells that overexpress TRF1/2. In summary, TeloTACs provide a nucleotide-based degradation approach for shortening the telomere and inhibiting tumor cell growth, representing a promising avenue for cancer treatment.}, }
@article {pmid37140180, year = {2023}, author = {Robertson, CM and Xue, Y and Chowdhury, S and Maringele, L}, title = {A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress.}, journal = {Molecular and cellular biology}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/10985549.2023.2193768}, pmid = {37140180}, issn = {1098-5549}, abstract = {Rif1 mediates telomere length, DNA replication, and DNA damage responses in budding yeast. Previous work identified several posttranslational modifications of Rif1, however none of these was shown to mediate the molecular or cellular responses to DNA damage, including telomere damage. We searched for such modifications using immunoblotting methods and the cdc13-1 and tlc1Δ models of telomere damage. We found that Rif1 is phosphorylated during telomere damage, and that serines 57 and 110 within a novel phospho-gate domain (PGD) of Rif1 are important for this modification, in cdc13-1 cells. The phosphorylation of Rif1 appeared to inhibit its accumulation on damaged chromosomes and the proliferation of cells with telomere damage. Moreover, we found that checkpoint kinases were upstream of this Rif1 phosphorylation and that the Cdk1 activity was essential for maintaining it. Apart from telomere damage, S57 and S110 were essential for Rif1 phosphorylation during the treatment of cells with genotoxic agents or during mitotic stress. We propose a speculative "Pliers" model to explain the role of the PGD phosphorylation during telomere and other types of damage.}, }
@article {pmid37140166, year = {2023}, author = {DeBoy, EA and Tassia, MG and Schratz, KE and Yan, SM and Cosner, ZL and McNally, EJ and Gable, DL and Xiang, Z and Lombard, DB and Antonarakis, ES and Gocke, CD and McCoy, RC and Armanios, M}, title = {Familial Clonal Hematopoiesis in a Long Telomere Syndrome.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2300503}, pmid = {37140166}, issn = {1533-4406}, support = {R01CA225027/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.<br><br>METHODS: We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.<br><br>RESULTS: A total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.<br><br>CONCLUSIONS: POT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).}, }
@article {pmid37140164, year = {2023}, author = {Vassiliou, G}, title = {Telomere Length and Clonal Hematopoiesis.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMe2303022}, pmid = {37140164}, issn = {1533-4406}, }
@article {pmid37140004, year = {2023}, author = {Gavia-García, G and Rosado-Pérez, J and Arista-Ugalde, TL and Aguiñiga-Sánchez, I and Santiago-Osorio, E and Mendoza-Núñez, VM}, title = {The consumption of Sechium edule (chayote) has antioxidant effect and prevents telomere attrition in older adults with metabolic syndrome.}, journal = {Redox report : communications in free radical research}, volume = {28}, number = {1}, pages = {2207323}, doi = {10.1080/13510002.2023.2207323}, pmid = {37140004}, issn = {1743-2928}, abstract = {OBJECTIVE: To determine the effect of the consumption of Sechium edule (1.5 g/day) for six months on oxidative stress (OxS) and inflammation markers and its association with telomere length (TL) in older adults with metabolic syndrome (MetS).<br><br>METHODS: The study was conducted in a sample of 48 older adults: placebo (EP) and experimental (EG) groups. Lipoperoxides, protein carbonylation, 8-OHdG, total oxidant status (TOS), SOD, GPx, H2O2 inhibition, total antioxidant status (TAS), inflammatory cytokines (IL6, IL10, TNF-&#x3b1;), and TL were measured before and six months post-treatment.<br><br>RESULTS: We found a significant decrease in the levels of lipoperoxides, protein carbonylation, 8-OHdG, TOS in the EG in comparison PG. Likewise, a significante increase of TAS, IL-6, and IL-10 levels was found at six months post-treatment in EG in comparison with PG. TL showed a statistically significant decrease in PG compared to post-treatment EG.<br><br>CONCLUSIONS: Our findigns showed that the supplementation of Sechium edule has antioxidant, and anti-inflammatory effects, and diminushion of shortening of telomeric DNA in older adults with MetS. This would be the first study that shows that the intervention with Sechium edule has a possible geroprotective effect by preventing telomeres from shortening as usually happens in these patients. Therefore, suggesting a protection of telomeric DNA and genomic DNA.}, }
@article {pmid37139235, year = {2023}, author = {Whittemore, K and Fossel, M}, title = {Editorial: Telomere length and species lifespan.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1199667}, pmid = {37139235}, issn = {1664-8021}, }
@article {pmid37139230, year = {2023}, author = {Liu, M and Luo, P and Liu, L and Wei, X and Bai, X and Li, J and Wu, L and Luo, M}, title = {Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1129247}, pmid = {37139230}, issn = {1664-8021}, abstract = {Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10[-4]), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10[-5]), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10[-6]), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10[-3]), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10[-4]), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10[-7]) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10[-4]). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10[-5]). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.}, }
@article {pmid37132239, year = {2023}, author = {Voituron, Y and Guillaume, O and Dumet, A and Zahn, S and Criscuolo, F}, title = {Temperature-independent telomere lengthening with age in the long-lived human fish (Proteus anguinus).}, journal = {Proceedings. Biological sciences}, volume = {290}, number = {1998}, pages = {20230503}, doi = {10.1098/rspb.2023.0503}, pmid = {37132239}, issn = {1471-2954}, mesh = {Animals ; Humans ; Adult ; *Longevity ; *Telomere Homeostasis ; Temperature ; Telomere ; Telomere Shortening ; Mammals ; Fishes ; }, abstract = {Despite a number of studies showing a negative relationship between age and telomere length, the universality of this pattern has been recently challenged, mainly in ectothermic animals exhibiting diverse effects of age on telomere shortening. However, data on ectotherms may be strongly affected by the thermal history of the individuals. We thus investigated the age-related changes in relative telomere length in the skin of a small but long-lived amphibian living naturally in a stable thermal environment over its entire life, allowing comparison with other homeothermic animals like birds and mammals. The present data showed a positive relation between telomere length and individual age, independent of sex and body size. A segmented analysis highlighted a breakpoint in the telomere length-age relationship, suggesting that telomere length reached a plateau at the age of 25 years. Further studies focusing on the biology of animals that live much longer than expected based on body mass will contribute to our better understanding of how ageing processes evolved and may also bring innovation for extending human health span.}, }
@article {pmid37131110, year = {2023}, author = {Kalal, AA and Shetty, RA and Manjappa, AB and Kulkarni, NV and Shetty, P}, title = {Prognostic significance of dysregulation of shelterin complex and its correlation with telomere length and cytogenetics in multiple myeloma.}, journal = {Journal, genetic engineering &amp; biotechnology}, volume = {21}, number = {1}, pages = {50}, pmid = {37131110}, issn = {2090-5920}, abstract = {BACKGROUND: MM (multiple myeloma) is a bone marrow disease with the accumulation of malignant plasma cells characterized by the neoplastic transformation of differentiated B cells. The onset and progression of cancer are greatly influenced by telomere dysfunction. We aimed to study the biomarker potential and prognostic significance of shelterin complex and hTERT. Telomere length and gene expression were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and these results were further correlated with clinical parameters.<br><br>RESULTS: Our study showed increased expression of all genes in complex, hTERT, and TL in MM (n&#x2009;=&#x2009;72) in comparison with controls (n&#x2009;=&#x2009;31). TRF2 (P&#x2009;=&#x2009;0.025) and hTERT (P&#x2009;=&#x2009;0.0002) displayed significant association among cytogenetic analysis. The receiver operative curve showed POT1 and RAP1 with a greater area under the curve (AUC). RAP1 (P&#x2009;=&#x2009;0.020) and hTERT (P&#x2009;=&#x2009;0.037) displayed to be independent prognostic markers for overall survival. Clinical parameters and genes were observed to be significantly correlated.<br><br>CONCLUSION: Our study findings showed variation in telomere-associated genes and suggest the participation of these genes as prognostic markers in MM. These results all together highlight the evaluation and role of genes involved in telomeric alteration and TL, providing the opportunity to study new therapeutic approaches in patients with MM.}, }
@article {pmid37130870, year = {2023}, author = {Zhao, N and Yin, G and Liu, C and Zhang, W and Shen, Y and Wang, D and Lin, Z and Yang, J and Mao, J and Guo, R and Zhang, Y and Wang, F and Liu, Z and Lu, X and Liu, L}, title = {Critically short telomeres derepress retrotransposons to promote genome instability in embryonic stem cells.}, journal = {Cell discovery}, volume = {9}, number = {1}, pages = {45}, pmid = {37130870}, issn = {2056-5968}, abstract = {Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.}, }
@article {pmid37129365, year = {2023}, author = {Schreglmann, SR and Goncalves, T and Grant-Peters, M and Kia, DA and Soreq, L and Ryten, M and Wood, NW and Bhatia, KP and Tomita, K}, title = {Age-related telomere attrition in the human putamen.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e13861}, doi = {10.1111/acel.13861}, pmid = {37129365}, issn = {1474-9726}, support = {C36439/A12097/CRUK_/Cancer Research UK/United Kingdom ; }, abstract = {Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.}, }
@article {pmid37128641, year = {2023}, author = {Aguilera, P and Dubarry, M and Géli, V and Simon, MN}, title = {NPCs and APBs: two HUBs of non-canonical homology-based recombination at telomeres?.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/15384101.2023.2206350}, pmid = {37128641}, issn = {1551-4005}, abstract = {Apart from a few rare exceptions, the maintenance of functional telomeres by recombination-based mechanisms is restricted to accidental and/or pathological situations. Originally described in the yeast S. cerevisiae, this mode of telomere repair has gained interest with the discovery of telomerase negative cancers that use alternative lengthening of telomeres (ALT cancer) dependent on homologous recombination. In both yeast and humans, it has been shown that recombination at telomeres is spatially regulated and occurs preferentially at the nuclear pore complexes (NPCs) in yeast and at ALT-associated promyelocytic leukemia nuclear bodies (APBs) in human cells. Here, we discuss the potential relationships between these two membrane-less structures and their role in enabling unconventional recombination pathways.}, }
@article {pmid37127563, year = {2023}, author = {Doherty, T and Dempster, E and Hannon, E and Mill, J and Poulton, R and Corcoran, D and Sugden, K and Williams, B and Caspi, A and Moffitt, TE and Delany, SJ and Murphy, TM}, title = {A comparison of feature selection methodologies and learning algorithms in the development of a DNA methylation-based telomere length estimator.}, journal = {BMC bioinformatics}, volume = {24}, number = {1}, pages = {178}, pmid = {37127563}, issn = {1471-2105}, support = {18/CRT/6183/SFI_/Science Foundation Ireland/Ireland ; }, abstract = {BACKGROUND: The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine-guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the challenge of high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, our aim was to test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We utilised both nested cross-validation and two independent test sets for the comparisons.<br><br>RESULTS: We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. This approach achieved a correlation between estimated and actual TL of 0.295 (83.4% CI [0.201, 0.384]) on the EXTEND test data set. Contrastingly, the baseline model of elastic net regression with no prior feature reduction stage performed less well in general-suggesting a prior feature-selection stage may have important utility. A previously developed TL estimator, DNAmTL, achieved a correlation of 0.216 (83.4% CI [0.118, 0.310]) on the EXTEND data. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities.<br><br>CONCLUSIONS: The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.}, }
@article {pmid37122888, year = {2023}, author = {Fattahi, M and Maghsudlu, M and Hasan Sheikhha, M}, title = {Is sperm telomere length altered in teratozoospermia specimens? A case-control study.}, journal = {International journal of reproductive biomedicine}, volume = {21}, number = {3}, pages = {229-236}, pmid = {37122888}, issn = {2476-4108}, abstract = {BACKGROUND: Male factor infertility is a multifactorial defect, and many of its etiologies are unknown. Teratozoospermia is determined by the existence of over 85% morphologically abnormal spermatozoa in semen which are almost incompetent in fertilization function. One of the most novel issues in genetic alterations studies is the variation of sperm telomere lengths (STL) and its collaboration with male infertility. The present study has been focused on STL alterations in teratozoospermia.<br><br>OBJECTIVE: Investigation of differences in telomere length of teratozoospermia specimens and sperms with normal parameters.<br><br>MATERIALS AND METHODS: In this case-control study, 60 men referred to Arak Fertility Clinic, Markazi province, Iran from November 2017 to February 2018 were categorized into teratozoospermia and normozoospermic groups. Sperm genomic DNA extraction was conducted, and STL were evaluated using quantitative polymerase chain reaction.<br><br>RESULTS: Statistical evaluation of relative telomere length was calculated by the ratio of telomere to single-copy gene for teratozoospermia and normal specimens. Results significantly demonstrated that relative telomere length in teratozoospermia samples is nearly 3 times shorter than in normal samples (p > 0.001).<br><br>CONCLUSION: Our results represent the reduction of telomeres length in teratozoospermia and suggest that this alteration might be one of the factors contributing to the sperm fertility potential of this kind of specimen. However, defining relevant molecular processes requires further detailed investigations.}, }
@article {pmid37119805, year = {2023}, author = {Ngo, K and Gittens, TH and Gonzalez, DI and Hatmaker, EA and Plotkin, S and Engle, M and Friedman, GA and Goldin, M and Hoerr, RE and Eichman, BF and Rokas, A and Benton, ML and Friedman, KL}, title = {A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyad076}, pmid = {37119805}, issn = {1943-2631}, abstract = {Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker's yeast, Saccharomyces cerevisiae, that act as hotspots of de novo telomere addition (termed Sites of Repair-associated Telomere Addition or SiRTAs), but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.}, }
@article {pmid37119246, year = {2023}, author = {Kong, PL and Looi, LM and Cheah, PL}, title = {Potential utility of telomere length assessment in breast cancer in a diagnostic histopathology setting.}, journal = {The Malaysian journal of pathology}, volume = {45}, number = {1}, pages = {51-63}, pmid = {37119246}, issn = {0126-8635}, abstract = {INTRODUCTION: Telomeres shorten with cell cycling but are restored above mortality threshold in many cancers making them potentially exploitable for differentiating malignant from benign tissues, and for cancer evaluation.<br><br>MATERIALS AND METHODS: We assessed telomeres in a diagnostic histopathology setting using quantitative fluorescence in situ hybridisation on 33 fibroadenoma (FA) and 73 invasive breast carcinoma of no special type (IBC-NST) (prototypes of benign and malignant breast tumours, respectively) with paired benign, non-lesional breast tissues (BNL). Telomere lengths were expressed as telomere/chromosome-2-centromere ratio (TCR). The telomere length cut-off for malignancy was also determined.<br><br>RESULTS: Mean TCR of IBC-NST was significantly shorter than FA and BNL (p<0.001). Mean TCR of FA was shorter than BNL but not significantly (p>0.05). TCR cut-off for IBC-NST based on FA was &#x2264;0.29 (sensitivity=75.3%; specificity=78.8%), and &#x2264;0.30 based on BNL (sensitivity=76.7%; specificity=89.0%). TCR of IBC-NST did not differ in relation to histological grade, nodal and hormonal status (p>0.05) but was significantly shorter in HER2-overexpressing cancers (p<0.05).<br><br>CONCLUSION: We have demonstrated a first-step to the development of methodologybased cut-off values of mean telomere length for distinguishing benign from malignant breast tissues. Telomere length may not value-add to the standard prognostic and predictive parameters, but has potential in relation to HER2.}, }
@article {pmid37118904, year = {2023}, author = {Lai, TP and Verhulst, S and Savage, SA and Gadalla, SM and Benetos, A and Toupance, S and Factor-Litvak, P and Susser, E and Aviv, A}, title = {Buildup from birth onward of short telomeres in human hematopoietic cells.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e13844}, doi = {10.1111/acel.13844}, pmid = {37118904}, issn = {1474-9726}, support = {R21 ES023582/ES/NIEHS NIH HHS/United States ; U01AG066529/AG/NIA NIH HHS/United States ; R01 HD071180/HD/NICHD NIH HHS/United States ; }, abstract = {Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere-Shortest-Length-Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age-dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth-89 years) from the general population, and 18 patients with dyskeratosis congenita-telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL-mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans.}, }
@article {pmid37118284, year = {2022}, author = {Aman, Y}, title = {Telomere vesicle transfer protects T cells from senescence.}, journal = {Nature aging}, volume = {2}, number = {10}, pages = {872}, doi = {10.1038/s43587-022-00296-8}, pmid = {37118284}, issn = {2662-8465}, }
@article {pmid37118131, year = {2022}, author = {Vinciguerra, M}, title = {Telomere oxidative lesions and cell senescence.}, journal = {Nature aging}, volume = {2}, number = {8}, pages = {690}, doi = {10.1038/s43587-022-00272-2}, pmid = {37118131}, issn = {2662-8465}, }
@article {pmid37115645, year = {2023}, author = {Singh, M and MacKenzie, D and Desai, S and Batista, N and Zhang, D}, title = {Diagnostic Biomarkers and Therapeutic Targets of Alternative Lengthening of Telomeres-Positive Cancers.}, journal = {Genetic testing and molecular biomarkers}, volume = {27}, number = {4}, pages = {123-125}, doi = {10.1089/gtmb.2023.29069.mas}, pmid = {37115645}, issn = {1945-0257}, }
@article {pmid37117760, year = {2022}, author = {Codd, V and Denniff, M and Swinfield, C and Warner, SC and Papakonstantinou, M and Sheth, S and Nanus, DE and Budgeon, CA and Musicha, C and Bountziouka, V and Wang, Q and Bramley, R and Allara, E and Kaptoge, S and Stoma, S and Jiang, T and Butterworth, AS and Wood, AM and Di Angelantonio, E and Thompson, JR and Danesh, JN and Nelson, CP and Samani, NJ}, title = {Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.}, journal = {Nature aging}, volume = {2}, number = {2}, pages = {170-179}, pmid = {37117760}, issn = {2662-8465}, abstract = {Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.}, }
@article {pmid37117759, year = {2022}, author = {Hägg, S and Zhan, Y}, title = {Telomere research entering the big data era.}, journal = {Nature aging}, volume = {2}, number = {2}, pages = {102-104}, pmid = {37117759}, issn = {2662-8465}, }
@article {pmid37118410, year = {2021}, author = {Saraswati, S and Martínez, P and Graña-Castro, O and Blasco, MA}, title = {Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis.}, journal = {Nature aging}, volume = {1}, number = {3}, pages = {269-283}, pmid = {37118410}, issn = {2662-8465}, abstract = {Accumulation of short telomeres is a hallmark of aging. Mutations in telomerase or telomere-binding proteins lead to telomere shortening or dysfunction and are at the origin of human pathologies known as 'telomere syndromes', which are characterized by loss of the regenerative capacity of tissues and fibrotic pathologies. Here, we generated two mouse models of kidney fibrosis, either by combining telomerase deficiency to induce telomere shortening and a low dose of folic acid, or by conditionally deleting Trf1, a component of the shelterin telomere protective complex, from the kidneys. We find that short telomeres sensitize the kidneys to develop fibrosis in response to folic acid and exacerbate the epithelial-to-mesenchymal transition (EMT) program. Trf1 deletion in kidneys led to fibrosis and EMT activation. Our findings suggest that telomere shortening or dysfunction may contribute to pathological, age-associated renal fibrosis by influencing the EMT program.}, }
@article {pmid37114543, year = {2023}, author = {Moraes, IB and Paiva, IM and Moreira-Júnior, RE and Sartori, BM and Franco, RR and Espindola, FS and Murgas, LDS and Brunialti-Godard, AL}, title = {Ethanol Preference Leads to Alterations in Telomere Length, Mitochondria Copy Number, and Antioxidant Enzyme Activity in Zebrafish Brains.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {28}, number = {4}, pages = {73}, doi = {10.31083/j.fbl2804073}, pmid = {37114543}, issn = {2768-6698}, abstract = {BACKGROUND: The motivations for and effects of ethanol consumption vary considerably among individuals, and as such, a significant proportion of the population is prone to substance abuse and its negative consequences in the physical, social, and psychological spheres. In a biological context, the characterization of these phenotypes provides clues for understanding the neurological complexity associated with ethanol abuse behavior. Therefore, the objective of this research was to characterize four ethanol preference phenotypes described in zebrafish: Light, Heavy, Inflexible, and Negative Reinforcement.<br><br>METHODS: To do this, we evaluated the telomere length, mtDNA copy number using real-time quantitative PCR (qPCR), and the activity of these antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the brain, and the interactions between these biomarkers. Changes observed in these parameters were associated with ethanol consumption and alcohol abuse.<br><br>RESULTS: The Heavy, Inflexible, and Negative Reinforcement phenotypes showed ethanol preference. This was particularly the case with the Inflexible phenotype, which was the group with the greatest ethanol preference. These three phenotypes showed telomere shortening as well as high SOD/CAT and/or GPx activities, while the Heavy phenotype also showed an increase in the mtDNA copy number. However, the Light phenotype, containing individuals without ethanol preference, did not demonstrate any changes in the analyzed parameters even after being exposed to the drug. Additionally, the PCA analysis showed a tendency to cluster the Light and Control groups differently from the other ethanol preference phenotypes. There was also a negative correlation between the results of the relative telomere length and SOD and CAT activity, providing further evidence of the biological relationship between these parameters.<br><br>CONCLUSIONS: Our results showed differential molecular and biochemistry patterns in individuals with ethanol preference, suggesting that the molecular and biochemical basis of alcohol abuse behavior extends beyond its harmful physiological effects, but rather is correlated with preference phenotypes.}, }
@article {pmid37113976, year = {2023}, author = {Duncan, E and Papatheodoulou, M and Metcalfe, NB and McLennan, D}, title = {Does pre-spawning catch and release angling affect offspring telomere dynamics in Atlantic salmon?.}, journal = {Conservation physiology}, volume = {11}, number = {1}, pages = {coad018}, pmid = {37113976}, issn = {2051-1434}, abstract = {The practice of 'catch and release' (C&amp;R) angling confers a balance between animal welfare, conservation efforts and preserving the socio-economic interests of recreational angling. However, C&amp;R angling can still cause exhaustion and physical injury, and often exposes the captured fish to the stress of air exposure. Therefore, the true conservation success of C&amp;R angling depends on whether the angled individuals then survive to reproduction and whether there are any persisting effects on subsequent generations. Here we tested the hypothesis that the stress of C&amp;R angling is then passed on to offspring. We experimentally manipulated the C&amp;R experience of wild adult salmon prior to the spawning season. These parental fish either underwent a C&amp;R simulation (which involved exercise with/without air exposure) or were left as control individuals. We then measured the telomere length of the arising offspring (at the larval stage of development) since previous studies have linked a shorter telomere length with reduced fitness/longevity and the rate of telomere loss is thought to be influenced by stress. Family-level telomere length was positively related to rate of growth. However, the telomere lengths of the salmon offspring were unrelated to the C&amp;R experience of their parents. This may be due to there being no intergenerational effect of parental stress exposure on offspring telomeres, or to any potential effects being buffered by the significant telomere elongation mechanisms that are thought to occur during the embryonic and larval stages of development. While this may suggest that C&amp;R angling has a minimal intergenerational effect on offspring fitness, there have been numerous other reports of negative C&amp;R effects, therefore we should still be aiming to mitigate and refine such practices, in order to minimize their impacts on fish populations.}, }
@article {pmid37113742, year = {2023}, author = {Yang, Q and Nie, Z and Zhu, Y and Hao, M and Liu, S and Ding, X and Wang, F and Wang, F and Geng, X}, title = {Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction.}, journal = {Oxidative medicine and cellular longevity}, volume = {2023}, number = {}, pages = {6897268}, pmid = {37113742}, issn = {1942-0994}, abstract = {BACKGROUND: Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown.<br><br>OBJECTIVE: We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study.<br><br>METHODS: Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis.<br><br>RESULTS: By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells.<br><br>CONCLUSION: Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.}, }
@article {pmid37113487, year = {2023}, author = {Wang, X and Wen, J and Qu, Q and Gu, S and Zhang, L and Li, Y and Qi, X}, title = {Association of weight range with telomere length: A retrospective cohort study.}, journal = {Frontiers in endocrinology}, volume = {14}, number = {}, pages = {1106283}, pmid = {37113487}, issn = {1664-2392}, abstract = {OBJECTIVE: Previous research has shown a significant association between weight and telomere length, but did not take into consideration weight range. The study was to investigate the association of weight range with telomere length.<br><br>METHODS: Data of 2918 eligible participants aged 25-84 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 cycle were analyzed. Information about demographic variables, lifestyle factors, anthropometric variables, and medical comorbidities were included. Univariate and multivariate linear regression model with adjustments for potential confounders were employed to determine the association between weight range and telomere length. A non-parametrically restricted cubic spline model was used to illustrate the possible non-linear relationship.<br><br>RESULTS: In univariate linear regression, BMImax, BMI range, and weight range all revealed significant negative associations with telomere length. However, annual rate of BMI/weight range showed a significant positive associations with telomere length. There was no significant association between telomere length and BMImin. After adjusting for potential confounders, the inverse associations persisted in BMImax (&#x3b2;=-0.003, P<0.001), BMI range (&#x3b2;=-0.002, P=0.003), and weight range (&#x3b2;=-0.001, P=0.001). Furthermore, annual rate of BMI range (&#x3b2;=-0.026, P=0.009) and weight range (&#x3b2;=-0.010, P=0.007) presented negative associations with telomere length, after adjusting for covariates in Model 2-4. The association between BMImin (&#x3b2; =-0.002, P=0.237) and telomere length still could not reach statistical significance in multivariate linear regression model. The results of restricted cubic spline analysis showed that BMImax (P for nonlinear =0.026), BMI range (P for nonlinear =0.022), weight range (P for nonlinear =0.035), annual rate of BMI range (P for nonlinear =0.030), and annual rate of weight range (P for nonlinear =0.027) all had nonlinear inverse associations with telomere length.<br><br>CONCLUSIONS: The study suggests that weight range is inversely associated with telomere length in U.S. adults. Larger weight fluctuation may accelerate telomere shortening and aging.}, }
@article {pmid37107603, year = {2023}, author = {Adwan Shekhidem, H and Sharvit, L and Huffman, DM and Manov, I and Atzmon, G and Shams, I}, title = {Damage-Free Shortening of Telomeres Is a Potential Strategy Supporting Blind Mole-Rat Longevity.}, journal = {Genes}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/genes14040845}, pmid = {37107603}, issn = {2073-4425}, abstract = {Telomere shortening or loss of shelterin components activates DNA damage response (DDR) pathways, leading to a replicative senescence that is usually coupled with a senescence-associated secretory phenotype (SASP). Recent studies suggested that telomere aberration that activates DDR may occur, irrespective of telomere length or loss of shelterin complex. The blind mole-rat (Spalax) is a subterranean rodent with exceptional longevity, and its cells demonstrate an uncoupling of senescence and SASP inflammatory components. Herein, we evaluated Spalax relative telomere length, telomerase activity, and shelterin expression, along with telomere-associated DNA damage foci (TAFs) levels with cell passage. We show that telomeres shorten in Spalax fibroblasts similar to the process in rats, and that the telomerase activity is lower. Moreover, we found lower DNA damage foci at the telomeres and a decline in the mRNA expression of two shelterin proteins, known as ATM/ATR repressors. Although additional studies are required for understanding the underling mechanism, our present results imply that Spalax genome protection strategies include effective telomere maintenance, preventing early cellular senescence induced by persistent DDR, thereby contributing to its longevity and healthy aging.}, }
@article {pmid37107534, year = {2023}, author = {Pennarun, G and Picotto, J and Bertrand, P}, title = {Close Ties between the Nuclear Envelope and Mammalian Telomeres: Give Me Shelter.}, journal = {Genes}, volume = {14}, number = {4}, pages = {}, doi = {10.3390/genes14040775}, pmid = {37107534}, issn = {2073-4425}, abstract = {The nuclear envelope (NE) in eukaryotic cells is essential to provide a protective compartment for the genome. Beside its role in connecting the nucleus with the cytoplasm, the NE has numerous important functions including chromatin organization, DNA replication and repair. NE alterations have been linked to different human diseases, such as laminopathies, and are a hallmark of cancer cells. Telomeres, the ends of eukaryotic chromosomes, are crucial for preserving genome stability. Their maintenance involves specific telomeric proteins, repair proteins and several additional factors, including NE proteins. Links between telomere maintenance and the NE have been well established in yeast, in which telomere tethering to the NE is critical for their preservation and beyond. For a long time, in mammalian cells, except during meiosis, telomeres were thought to be randomly localized throughout the nucleus, but recent advances have uncovered close ties between mammalian telomeres and the NE that play important roles for maintaining genome integrity. In this review, we will summarize these connections, with a special focus on telomere dynamics and the nuclear lamina, one of the main NE components, and discuss the evolutionary conservation of these mechanisms.}, }
@article {pmid37106187, year = {2023}, author = {Lanna, A and D'Ambra, C}, title = {Detection of Telomere Transfer at Immunological Synapse.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2654}, number = {}, pages = {251-261}, pmid = {37106187}, issn = {1940-6029}, abstract = {Eukaryotes solve the DNA-end replication problem synthesizing hexameric chromosome ends known as telomeres. Recent studies have uncovered unexpected functions of telomeres in linking synaptic signaling and vesicle transport, with at least one pathway directly involved in transferring telomeres through the immune synapse. These emerging forms of cellular communication may originate a new class of antiaging interventions based on telomere transplants.}, }
@article {pmid37104965, year = {2023}, author = {de Punder, K and Heim, C and Martens, DS and Wadhwa, PD and Entringer, S}, title = {Maximal telomerase activity capacity (mTAC) underlies the link between the cortisol response to stress and telomere length.}, journal = {Psychoneuroendocrinology}, volume = {153}, number = {}, pages = {106120}, doi = {10.1016/j.psyneuen.2023.106120}, pmid = {37104965}, issn = {1873-3360}, abstract = {Exposure to various forms of stress has been associated with shorter telomere length (TL). However, the molecular underpinnings of this effect are poorly understood. Based on an understanding of the key role of the reverse transcriptase enzyme telomerase in regulating TL, and building upon our previous work in developing and validating a biomarker of the capacity of cells to express telomerase (maximal telomerase activity capacity (mTAC)), we examine here the hypotheses that mTAC is positively associated with TL and that the effect of stress on TL is mediated by individual differences in mTAC. In a proof-of-principle study of 28 healthy women and men we quantified the cortisol response to a standardized stress challenge, the Trier Social Stress Test (TSST), and we concurrently assessed peripheral blood mononuclear cell (PBMC) mTAC and TL. Our results indicated that higher mTAC levels were associated with longer TL (r = 0.50, p = .01). Moreover, mediational analysis suggested that the effect of the cortisol stress response on TL was mediated by mTAC (completely standardized β = -0.17, bootstrap CI95 %: -0.44 to -0.01). Thus, our findings support the premise that individual differences in the capacity of cells to up-regulate telomerase may represent a key mediator in the link between stress and TL.}, }
@article {pmid37105990, year = {2023}, author = {Broderick, R and Cherdyntseva, V and Nieminuszczy, J and Dragona, E and Kyriakaki, M and Evmorfopoulou, T and Gagos, S and Niedzwiedz, W}, title = {Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2's nuclease activity.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {2428}, pmid = {37105990}, issn = {2041-1723}, abstract = {Telomerase-independent cancer proliferation via the alternative lengthening of telomeres (ALT) relies upon two distinct, largely uncharacterized, break-induced-replication (BIR) processes. How cancer cells initiate and regulate these terminal repair mechanisms is unknown. Here, we establish that the EXD2 nuclease is recruited to ALT telomeres to direct their maintenance. We demonstrate that EXD2 loss leads to telomere shortening, elevated telomeric sister chromatid exchanges, C-circle formation as well as BIR-mediated telomeric replication. We discover that EXD2 fork-processing activity triggers a switch between RAD52-dependent and -independent ALT-associated BIR. The latter is suppressed by EXD2 but depends specifically on the fork remodeler SMARCAL1 and the MUS81 nuclease. Thus, our findings suggest that processing of stalled replication forks orchestrates elongation pathway choice at ALT telomeres. Finally, we show that co-depletion of EXD2 with BLM, DNA2 or POLD3 confers synthetic lethality in ALT cells, identifying EXD2 as a potential druggable target for ALT-reliant cancers.}, }
@article {pmid37105911, year = {2023}, author = {Dang, MJ and Li, T and Zhao, LL and Li, Y and Wang, XY and Wu, YL and Lu, JL and Lu, ZW and Yang, Y and Feng, YX and Wang, HY and Jian, YT and Fan, SH and Jiang, Y and Zhang, GL}, title = {Leukocyte Telomere Length and Lacunar Stroke: A Mendelian Randomization Study.}, journal = {Biomedical and environmental sciences : BES}, volume = {36}, number = {4}, pages = {367-370}, doi = {10.3967/bes2023.042}, pmid = {37105911}, issn = {2214-0190}, }
@article {pmid37104389, year = {2023}, author = {McKnight, I and Raines, R and White, H and Nosoudi, N and Lee, C and Lee, PHU and Shim, JW}, title = {Mutability of druggable kinases and pro-inflammatory cytokines by their proximity to telomeres and A+T content.}, journal = {PloS one}, volume = {18}, number = {4}, pages = {e0283470}, doi = {10.1371/journal.pone.0283470}, pmid = {37104389}, issn = {1932-6203}, abstract = {Mutations of protein kinases and cytokines are common and can cause cancer and other diseases. However, our understanding of the mutability in these genes remains rudimentary. Therefore, given previously known factors which are associated with high mutation rates, we analyzed how many genes encoding druggable kinases match (i) proximity to telomeres or (ii) high A+T content. We extracted this genomic information using the National Institute of Health Genome Data Viewer. First, among 129 druggable human kinase genes studied, 106 genes satisfied either factors (i) or (ii), resulting in an 82% match. Moreover, a similar 85% match rate was found in 73 genes encoding pro-inflammatory cytokines of multisystem inflammatory syndrome in children. Based on these promising matching rates, we further compared these two factors utilizing 20 de novo mutations of mice exposed to space-like ionizing radiation, in order to determine if these seemingly random mutations were similarly predictable with this strategy. However, only 10 of these 20 murine genetic loci met (i) or (ii), leading to only a 50% match. When compared with the mechanisms of top-selling FDA approved drugs, this data suggests that matching rate analysis on druggable targets is feasible to systematically prioritize the relative mutability-and therefore therapeutic potential-of the novel candidates.}, }
@article {pmid37102475, year = {2023}, author = {Penrice, DD and Jalan-Sakrikar, N and Jurk, D and Passos, JF and Simonetto, DA}, title = {Telomere dysfunction in chronic liver disease: The link from aging.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/HEP.0000000000000426}, pmid = {37102475}, issn = {1527-3350}, }
@article {pmid37096215, year = {2023}, author = {Tometten, M and Kirschner, M and Meyer, R and Begemann, M and Halfmeyer, I and Vieri, M and Kricheldorf, K and Maurer, A and Platzbecker, U and Radsak, M and Schafhausen, P and Corbacioglu, S and Höchsmann, B and Matthias Wilk, C and Hinze, C and Chromik, J and Heuser, M and Kreuter, M and Koschmieder, S and Panse, J and Isfort, S and Kurth, I and Brümmendorf, TH and Beier, F}, title = {Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria.}, journal = {HemaSphere}, volume = {7}, number = {5}, pages = {e874}, pmid = {37096215}, issn = {2572-9241}, abstract = {Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.}, }
@article {pmid37094463, year = {2023}, author = {Ruan, Y and Lv, W and Li, S and Cheng, Y and Wang, D and Zhang, C and Shimizu, K}, title = {Identification of telomere-related genes associated with aging-related molecular clusters and the construction of a diagnostic model in Alzheimer's disease based on a bioinformatic analysis.}, journal = {Computers in biology and medicine}, volume = {159}, number = {}, pages = {106922}, doi = {10.1016/j.compbiomed.2023.106922}, pmid = {37094463}, issn = {1879-0534}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is strongly associated with aging. Telomeres are DNA sequences that protect chromosomes from damage and shorten with age. Telomere-related genes (TRGs) may play a role in AD's pathogenesis.<br><br>OBJECTIVES: To identify TRGs related to aging clusters in AD patients, explore their immunological characteristics, and build a TRG-based prediction model for AD and AD subtypes.<br><br>METHODS: We analyzed the gene expression profiles of 97 AD samples from the GSE132903 dataset, using aging-related genes (ARGs) as clustering variables. We also assessed immune-cell infiltration in each cluster. We performed a weighted gene co-expression network analysis to identify cluster-specific differentially expressed TRGs. We compared four machine-learning models (random forest, generalized linear model [GLM], gradient boosting model, and support vector machine) for predicting AD and AD subtypes based on TRGs and validated TRGs by conducting an artificial neural network (ANN) analysis and a nomogram model.<br><br>RESULTS: We identified two aging clusters in AD patients with distinct immunological features: Cluster A had higher immune scores than Cluster B. Cluster A and the immune system are intimately associated, and this association could affect immunological function and result in AD via the digestive system. The GLM predicted AD and AD subtypes most accurately and was validated by the ANN analysis and nomogram model.<br><br>CONCLUSION: Our analyses revealed novel TRGs associated with aging clusters in AD patients and their immunological characteristics. We also developed a promising prediction model based on TRGs for assessing AD risk.}, }
@article {pmid37090094, year = {2023}, author = {Zhou, Y and Xiong, J and Shu, Z and Dong, C and Gu, T and Sun, P and He, S and Jiang, M and Xia, Z and Xue, J and Khan, WU and Chen, F and Cheng, ZM}, title = {The telomere-to-telomere genome of Fragaria vesca reveals the genomic evolution of Fragaria and the origin of cultivated octoploid strawberry.}, journal = {Horticulture research}, volume = {10}, number = {4}, pages = {uhad027}, pmid = {37090094}, issn = {2662-6810}, abstract = {Fragaria vesca, commonly known as wild or woodland strawberry, is the most widely distributed diploid Fragaria species and is native to Europe and Asia. Because of its small plant size, low heterozygosity, and relative ease of genetic transformation, F. vesca has been a model plant for fruit research since the publication of its Illumina-based genome in 2011. However, its genomic contribution to octoploid cultivated strawberry remains a long-standing question. Here, we de novo assembled and annotated a telomere-to-telomere, gap-free genome of F. vesca 'Hawaii 4', with all seven chromosomes assembled into single contigs, providing the highest completeness and assembly quality to date. The gap-free genome is 220 785 082 bp in length and encodes 36 173 protein-coding gene models, including 1153 newly annotated genes. All 14 telomeres and seven centromeres were annotated within the seven chromosomes. Among the three previously recognized wild diploid strawberry ancestors, F. vesca, F. iinumae, and F. viridis, phylogenomic analysis showed that F. vesca and F. viridis are the ancestors of the cultivated octoploid strawberry F. × ananassa, and F. vesca is its closest relative. Three subgenomes of F. × ananassa belong to the F. vesca group, and one is sister to F. viridis. We anticipate that this high-quality, telomere-to-telomere, gap-free F. vesca genome, combined with our phylogenomic inference of the origin of cultivated strawberry, will provide insight into the genomic evolution of Fragaria and facilitate strawberry genetics and molecular breeding.}, }
@article {pmid37087699, year = {2023}, author = {Voirin, CJ and Tsunekage, T and Liu, Y and Alexy, KF and Levin, II}, title = {Brood size is associated with apparent telomere lengthening in nestling barn swallows.}, journal = {Oecologia}, volume = {}, number = {}, pages = {}, pmid = {37087699}, issn = {1432-1939}, abstract = {Early life for animals is often a time of rapid growth and development. In a resource-limited environment, life history theory predicts that there must be trade-offs between resource sinks in ways that optimize future survival and reproductive success. Telomeres have emerged as putative indicators of these early life trade-offs, but there are conflicting accounts as to how developmental traits and conditions impact telomere length and dynamics. For 2 years, we studied the nestlings of a breeding population of barn swallows from day 6 to day 12 of life, measuring various ontogenetic factors to understand to what extent they explain variation in telomere length and dynamics. We unexpectedly found that telomeres lengthened between the two sampling points. Nestlings in large broods had shorter telomeres, but surprisingly, individuals that grew faster from day 6 to day 12 had longer telomeres and more telomere lengthening. Nestlings with higher mass relative to their nestmates on d6 had shorter telomeres, suggesting that the relatively fast growth barn swallows experience early in development is more costly than the relatively slower growth later in development. These effects were only found in the first year of study. Telomere lengthening may be due to the initiation of new hematopoietic cell lines during development or the expression of telomerase early in life. Favorable early life conditions and high parental investment could allow for more growth with little to no cost to telomere length or dynamics.}, }
@article {pmid37085672, year = {2023}, author = {Piñeiro-Hermida, S and Bosso, G and Sánchez-Vázquez, R and Martínez, P and Blasco, MA}, title = {Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {37085672}, issn = {1476-5403}, abstract = {Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8[+] T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.}, }
@article {pmid37083294, year = {2023}, author = {}, title = {Telomere Shortening Induces T-cell Dysfunction and Squamous Cell Cancers.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1}, doi = {10.1158/2159-8290.CD-RW2023-059}, pmid = {37083294}, issn = {2159-8290}, abstract = {Patients with short telomere syndromes are predisposed to squamous cell carcinomas due to T-cell dysfunction.}, }
@article {pmid37079368, year = {2023}, author = {Cortez Cardoso Penha, R and Smith-Byrne, K and Atkins, JR and Haycock, PC and Kar, S and Codd, V and Samani, NJ and Nelson, C and Milojevic, M and Gabriel, AAG and Amos, C and Brennan, P and Hung, RJ and Kachuri, L and Mckay, JD}, title = {Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, doi = {10.7554/eLife.83118}, pmid = {37079368}, issn = {2050-084X}, support = {K99CA246076/NH/NIH HHS/United States ; K99CA246076/CRUK_/Cancer Research UK/United Kingdom ; C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; INTEGRAL NIH 5U19CA203654-03/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.<br><br>METHODS: We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).<br><br>RESULTS: Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.<br><br>CONCLUSIONS: This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.<br><br>FUNDING: Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).}, }
@article {pmid37077333, year = {2023}, author = {Zheng, B and Fu, J}, title = {Telomere dysfunction in some pediatric congenital and growth-related diseases.}, journal = {Frontiers in pediatrics}, volume = {11}, number = {}, pages = {1133102}, pmid = {37077333}, issn = {2296-2360}, abstract = {Telomere wear and dysfunction may lead to aging-related diseases. Moreover, increasing evidence show that the occurrence, development, and prognosis of some pediatric diseases are also related to telomere dysfunction. In this review, we systematically analyzed the relationship between telomere biology and some pediatric congenital and growth-related diseases and proposed new theoretical basis and therapeutic targets for the treatment of these diseases.}, }
@article {pmid37074465, year = {2023}, author = {Saradadevi, GP and Fultz, D and Ramgopal, MK and Subramanian, AT and Prince, G and Thakur, V and Mohannath, G}, title = {Structural variation among assembled genomes facilitates development of rapid and low-cost NOR-linked markers and NOR-telomere junction mapping in Arabidopsis.}, journal = {Plant cell reports}, volume = {}, number = {}, pages = {}, pmid = {37074465}, issn = {1432-203X}, abstract = {Genome-wide structural variants we identified and new NOR-linked markers we developed would be useful for future genome-wide association studies (GWAS), and for new gene/trait mapping purposes. Bioinformatic alignment of the assembled genomes of Col-0 and Sha ecotypes of Arabidopsis thaliana revealed ~ 13,000 genome-wide structural variants involving simple insertions or deletions and repeat contractions or expansions. Using some of these structural variants, we developed new, rapid, and low-cost PCR-based molecular markers that are genetically linked to the nucleolus organizer regions (NORs). A. thaliana has two NORs, one each on chromosome 2 (NOR2) and chromosome 4 (NOR4). Both NORs are ~ 4 Mb each, and hundreds of 45S ribosomal RNA (rRNA) genes are tandemly arrayed at these loci. Using previously characterized recombinant inbred lines (RILs) derived from Sha x Col-0 crosses, we validated the utility of the newly developed NOR-linked markers in genetically mapping rRNA genes and the associated telomeres to either NOR2 or NOR4. Lastly, we sequenced Sha genome using Oxford Nanopore Technology (ONT) and used the data to obtain sequences of NOR-telomere junctions, and with the help of RILs, we mapped them as new genetic markers to their respective NORs (NOR2-TEL2N and NOR4-TEL4N). The structural variants obtained from this study would serve as valuable data for genome-wide association studies (GWAS), and to rapidly design more genome-wide genetic (molecular) markers for new gene/trait mapping purposes.}, }
@article {pmid37070671, year = {2023}, author = {Mender, I and Siteni, S and Barron, S and Flusche, AM and Kubota, N and Yu, C and Cornelius, C and Tedone, E and Maziveyi, M and Grichuk, A and Venkateswaran, N and Conacci Sorrell, M and Hoshida, Y and Kang, R and Tang, D and Gryaznov, S and Shay, JW}, title = {Activating an Adaptive Immune Response with a Telomerase-mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1158/1535-7163.MCT-23-0039}, pmid = {37070671}, issn = {1538-8514}, abstract = {A select group of hepatocellular carcinomas (HCC) patients benefit from surgical, radiological, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, since HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive anti-tumor immunity in HCC. Importantly, the extracellular HMGB1 (high-mobility group box 1) protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.}, }
@article {pmid37066381, year = {2023}, author = {Ertunc, O and Smearman, E and Zheng, Q and Hicks, JL and Brosnan-Cashman, JA and Jones, T and Gomes-Alexandre, C and Trabzonlu, L and Meeker, AK and De Marzo, AM and Heaphy, CM}, title = {Chromogenic detection of telomere lengths in situ aids the identification of precancerous lesions in the prostate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.04.04.535575}, pmid = {37066381}, abstract = {Telomeres are terminal chromosomal elements that are essential for the maintenance of genomic integrity. The measurement of telomere content provides useful diagnostic and prognostic information, and fluorescent methods have been developed for this purpose. However, fluorescent-based tissue assays are cumbersome for investigators to undertake, both in research and clinical settings. Here, a robust chromogenic in situ hybridization (CISH) approach was developed to visualize and quantify telomere content at single cell resolution in human prostate tissues, both frozen and formalin-fixed, paraffin-embedded (FFPE). This new assay ("Telo-CISH") produces permanently stained slides that are viewable with a standard light microscope, thus avoiding the need for specialized equipment and storage. The assay is compatible with standard immunohistochemistry, thereby allowing simultaneous assessment of histomorphology, identification of specific cell types, and assessment of telomere status. In addition, Telo-CISH eliminates the problem of autofluorescent interference that frequently occurs with fluorescent-based methods. Using this new assay, we demonstrate successful application of Telo-CISH to help identify precancerous lesions in the prostate by the presence of markedly short telomeres specifically in the luminal epithelial cells. In summary, with fewer restrictions on the types of tissues that can be tested, and increased histologic information provided, the advantages presented by this novel chromogenic assay should extend the applicability of tissue-based telomere length assessment in research and clinical settings.}, }
@article {pmid37065841, year = {2023}, author = {Francis, M and Lindrose, A and O'Connell, S and Tristano, RI and McGarvey, C and Drury, S}, title = {The interaction of socioeconomic stress and race on telomere length in children: A systematic review and meta-analysis.}, journal = {SSM - population health}, volume = {22}, number = {}, pages = {101380}, pmid = {37065841}, issn = {2352-8273}, abstract = {RATIONALE: Proposed mechanisms relating early life exposures to poor health suggest that biologic indicators of risk are observable in childhood. Telomere length (TL) is a biomarker of aging, psychosocial stress, and a range of environmental exposures. In adults, exposure to early life adversity, including low socioeconomic status (SES), is predictive of shorter TL. However, results in pediatric populations have been mixed. Defining the true relation between TL and SES in childhood is expected to enhance the understanding of the biological pathways through which socioeconomic factors influence health across the life span.<br><br>OBJECTIVE: The aim of this meta-analysis was to systematically review and quantitatively assess the published literature to better understand how SES, race, and TL are related in pediatric populations.<br><br>METHODS: Studies in the United States in any pediatric population with any measure of SES were included and identified through the following electronic databases: PubMed, EMBASE, Web of Science, Medline, Socindex, CINAHL, and Psychinfo. Analysis utilized a multi-level random-effects meta-analysis accounting for multiple effect sizes within a study.<br><br>RESULTS: Thirty-two studies were included with a total of 78 effect sizes that were categorized into income-based, education-based, and composite indicators. Only three studies directly tested the relation between SES and TL as the primary study aim. In the full model, there was a significant relation between SES and TL (r&#xa0;=&#xa0;0.0220 p&#xa0;=&#xa0;0.0286). Analysis by type of SES categorization identified a significant moderating effect of income on TL (r&#xa0;=&#xa0;0.0480, 95% CI: 0.0155 to 0.0802, p&#xa0;=&#xa0;0.0045) but no significant effect for education or composite SES.<br><br>CONCLUSIONS: There is an overall association between SES and TL that is predominately due to the association with income-based SES measures implicating income disparities as a key target for efforts to address health inequity across the life span. Identification of associations between family income and biological changes in children that predict life-span health risk provides key data to support public health policies addressing economic inequality in families and presents a unique opportunity to assess the effect of prevention efforts at the biologic level.}, }
@article {pmid37061546, year = {2023}, author = {Lai, KY and Webster, C and Kumari, S and Gallacher, JEJ and Sarkar, C}, title = {The associations of socioeconomic status with incident dementia and Alzheimer's disease are modified by leucocyte telomere length: a population-based cohort study.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {6163}, pmid = {37061546}, issn = {2045-2322}, support = {MR/T0333771/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Socio-economic status (SES) and biological aging are risk factors for dementia, including Alzheimer's disease, however, it is less clear if the associations with SES vary sufficiently across different biological age strata. We used data from 331,066 UK Biobank participants aged 38-73 with mean follow-up of 12 years to examine if associations between SES (assessed by educational attainment, employment status and household income) and dementia and Alzheimer's disease are modified by biological age (assessed by leucocyte telomere length: LTL). Diagnosis of events was ascertained through hospital admissions data. Cox regressions were used to estimate hazard ratios [HRs]. A consistent dose-response relationship was found, with participants in low SES and shorter LTL strata (double-exposed group) reporting 3.28 (95% confidence interval [CI] 2.57-4.20) and 3.44 (95% CI 2.35-5.04) times higher risks of incident dementia and Alzheimer's disease respectively, compared to those of high SES and longer LTL (least-exposed group). Of interest is a synergistic interaction between SES and LTL to increase risk of dementia (RERI 0.57, 95% CI 0.07-1.06) and Alzheimer's disease (RERI 0.79, 95% CI 0.02-1.56). Our findings that SES and biological age (LTL) are synergistic risk factors of dementia and Alzheimer's disease may suggest the need to target interventions among vulnerable sub-groups.}, }
@article {pmid37060569, year = {2023}, author = {Savoca, V and Rivosecchi, J and Gaiatto, A and Rossi, A and Mosca, R and Gialdini, I and Zubovic, L and Tebaldi, T and Macchi, P and Cusanelli, E}, title = {TERRA stability is regulated by RALY and polyadenylation in a telomere-specific manner.}, journal = {Cell reports}, volume = {42}, number = {4}, pages = {112406}, doi = {10.1016/j.celrep.2023.112406}, pmid = {37060569}, issn = {2211-1247}, abstract = {Telomeric repeat-containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres that plays key roles in telomere maintenance. A fraction of TERRA is polyadenylated, and the presence of the poly(A) tail influences TERRA localization and stability. However, the mechanisms of TERRA biogenesis remain mostly elusive. Here, we show that the stability of TERRA transcripts is regulated by the RNA-binding protein associated with lethal yellow mutation (RALY). RALY depletion results in lower TERRA levels, impaired localization of TERRA at telomeres, and ultimately telomere damage. Importantly, we show that TERRA polyadenylation is telomere specific and that RALY preferentially stabilizes non-polyadenylated TERRA transcripts. Finally, we report that TERRA interacts with the poly(A)-binding protein nuclear 1 (PABPN1). Altogether, our results indicate that TERRA stability is regulated by the interplay between RALY and PABPN1, defined by the TERRA polyadenylation state. Our findings also suggest that different telomeres may trigger distinct TERRA-mediated responses.}, }
@article {pmid37059728, year = {2023}, author = {Rai, R and Biju, K and Sun, W and Sodeinde, T and Al-Hiysat, A and Morgan, J and Ye, X and Li, X and Chen, Y and Chang, S}, title = {Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2[B] and RAP1.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {2144}, pmid = {37059728}, issn = {2041-1723}, abstract = {Double-strand breaks (DSBs) due to genotoxic stress represent potential threats to genome stability. Dysfunctional telomeres are recognized as DSBs and are repaired by distinct DNA repair mechanisms. RAP1 and TRF2 are telomere binding proteins essential to protect telomeres from engaging in homology directed repair (HDR), but how this occurs remains unclear. In this study, we examined how the basic domain of TRF2 (TRF2[B]) and RAP1 cooperate to repress HDR at telomeres. Telomeres lacking TRF2[B] and RAP1 cluster into structures termed ultrabright telomeres (UTs). HDR factors localize to UTs, and UT formation is abolished by RNaseH1, DDX21 and ADAR1p110, suggesting that they contain DNA-RNA hybrids. Interaction between the BRCT domain of RAP1 and KU70/KU80 is also required to repress UT formation. Expressing TRF2[∆B] in Rap1[-/-] cells resulted in aberrant lamin A localization in the nuclear envelope and dramatically increased UT formation. Expressing lamin A phosphomimetic mutants induced nuclear envelope rupturing and aberrant HDR-mediated UT formation. Our results highlight the importance of shelterin and proteins in the nuclear envelope in repressing aberrant telomere-telomere recombination to maintain telomere homeostasis.}, }
@article {pmid37046606, year = {2023}, author = {Sohn, EJ and Goralsky, JA and Shay, JW and Min, J}, title = {The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT).}, journal = {Cancers}, volume = {15}, number = {7}, pages = {}, doi = {10.3390/cancers15071945}, pmid = {37046606}, issn = {2072-6694}, abstract = {As detailed by the end replication problem, the linear ends of a cell's chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10-15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses.}, }
@article {pmid37046137, year = {2023}, author = {Kuan, XY and Fauzi, NSA and Ng, KY and Bakhtiar, A}, title = {Exploring the Causal Relationship Between Telomere Biology and Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {37046137}, issn = {1559-1182}, abstract = {Telomeres, also known as the "protective caps" of our chromosomes, shorten with each cell cycle due to the end replication problem. This process, termed telomere attrition, is associated with many age-related disorders, such as Alzheimer's disease (AD). Despite the numerous studies conducted in this field, the role of telomere attrition in the onset of the disease remains unclear. To investigate the causal relationship between short telomeres and AD, this review aims to highlight the primary factors that regulate telomere length and maintain its integrity, with an additional outlook on the role of oxidative stress, which is commonly associated with aging and molecular damage. Although some findings thus far might be contradictory, telomere attrition likely plays a crucial role in the progression of AD due to its close association with oxidative stress. The currently available treatments for AD are only symptomatic without affecting the progression of the disease. The components of telomere biology discussed in this paper have previously been studied as an alternative treatment option for several diseases and have exhibited promising in vitro and in vivo results. Hence, this should provide a basis for future research to develop a potential therapeutic strategy for AD. (Created with BioRender.com).}, }
@article {pmid37042812, year = {2023}, author = {Sosa Ponce, ML and Remedios, MH and Moradi-Fard, S and Cobb, JA and Zaremberg, V}, title = {SIR telomere silencing depends on nuclear envelope lipids and modulates sensitivity to a lysolipid.}, journal = {The Journal of cell biology}, volume = {222}, number = {7}, pages = {}, doi = {10.1083/jcb.202206061}, pmid = {37042812}, issn = {1540-8140}, support = {MOP-82736/CAPMC/CIHR/Canada ; }, abstract = {The nuclear envelope (NE) is important in maintaining genome organization. The role of lipids in communication between the NE and telomere regulation was investigated, including how changes in lipid composition impact gene expression and overall nuclear architecture. Yeast was treated with the non-metabolizable lysophosphatidylcholine analog edelfosine, known to accumulate at the perinuclear ER. Edelfosine induced NE deformation and disrupted telomere clustering but not anchoring. Additionally, the association of Sir4 at telomeres decreased. RNA-seq analysis showed altered expression of Sir-dependent genes located at sub-telomeric (0-10 kb) regions, consistent with Sir4 dispersion. Transcriptomic analysis revealed that two lipid metabolic circuits were activated in response to edelfosine, one mediated by the membrane sensing transcription factors, Spt23/Mga2, and the other by a transcriptional repressor, Opi1. Activation of these transcriptional programs resulted in higher levels of unsaturated fatty acids and the formation of nuclear lipid droplets. Interestingly, cells lacking Sir proteins displayed resistance to unsaturated-fatty acids and edelfosine, and this phenotype was connected to Rap1.}, }
@article {pmid37041499, year = {2023}, author = {Baird, A and Gomes, M and Souza, CA and Magner, K and Alvarez, G}, title = {Short Telomere Syndrome presenting with pulmonary fibrosis, liver cirrhosis and hepatopulmonary syndrome: a case report.}, journal = {BMC pulmonary medicine}, volume = {23}, number = {1}, pages = {114}, pmid = {37041499}, issn = {1471-2466}, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.<br><br>CASE PRESENTATION: We describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with&#xa0;chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10[th] percentile for the patient's age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18&#xa0;months after the initial diagnosis was made.<br><br>CONCLUSIONS: Short Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.}, }
@article {pmid37037617, year = {2023}, author = {Schratz, KE and Flasch, DA and Atik, CC and Cosner, ZL and Blackford, AL and Yang, W and Gable, DL and Vellanki, PJ and Xiang, Z and Gaysinskaya, V and Vonderheide, RH and Rooper, LM and Zhang, J and Armanios, M}, title = {T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers.}, journal = {Cancer cell}, volume = {41}, number = {4}, pages = {807-817.e6}, doi = {10.1016/j.ccell.2023.03.005}, pmid = {37037617}, issn = {1878-3686}, abstract = {Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found patients with STS are only predisposed to squamous cell carcinoma of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients' predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.}, }
@article {pmid37034403, year = {2023}, author = {Howpay Manage, SA and Zhu, J and Fleming, AM and Burrows, CJ}, title = {Promoters vs. telomeres: AP-endonuclease 1 interactions with abasic sites in G-quadruplex folds depend on topology.}, journal = {RSC chemical biology}, volume = {4}, number = {4}, pages = {261-270}, pmid = {37034403}, issn = {2633-0679}, abstract = {The DNA repair endonuclease APE1 is responsible for the cleavage of abasic sites (AP) in DNA as well as binding AP in promoter G-quadruplex (G4) folds in some genes to regulate transcription. The present studies focused on the topological properties of AP-bearing G4 folds and how they impact APE1 interaction. The human telomere sequence with a tetrahydrofuran model (F) of an AP was folded in K[+]- or Na[+]-containing buffers to adopt hybrid- or basket-folds, respectively. Endonuclease and binding assays were performed with APE1 and the G4 substrates, and the data were compared to prior work with parallel-stranded VEGF and NEIL3 promoter G4s to identify topological differences. The APE1-catalyzed endonuclease assays led to the conclusion that telomere G4 folds were slightly better substrates than the promoter G4s, but the yields were all low compared to duplex DNA. In the binding assays, G4 topological differences were observed in which APE1 bound telomere G4s with dissociation constants similar to single-stranded DNA, and promoter G4s were bound with nearly ten-fold lower values similar to duplex DNA. An in-cellulo assay with the telomere G4 in a model promoter bearing a lesion failed to regulate transcription. These data support a hypothesis that G4 topology in gene promoters is a critical feature that APE1 recognizes for gene regulation.}, }
@article {pmid37033949, year = {2023}, author = {Wei, D and Jiang, Y and Cheng, J and Wang, H and Sha, K and Zhao, J}, title = {Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1023991}, pmid = {37033949}, issn = {1664-3224}, abstract = {BACKGROUND: Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study.<br><br>METHODS: LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran's Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome.<br><br>RESULTS: In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis.<br><br>CONCLUSION: Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.}, }
@article {pmid37034531, year = {2023}, author = {Vukašinović, A and Ostanek, B and Klisic, A and Kafedžić, S and Zdravković, M and Ilić, I and Sopić, M and Hinić, S and Stefanović, M and Memon, L and Gaković, B and Bogavac-Stanojević, N and Spasojević-Kalimanovska, V and Marc, J and Nešković, AN and Kotur-Stevuljević, J}, title = {Telomere-telomerase system status in patients with acute myocardial infarction with ST-segment elevation - relationship with oxidative stress.}, journal = {Archives of medical science : AMS}, volume = {19}, number = {2}, pages = {313-323}, pmid = {37034531}, issn = {1734-1922}, abstract = {INTRODUCTION: Telomeres are protective chromosomal ends. Short telomeres are a proven biomarker of biological aging. We aimed to find an association of telomere length and telomerase activity in circulating leukocytes and thromboaspirates of patients with acute myocardial infarction. Furthermore, association of the telomere-telomerase system with oxidative stress markers (as common risk factors for coronary artery disease (CAD)) was tested.<br><br>MATERIAL AND METHODS: Patients were selected from the patients admitted to the intensive care unit with acute myocardial infarction with ST-segment elevation (STEMI), with the following inclusion criteria - STEMI patients between 18 and 80 years old of both genders and candidates for primary percutaneous coronary intervention, with infarction pain present for a maximum of 12 h. In all the patients leukocyte telomere length, telomerase activity and scores related to oxidative-stress status (Protective, Damage and OXY) were evaluated.<br><br>RESULTS: Patients were divided into different groups: with stable angina pectoris (AP) (n = 22), acute myocardial infarction with: STEMI (n = 93), non-obstructive coronary arteries (MINOCA) (n = 7), blood vessel rupture (n = 6) at three time points, and compared to the group of 84 healthy subjects. Telomerase activity was significantly higher in all CAD sub-groups compared to the control group (AP = 0.373 (0.355-0.386), STEMI = 0.375 (0.349-0.395), MINOCA = 0.391 (0.366-0.401), blood vessel rupture = 0.360 (0.352-0.385) vs. CG = 0.069 (0.061-0.081), p < 0.001), while telomeres were significantly shorter in STEMI, MINOCA and blood vessel rupture groups compared to the control group (STEMI = 1.179 (0.931-1.376), MINOCA = 1.026 (0.951-1.070), blood vessel rupture = 1.089 (0.842-1.173) vs. CG = 1.329 (1.096-1.624), p = 0.030]. Values of OXY score were significantly higher in STEMI and MINOCA patients compared to the control group and AP patients (5.83 (4.55-7.54) and 10.28 (9.19-10.72) vs. 4.94 (3.29-6.18) and 4.18 (2.58-4.86), p < 0.001). Longer telomeres and higher telomerase activity were found in thromboaspirates, compared to the peripheral blood leukocytes in the same patients (1.25 (1.01-1.84) vs. 1.18 (0.909-1.516), p = 0.036; and 0.366 (0.367-0.379) vs. 0.366 (0.367-0.379), p < 0.001, respectively). In addition, telomere length and telomerase activity had good diagnostic ability to separate STEMI patients from healthy persons.<br><br>CONCLUSIONS: Leukocyte telomere length and telomerase activity can differentiate CAD patients from healthy persons, and relate CAD to oxidative stress.}, }
@article {pmid37031574, year = {2023}, author = {Flor-Alemany, M and Acosta-Manzano, P and Migueles, JH and Varela-López, A and Baena-García, L and Quiles, JL and Aparicio, VA}, title = {Influence of an exercise intervention plus an optimal Mediterranean diet adherence during pregnancy on the telomere length of the placenta. The GESTAFIT project.}, journal = {Placenta}, volume = {136}, number = {}, pages = {42-45}, doi = {10.1016/j.placenta.2023.04.002}, pmid = {37031574}, issn = {1532-3102}, abstract = {We aimed to investigate whether the effects of exercise on placental relative telomere length (RTL) after delivery are modulated by the Mediterranean diet [MD] adherence in 65 pregnant women (control n = 34, exercise n = 31). No differences were found in placental RTL between the exercise and the control groups (p = 0.557). The interaction-term between exercise and MD adherence with placental RTL was significant (p = 0.001). Specifically, women in the exercise group showed longer placental RTL after birth compared to controls (referent group), only for those women with a high MD adherence (mean difference = 0.467, p=0.010). A concurrent-exercise training plus an optimal MD adherence during pregnancy might prevent the placental RTL shortening.}, }
@article {pmid37028414, year = {2023}, author = {Gaela, VM and Chen, LY}, title = {Ends end it via mitochondria: A telomere-dependent tumor suppressive mechanism acts during replicative crisis.}, journal = {Molecular cell}, volume = {83}, number = {7}, pages = {1027-1029}, doi = {10.1016/j.molcel.2023.03.012}, pmid = {37028414}, issn = {1097-4164}, abstract = {Nassour et al.[1] report that telomere dysfunction communicates with mitochondria via the ZBP1-TERRA-MAVS axis. This pathway activates a detrimental innate immune response that may promote the elimination of cells prone to oncogenic transformation during replicative crisis, thus serving as a telomere-dependent tumor-suppressive mechanism.}, }
@article {pmid37025175, year = {2023}, author = {González-Amor, M and Dorado, B and Andrés, V}, title = {Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.}, journal = {Frontiers in cell and developmental biology}, volume = {11}, number = {}, pages = {1128594}, pmid = {37025175}, issn = {2296-634X}, abstract = {Population aging and age-related cardiovascular disease (CVD) are becoming increasingly prevalent worldwide, generating a huge medical and socioeconomic burden. The complex regulation of aging and CVD and the interaction between these processes are crucially dependent on cellular stress responses. Interferon-stimulated gene-15 (ISG15) encodes a ubiquitin-like protein expressed in many vertebrate cell types that can be found both free and conjugated to lysine residues of target proteins via a post-translational process termed ISGylation. Deconjugation of ISG15 (deISGylation) is catalyzed by the ubiquitin-specific peptidase 18 (USP18). The ISG15 pathway has mostly been studied in the context of viral and bacterial infections and in cancer. This minireview summarizes current knowledge on the role of ISG15 in age-related telomere shortening, genomic instability, and DNA damage accumulation, as well as in hypertension, diabetes, and obesity, major CVD risk factors prevalent in the elderly population.}, }
@article {pmid37024489, year = {2023}, author = {Kusuma, FK and Prabhu, A and Tieo, G and Ahmed, SM and Dakle, P and Yong, WK and Pathak, E and Madan, V and Jiang, YY and Tam, WL and Kappei, D and Dröge, P and Koeffler, HP and Jeitany, M}, title = {Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {1919}, pmid = {37024489}, issn = {2041-1723}, abstract = {Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.}, }
@article {pmid37021555, year = {2023}, author = {Wang, H and Ma, T and Zhang, X and Chen, W and Lan, Y and Kuang, G and Hsu, SJ and He, Z and Chen, Y and Stewart, J and Bhattacharjee, A and Luo, Z and Price, C and Feng, X}, title = {CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkad237}, pmid = {37021555}, issn = {1362-4962}, support = {RO1 GM041803/NH/NIH HHS/United States ; }, abstract = {CST (CTC1-STN1-TEN1) is a telomere associated complex that binds ssDNA and is required for multiple steps in telomere replication, including termination of G-strand extension by telomerase and synthesis of the complementary C-strand. CST contains seven OB-folds which appear to mediate CST function by modulating CST binding to ssDNA and the ability of CST to recruit or engage partner proteins. However, the mechanism whereby CST achieves its various functions remains unclear. To address the mechanism, we generated a series of CTC1 mutants and studied their effect on CST binding to ssDNA and their ability to rescue CST function in CTC1-/- cells. We identified the OB-B domain as a key determinant of telomerase termination but not C-strand synthesis. CTC1-ΔB expression rescued C-strand fill-in, prevented telomeric DNA damage signaling and growth arrest. However, it caused progressive telomere elongation and the accumulation of telomerase at telomeres, indicating an inability to limit telomerase action. The CTC1-ΔB mutation greatly reduced CST-TPP1 interaction but only modestly affected ssDNA binding. OB-B point mutations also weakened TPP1 association, with the deficiency in TPP1 interaction tracking with an inability to limit telomerase action. Overall, our results indicate that CTC1-TPP1 interaction plays a key role in telomerase termination.}, }
@article {pmid37021005, year = {2023}, author = {Domínguez-de-Barros, A and Sifaoui, I and Borecka, Z and Dorta-Guerra, R and Lorenzo-Morales, J and Castro-Fuentes, R and Córdoba-Lanús, E}, title = {An approach to the effects of longevity, sexual maturity, and reproduction on telomere length and oxidative stress in different Psittacidae species.}, journal = {Frontiers in genetics}, volume = {14}, number = {}, pages = {1156730}, pmid = {37021005}, issn = {1664-8021}, abstract = {Introduction: Aging is a multifactorial process that includes molecular changes such as telomere shortening. Telomeres shorten progressively with age in vertebrates, and their shortening rate has a significant role in determining the lifespan of a species. However, DNA loss can be enhanced by oxidative stress. The need for novel animal models has recently emerged as a tool to gather more information about the human aging process. Birds live longer than other mammals of the same size, and Psittacidae species are the most persevering of them, due to special key traits. Methods: We aimed to determine telomere length by qPCR, and oxidative stress status using colorimetric and fluorescence methods in different species of the order Psittaciformes with different lifespans. Results: We found that telomeres shorten with age for both long- and short-lived birds (p < 0.001 and p = 0.004, respectively), with long-lived birds presenting longer telomeres than short-lived ones (p = 0.001). In addition, short-lived birds accumulated more oxidative stress products than long-lived birds (p = 0.013), who showed a better antioxidant capacity (p < 0.001). Breeding was found related to telomere shortening in all species (p < 0.001 and p = 0.003 for long- and short-lived birds). Short-lived birds, especially breeding females, increased their oxidative stress products when breeding (p = 0.021), whereas long-lived birds showed greater resistance and even increased their antioxidant capacity (p = 0.002). Conclusion: In conclusion, the relationship between age and telomere length in Psittacidae was verified. The influence of breeding increased cumulative oxidative damage in short-lived species, while long-lived species may counteract this damage.}, }
@article {pmid37020849, year = {2023}, author = {Lu, L and Zeng, H and Wan, B and Sun, M}, title = {Leukocyte telomere length and bipolar disorder risk: evidence from Mendelian randomization analysis.}, journal = {PeerJ}, volume = {11}, number = {}, pages = {e15129}, pmid = {37020849}, issn = {2167-8359}, abstract = {OBJECTIVE: We aim to test whether leukocyte telomere length (LTL) is causally associated with the risk of bipolar disorder (BD) using the Mendelian randomization (MR) method.<br><br>METHODS: Results of a genome-wide association study (GWAS) conducted with 472,174 individuals of European descent were used to screen for single-nucleotide polymorphisms (SNPs) related with LTL traits. Summary-level data for BD (7,647 cases and 27,303 controls) were obtained from UK Biobank. An inverse-variance-weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger, maximum likelihood, MR-pleiotropy residual sum outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS) methods. Finally, the MR Steiger test was utilized to validate the hypothesized relationship between exposure and outcome.<br><br>RESULTS: Two-sample MR analysis revealed inverse relationships between genetically predicted LTL and BD risk (IVW OR [odds ratio] = 0.800, 95% CI [0.647-0.989] P = 0.039). Genetically predicted LTL exhibits a consistent connection with BD across five MR methods. Sensitivity analyses showed that the genetically determined effect of LTL on BD was stable and reliable. Furthermore, the MR Steiger test demonstrated that LTL was causal for BD rather than the opposite (P < 0.001).<br><br>CONCLUSION: Our findings show that genetically determined LTL reduces the risk of BD. More research is required to clarify the mechanisms underlying this apparent causal connection. In addition, these findings may be useful for developing strategies for the prevention and treatment of BD.}, }
@article {pmid37018627, year = {2023}, author = {Ling, X and Cui, H and Chen, Q and Yang, W and Zou, P and Yang, H and Zhou, N and Deng, J and Liu, J and Cao, J and Ao, L}, title = {Sperm telomere length is associated with sperm nuclear DNA integrity and mitochondrial DNA abnormalities among healthy male college students in Chongqing, China.}, journal = {Human reproduction (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/humrep/dead065}, pmid = {37018627}, issn = {1460-2350}, abstract = {STUDY QUESTION: Is sperm telomere length (STL) associated with sperm nuclear DNA damage and mitochondrial DNA abnormalities?<br><br>SUMMARY ANSWER: Sperm telomere length is related to sperm nuclear DNA integrity and mitochondrial DNA abnormalities in healthy young college students.<br><br>WHAT IS KNOWN ALREADY: Many studies have revealed the correlations between sperm genetic alterations in both the nucleus and mitochondria and sperm functionality, however, the possible associations between the telomere, an important component of chromosome, and conventional indicators of mitochondrial DNA and nuclear DNA changes have not been investigated.<br><br>STUDY DESIGN, SIZE, DURATION: A prospective cohort study, Male Reproductive Health in Chongqing College Students (MARHCS), was conducted from June 2013 to June 2015. We pooled data collected from the follow-up study in 2014 and a total of 444 participants were included.<br><br>STL was measured by quantitative (Q)-PCR. Sperm nuclear DNA integrity was determined using sperm chromatin structure assay (SCSA) and comet assay. Mitochondrial DNA damage was assessed by mitochondrial DNA copy number (mtDNAcn) evaluated with Q-PCR, and mtDNA integrity was determined with long PCR.<br><br>The univariable-linear regression analysis revealed that STL was significantly positively correlated with markers of sperm nuclear DNA damage including the DNA fragmentation index (DFI) and comet parameters (the percentage of DNA in the tail, tail length, comet length, and tail moment). Additionally, STL was also significantly positively correlated with mtDNAcn and significantly negatively correlated with mtDNA integrity. After adjustment for potential confounders, these relationships remained appreciable. Moreover, we investigated potential effects of biometric factors, including age, parental age at conception, and BMI on STL and found that STL was increased with paternal age at conception.<br><br>A mechanistic explanation of the correlation between STL, sperm nuclear DNA integrity, and mtDNA abnormalities cannot be provided with a cross-sectional study design, so well-designed longitudinal studies are still necessary. In addition, a single semen samples were provided and were not all obtained at the same time point, which may increase the intraindividual bias in this study.<br><br>The findings extend the literature including assessment of mitochondrial dysfunction, sperm nuclear DNA damage, and telomere length and provide new insights into the relevance of STL in male reproduction.<br><br>This work was supported by the National Natural Science Foundation of China (No. 82073590), the National Natural Science Foundation of China (No. 81903363), the National Natural Science Foundation of China (No. 82130097), and the National Key R&amp;D Program of China (2022YFC2702900). The authors declare no conflicts of interest.<br><br>TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid37014460, year = {2023}, author = {Salem, S and Ashaat, E}, title = {Association of Relative Telomere Length and LINE-1 Methylation with Autism but not with Severity.}, journal = {Journal of autism and developmental disorders}, volume = {}, number = {}, pages = {}, pmid = {37014460}, issn = {1573-3432}, abstract = {Autism is associated with genomic instability, which is regulated by telomere length (TL) and index of global methylation (LINE-1). This study will determine relative TL (RTL) and LINE-1 methylation percentage for 69 patients and 33 control subjects to evaluate their potential role as biomarkers for autism. The results displayed a significant decrease of both RTL and LINE-1 methylation in autistic cases relative to controls (P < 0.001). Analysis of receiver operating characteristics curve revealed that both of RTL and LINE-1 methylation percentage have the ability to serve as autism biomarkers (area under the curve = 0.817 and 0.889, respectively). The statistical analysis revealed positive correlation between the two biomarkers (correlation coefficient = 0.439 and P < 0.001).}, }
@article {pmid37013192, year = {2023}, author = {Moreno, SP and Fusté, JM and Kaiser, M and Li, JSZ and Nassour, J and Haggblom, C and Denchi, EL and Karlseder, J}, title = {TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.}, journal = {iScience}, volume = {26}, number = {4}, pages = {106405}, pmid = {37013192}, issn = {2589-0042}, abstract = {The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.}, }
@article {pmid37012261, year = {2023}, author = {Wojcicki, JM and Gill, RM and Wilson, L and Lin, J and Rosenthal, P}, title = {Shorter leukocyte telomere length protects against NAFLD progression in children.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {5446}, pmid = {37012261}, issn = {2045-2322}, abstract = {Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006-0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78-4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH.}, }
@article {pmid37010429, year = {2023}, author = {Zhu, M and Wu, C and Wu, X and Song, G and Li, M and Wang, Q}, title = {POP1 promotes the progression of breast cancer through maintaining telomere integrity.}, journal = {Carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/carcin/bgad017}, pmid = {37010429}, issn = {1460-2180}, abstract = {Breast cancer is one of the most common and disastrous neoplasm for women worldwide, especially triple negative breast cancer (TNBC). Emerging evidences have demonstrated that RNase subunits are closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of Processing of Precursor 1 (POP1), a core component of RNase subunits, in breast cancer development have not been fully defined. Our study identified the POP1was upregulated in breast cancer cell lines and tissues and patients with higher POP1 expression were associated with poor outcomes. Overexpression of POP1 promoted cell progression in breast cancer cells, whereas silencing of POP1 induced cell cycle arrest. Moreover, Xenograft model reproduced its growth regulatory roles in breast cancer in vivo. Mechanistically, POP1 interacted and activated the telomerase complex by stabilizing the telomerase RNA component (TERC), thus protecting telomeres from shortening during division. Collectively, our findings demonstrate POP1 may as a novel prognostic marker and a therapeutic target for the management of breast cancer.}, }
@article {pmid37003649, year = {2023}, author = {Luna-Carrascal, J and Olivero-Verbel, J and Acosta-Hoyos, AJ and Quintana-Sosa, M}, title = {Auto repair workers exposed to PM2.5 particulate matter in Barranquilla, Colombia: Telomere length and hematological parameters.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {887}, number = {}, pages = {503597}, doi = {10.1016/j.mrgentox.2023.503597}, pmid = {37003649}, issn = {1879-3592}, abstract = {Exposure to 2.5 µm particulate matter (PM2.5) in automotive repair shops is associated with risks to health. We evaluated the effects of occupational exposure to PM2.5 among auto repair-shop workers. Blood and urine samples were collected from 110 volunteers from Barranquilla, Colombia: 55 active workers and 55 controls. PM2.5 concentrations were assessed at each of the sampling sites and chemical content was analyzed by SEM-EDS electron microscopy. The biological samples obtained were peripheral blood (hematological profiling, DNA extraction) and urine (malondialdehyde concentration). Telomere length was assessed by qPCR and polymorphisms in the glutathione transferase genes GSTT1 and GSTM1 by PCR-RFLP, with confirmation by allelic exclusion. White blood cell (WBC), lymphocyte (LYM%) and platelet (PLT) counts and the malondialdehyde concentration were higher (4.10 ± 0.93) in the exposed group compared to the control group (1.56 ± 0.96). TL was shorter (5071 ± 891) in the exposed individuals compared to the control group (6271 ± 805). White blood cell (WBC) and platelet counts were positively associated with exposure. Age and TBARS were correlated with TL in exposed individuals. The GSTT1 gene alleles were not in Hardy-Weinberg (H-W) equilibrium. The GSTM1 gene alleles were in H-W equilibrium and allelic exclusion analysis confirmed the presence of heterozygous GSTM1 genotypes. SEM-EDS analysis showed the presence of potentially toxic elements, including Mg, Al, Fe, Mn, Rh, Zn, and Cu. Auto repair shop workers showed effects that may be associated with exposure to mixtures of pollutants present in PM2.5. The GSTM1 and GSTT1 genes had independent modulatory effects.}, }
@article {pmid37003504, year = {2023}, author = {Jones, CY and Williams, CL and Moreno, SP and Morris, DK and Mondello, C and Karlseder, J and Bertuch, AA}, title = {Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {104665}, doi = {10.1016/j.jbc.2023.104665}, pmid = {37003504}, issn = {1083-351X}, abstract = {Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.}, }
@article {pmid37002420, year = {2023}, author = {Zlotorynski, E}, title = {RPA dynamics at telomeres.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, pmid = {37002420}, issn = {1471-0080}, }
@article {pmid36999631, year = {2023}, author = {Liu, CC and Chan, HR and Su, GC and Hsieh, YZ and Lei, KH and Kato, T and Yu, TY and Kao, YW and Cheng, TH and Chi, P and Lin, JJ}, title = {Flap endonuclease Rad27 cleaves the RNA of R-loop structures to suppress telomere recombination.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkad236}, pmid = {36999631}, issn = {1362-4962}, abstract = {The long non-coding telomeric RNA transcript TERRA, in the form of an RNA-DNA duplex, regulates telomere recombination. In a screen for nucleases that affects telomere recombination, mutations in DNA2, EXO1, MRE11 and SAE2 cause severe delay in type II survivor formation, indicating that type II telomere recombination is mediated through a mechanism similar to repairing double-strand breaks. On the other hand, mutation in RAD27 results in early formation of type II recombination, suggesting that RAD27 acts as a negative regulator in telomere recombination. RAD27 encodes a flap endonuclease that plays a role in DNA metabolism, including replication, repair and recombination. We demonstrate that Rad27 suppresses the accumulation of the TERRA-associated R-loop and selectively cleaves TERRA of R-loop and double-flapped structures in vitro. Moreover, we show that Rad27 negatively regulates single-stranded C-rich telomeric DNA circles (C-circles) in telomerase-deficient cells, revealing a close correlation between R-loop and C-circles during telomere recombination. These results demonstrate that Rad27 participates in telomere recombination by cleaving TERRA in the context of an R-loop or flapped RNA-DNA duplex, providing mechanistic insight into how Rad27 maintains chromosome stability by restricting the accumulation of the R-loop structure within the genome.}, }
@article {pmid36999210, year = {2023}, author = {Gao, M and Zheng, G and Li, Y and Zhang, Y and Hu, P and Pan, Y}, title = {Telomere length in multiple cancer: Insight into recurrence risk from a Meta-analysis.}, journal = {Journal of gastroenterology and hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgh.16186}, pmid = {36999210}, issn = {1440-1746}, abstract = {BACKGROUND: Several studies have revealed the relationships between telomere length and the risk and mortality of numerous cancers. This meta-analysis aims to insightfully clarify the potential relationship between telomere length and the recurrence of multiple cancers.<br><br>METHODS: PubMed database was used to search and identify interrelated citations. These reports investigated the relationship between telomere length and various cancer recurrences. Meta-analysis pooled data from studies that reported risk ratio (RR) of 95 (CI = 95%) confidence intervals and/or P-values. The cancer recurrence was investigated from an overall standpoint to the multiple levels of subtypes of cancers.<br><br>RESULTS: The meta-analysis involved 5,907 recurrent multiple cancer patients from 13 cohort studies. Compared to these cancer recurrence cases and the telomere length differences, there was no significant correlation between telomere length and cancer recurrence risk (short telomeres versus long telomeres; RR = 0.93, 95% CI: 0.72~1.20, P = 0.59). Additionally, a negative association was observed between telomere length and cancer recurrence in gastrointestinal cancer and a positive association in head and neck cancer, while telomere length had little effect on the recurrence of hematological malignancies and genitourinary cancer in this analysis.<br><br>CONCLUSION: There was no significant relationship between recurrence and telomere length in 5,907 cases in 13 studies. However, there was a correlation between specific tumors. These results suggested that telomere length as a recurrence marker or telomere length to determine the possibility of recurrence must be evaluated on the specific type of cancer.}, }
@article {pmid36997693, year = {2023}, author = {Bryan, TM}, title = {Nucleotide metabolism regulates human telomere length via telomerase activation.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {36997693}, issn = {1546-1718}, }
@article {pmid36993206, year = {2023}, author = {Ngo, K and Gittens, TH and Gonzalez, DI and Hatmaker, EA and Plotkin, S and Engle, M and Friedman, GA and Goldin, M and Hoerr, RE and Eichman, BF and Rokas, A and Benton, ML and Friedman, KL}, title = {A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.03.20.533556}, pmid = {36993206}, abstract = {Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker’s yeast, Saccharomyces cerevisiae , that act as hotspots of de novo telomere addition (termed Sites of Repair-associated Telomere Addition or SiRTAs), but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.}, }
@article {pmid36991019, year = {2023}, author = {Li, F and Wang, Y and Hwang, I and Jang, JY and Xu, L and Deng, Z and Yu, EY and Cai, Y and Wu, C and Han, Z and Huang, YH and Huang, X and Zhang, L and Yao, J and Lue, NF and Lieberman, PM and Ying, H and Paik, J and Zheng, H}, title = {Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {1756}, pmid = {36991019}, issn = {2041-1723}, abstract = {Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.}, }
@article {pmid36989559, year = {2023}, author = {Ali, JH and Abdeen, Z and Azmi, K and Berman, T and Jager, K and Barnett-Itzhaki, Z and Walter, M}, title = {Influence of exposure to pesticides on telomere length and pregnancy outcome: Diethylphosphates but not Dimethylphosphates are associated with accelerated telomere attrition in a Palestinian cohort.}, journal = {Ecotoxicology and environmental safety}, volume = {256}, number = {}, pages = {114801}, doi = {10.1016/j.ecoenv.2023.114801}, pmid = {36989559}, issn = {1090-2414}, abstract = {Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.}, }
@article {pmid36989538, year = {2023}, author = {Valeeva, LR and Abdulkina, LR and Agabekian, IA and Shakirov, EV}, title = {TELOMERE BIOLOGY AND RIBOSOME BIOGENESIS: STRUCTURAL AND FUNCTIONAL INTERCONNECTIONS.}, journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire}, volume = {}, number = {}, pages = {}, doi = {10.1139/bcb-2022-0383}, pmid = {36989538}, issn = {1208-6002}, abstract = {Telomeres are the nucleoprotein structures which play a pivotal role in the protection and maintenance of eukaryotic chromosomes. Telomeres and the enzyme telomerase which replenishes telomeric DNA lost during replication are important factors necessary to ensure continued cell proliferation. Cell proliferation is also dependent on proper and efficient protein synthesis, which is carried out by ribosomes. Mutations in genes involved in either ribosome biogenesis or telomere biology result in cellular abnormalities and can cause human genetic diseases, defined as ribosomopathies and telomeropathies, respectively. Interestingly, recent discoveries indicate that many of the ribosome assembly and rRNA maturation factors have additional non-canonical functions in telomere biology. Similarly, several key proteins and enzymes involved in telomere biology, including telomerase, have unexpected roles in rRNA transcription and maturation. These observations point to an intriguing crosstalk mechanism potentially explaining the multiple pleiotropic symptoms of mutations in many causal genes identified in various telomeropathy and ribosomopathy diseases. In this review, we provide a brief summary of eukaryotic telomere and rDNA loci structures, highlight several universal features of rRNA and telomerase biogenesis, evaluate intriguing interconnections between telomere biology and ribosome assembly, and conclude with an assessment of overlapping features of human diseases of telomeropathies and ribosomopathies.}, }
@article {pmid36986204, year = {2023}, author = {Kuo, CL and Kirk, B and Xiang, M and Pilling, LC and Kuchel, GA and Kremer, R and Duque, G}, title = {Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.}, journal = {Nutrients}, volume = {15}, number = {6}, pages = {}, doi = {10.3390/nu15061474}, pmid = {36986204}, issn = {2072-6643}, support = {NR018963-01A1/NH/NIH HHS/United States ; }, abstract = {Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), suggesting a close association between vitamin D and LTL. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n = 148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Serum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (≤16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized β = -0.018, 95% CI -0.033 to -0.003, p = 0.022) and 0.048 SD (standardized β = -0.048, 95% CI -0.083 to -0.014, p = 0.006), respectively. Additionally, the high serum 25OHD groups (>95.9 nmol/L) had 0.038 SD (standardized β = -0.038, 95% CI -0.072 to -0.004, p = 0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusions: In this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Our findings could be affected by unmeasured confounders. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated.}, }
@article {pmid36986083, year = {2023}, author = {Wei, Y and Li, Z and Lai, H and Lu, P and Zhang, B and Song, L and Zhang, L and Shen, M}, title = {Instant Coffee Is Negatively Associated with Telomere Length: Finding from Observational and Mendelian Randomization Analyses of UK Biobank.}, journal = {Nutrients}, volume = {15}, number = {6}, pages = {}, doi = {10.3390/nu15061354}, pmid = {36986083}, issn = {2072-6643}, abstract = {Telomere length, as a biomarker of accelerated aging, is closely related to many chronic diseases. We aimed to explore the association between coffee consumption and telomere length. Our study included 468,924 participants from the UK Biobank. Multivariate linear models (observational analyses) were conducted to evaluate the associations of coffee intake, instant coffee intake, and filtered coffee intake with telomere length. In addition, we evaluated the causality of these associations in Mendelian randomization (MR) analyses by four methods (inverse-variance weighted (IVW), MR pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, and weighted median). Observational analyses indicated that coffee intake and instant coffee intake were negatively correlated with telomere length, which was equal to 0.12 year of age-related decrease in telomere length for each additional cup of coffee intake (p < 0.001), and 0.38 year of age-related decrease in telomere length for each additional cup of instant coffee intake (p < 0.001), respectively. There was no significant correlation between filtered coffee and telomere length (p = 0.862). Mendelian randomization analyses supported the results of observational analyses. Coffee intake was found to have a causal effect on telomere length through weighted median analysis (p = 0.022), and instant coffee intake had a causal effect on telomere length through IVW analysis (p = 0.019) and MR-PRESSO analysis (p = 0.028). No causal relationship was found between filtered coffee intake and telomere length (p > 0.05). Coffee intake, particularly instant coffee, was found to have an important role in shortening telomere length.}, }
@article {pmid36982772, year = {2023}, author = {M'Kacher, R and Colicchio, B and Junker, S and El Maalouf, E and Heidingsfelder, L and Plesch, A and Dieterlen, A and Jeandidier, E and Carde, P and Voisin, P}, title = {High Resolution and Automatable Cytogenetic Biodosimetry Using In Situ Telomere and Centromere Hybridization for the Accurate Detection of DNA Damage: An Overview.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, doi = {10.3390/ijms24065699}, pmid = {36982772}, issn = {1422-0067}, abstract = {In the event of a radiological or nuclear accident, or when physical dosimetry is not available, the scoring of radiation-induced chromosomal aberrations in lymphocytes constitutes an essential tool for the estimation of the absorbed dose of the exposed individual and for effective triage. Cytogenetic biodosimetry employs different cytogenetic assays including the scoring of dicentrics, micronuclei, and translocations as well as analyses of induced premature chromosome condensation to define the frequency of chromosome aberrations. However, inherent challenges using these techniques include the considerable time span from sampling to result, the sensitivity and specificity of the various techniques, and the requirement of highly skilled personnel. Thus, techniques that obviate these challenges are needed. The introduction of telomere and centromere (TC) staining have successfully met these challenges and, in addition, greatly improved the efficiency of cytogenetic biodosimetry through the development of automated approaches, thus reducing the need for specialized personnel. Here, we review the role of the various cytogenetic dosimeters and their recent improvements in the management of populations exposed to genotoxic agents such as ionizing radiation. Finally, we discuss the emerging potentials to exploit these techniques in a wider spectrum of medical and biological applications, e.g., in cancer biology to identify prognostic biomarkers for the optimal triage and treatment of patients.}, }
@article {pmid36982042, year = {2023}, author = {Prieto-Botella, D and Martens, DS and Valera-Gran, D and Subiza-Pérez, M and Tardón, A and Lozano, M and Casas, M and Bustamante, M and Jimeno-Romero, A and Fernández-Somoano, A and Llop, S and Vrijheid, M and Nawrot, TS and Navarrete-Muñoz, EM}, title = {Sedentary Behaviour and Telomere Length Shortening during Early Childhood: Evidence from the Multicentre Prospective INMA Cohort Study.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {6}, pages = {}, doi = {10.3390/ijerph20065134}, pmid = {36982042}, issn = {1660-4601}, abstract = {Sedentary behaviour (SB) may be related to telomere length (TL) attrition due to a possible pro-inflammatory effect. This study examined the association between parent-reported sedentary behaviour (SB) and leukocyte TL at the age of 4 and telomere tracking from 4 to 8 years. In the Spanish birth cohort Infancia y Medio Ambiente (INMA) project, we analysed data from children who attended follow-up visits at age 4 (n = 669) and 8 (n = 530). Multiple robust regression models were used to explore the associations between mean daily hours of SB (screen time, other sedentary activities, and total SB) at 4 years categorised into tertiles and TL at 4 years and difference in TL rank between age 4 and 8, respectively. At the age of 4, the results showed that children with the highest screen time (1.6-5.0 h/day) had a shorter TL of -3.9% (95% CI: -7.4, -0.4; p = 0.03) compared with children in the lowest tertile (0.0-1.0 h/day). Between 4 and 8 years, a higher screen time (highest tertile group vs. lowest tertile) was associated with a decrease in the LTL rank of -1.9% (95% CI: -3.8, -0.1; p = 0.03) from 4 to 8 years. Children exposed to a higher screen time at 4 years were more prone to have shorter TL at 4 and between 4 and 8 years of age. This study supports the potential negative effect of SB during childhood on cellular longevity.}, }
@article {pmid36981836, year = {2023}, author = {Duchaine, CS and Brisson, C and Diorio, C and Talbot, D and Maunsell, E and Carmichael, PH and Giguère, Y and Gilbert-Ouimet, M and Trudel, X and Ndjaboué, R and Vézina, M and Milot, A and Mâsse, B and Dionne, CE and Laurin, D}, title = {Work-Related Psychosocial Factors and Global Cognitive Function: Are Telomere Length and Low-Grade Inflammation Potential Mediators of This Association?.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {6}, pages = {}, doi = {10.3390/ijerph20064929}, pmid = {36981836}, issn = {1660-4601}, support = {201403MOP-32544-BCA-CFBA-52569 to DL and CB, and 201810GSD-422016-DRB-CFBA-280487 to CSD/CAPMC/CIHR/Canada ; }, abstract = {The identification of modifiable factors that could maintain cognitive function is a public health priority. It is thought that some work-related psychosocial factors help developing cognitive reserve through high intellectual complexity. However, they also have well-known adverse health effects and are considered to be chronic psychosocial stressors. Indeed, these stressors could increase low-grade inflammation and promote oxidative stress associated with accelerated telomere shortening. Both low-grade inflammation and shorter telomeres have been associated with a cognitive decline. This study aimed to evaluate the total, direct, and indirect effects of work-related psychosocial factors on global cognitive function overall and by sex, through telomere length and an inflammatory index. A random sample of 2219 participants followed over 17 years was included in this study, with blood samples and data with cognitive function drawn from a longitudinal study of 9188 white-collar workers (51% female). Work-related psychosocial factors were evaluated according to the Demand-Control-Support and the Effort-Reward Imbalance (ERI) models. Global cognitive function was evaluated with the validated Montreal Cognitive Assessment (MoCA). Telomere length and inflammatory biomarkers were measured using standardised protocols. The direct and indirect effects were estimated using a novel mediation analysis method developed for multiple correlated mediators. Associations were observed between passive work or low job control, and shorter telomeres among females, and between low social support at work, ERI or iso-strain, and a higher inflammatory index among males. An association was observed with higher cognitive performance for longer telomeres, but not for the inflammatory index. Passive work overall, and low reward were associated with lower cognitive performance in males; whereas, high psychological demand in both males and females and high job strain in females were associated with a higher cognitive performance. However, none of these associations were mediated by telomere length or the inflammatory index. This study suggests that some work-related psychosocial factors could be associated with shorter telomeres and low-grade inflammation, but these associations do not explain the relationship between work-related psychosocial factors and global cognitive function. A better understanding of the biological pathways, by which these factors affect cognitive function, could guide future preventive strategies to maintain cognitive function and promote healthy aging.}, }
@article {pmid36980987, year = {2023}, author = {Holesova, Z and Krasnicanova, L and Saade, R and Pös, O and Budis, J and Gazdarica, J and Repiska, V and Szemes, T}, title = {Telomere Length Changes in Cancer: Insights on Carcinogenesis and Potential for Non-Invasive Diagnostic Strategies.}, journal = {Genes}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/genes14030715}, pmid = {36980987}, issn = {2073-4425}, abstract = {Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes in telomere length may thus contribute to the development of various diseases including cancer. Understanding the role of telomeric DNA in carcinogenesis and detecting the presence of cell-free telomeric DNA (cf-telDNA) in body fluids offer a potential biomarker for novel cancer screening and diagnostic strategies. Liquid biopsy is becoming increasingly popular due to its undeniable benefits over conventional invasive methods. However, the organization and function of cf-telDNA in the extracellular milieu are understudied. This paper provides a review based on 3,398,017 cancer patients, patients with other conditions, and control individuals with the aim to shed more light on the inconsistent nature of telomere lengthening/shortening in oncological contexts. To gain a better understanding of biological factors (e.g., telomerase activation, alternative lengthening of telomeres) affecting telomere homeostasis across different types of cancer, we summarize mechanisms responsible for telomere length maintenance. In conclusion, we compare tissue- and liquid biopsy-based approaches in cancer assessment and provide a brief outlook on the methodology used for telomere length evaluation, highlighting the advances of state-of-the-art approaches in the field.}, }
@article {pmid36980962, year = {2023}, author = {da Mota, THA and Camargo, R and Biojone, ER and Guimarães, AFR and Pittella-Silva, F and de Oliveira, DM}, title = {The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia.}, journal = {Genes}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/genes14030691}, pmid = {36980962}, issn = {2073-4425}, abstract = {Telomeres and telomerase are closely linked to uncontrolled cellular proliferation, immortalization and carcinogenesis. Telomerase has been largely studied in the context of cancer, including leukemias. Deregulation of human telomerase gene hTERT is a well-established step in leukemia development. B-acute lymphoblastic leukemia (B-ALL) recovery rates exceed 90% in children; however, the relapse rate is around 20% among treated patients, and 10% of these are still incurable. This review highlights the biological and clinical relevance of telomerase for B-ALL and the implications of its canonical and non-canonical action on signaling pathways in the context of disease and treatment. The physiological role of telomerase in lymphocytes makes the study of its biomarker potential a great challenge. Nevertheless, many works have demonstrated that high telomerase activity or hTERT expression, as well as short telomeres, correlate with poor prognosis in B-ALL. Telomerase and related proteins have been proven to be promising pharmacological targets. Likewise, combined therapy with telomerase inhibitors may turn out to be an alternative strategy for B-ALL.}, }
@article {pmid36980890, year = {2023}, author = {Zeinoun, B and Teixeira, MT and Barascu, A}, title = {TERRA and Telomere Maintenance in the Yeast Saccharomyces cerevisiae.}, journal = {Genes}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/genes14030618}, pmid = {36980890}, issn = {2073-4425}, abstract = {Telomeres are structures made of DNA, proteins and RNA found at the ends of eukaryotic linear chromosomes. These dynamic nucleoprotein structures protect chromosomal tips from end-to-end fusions, degradation, activation of damage checkpoints and erroneous DNA repair events. Telomeres were thought to be transcriptionally silent regions because of their constitutive heterochromatin signature until telomeric long non-coding RNAs (LncRNAs) were discovered. One of them, TERRA (TElomeric Repeat-containing RNA), starts in the subtelomeric regions towards the chromosome ends from different telomeres and has been extensively studied in many evolutionarily distant eukaryotes. Changes in TERRA's expression can lead to telomeric dysfunction, interfere with the replicative machinery and impact telomere length. TERRA also co-localizes in vivo with telomerase, and can form RNA:DNA hybrid structures called R-loops, which have been implicated in the onset of senescence and the alternative lengthening of telomere (ALT) pathway. Yet, the molecular mechanisms involving TERRA, as well as its function, remain elusive. Here, we review the current knowledge of TERRA transcription, structure, expression, regulation and its multiple telomeric and extra-telomeric functions in the budding yeast Saccharomyces cerevisiae.}, }
@article {pmid36980881, year = {2023}, author = {Hill, C and Duffy, S and Coulter, T and Maxwell, AP and McKnight, AJ}, title = {Harnessing Genomic Analysis to Explore the Role of Telomeres in the Pathogenesis and Progression of Diabetic Kidney Disease.}, journal = {Genes}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/genes14030609}, pmid = {36980881}, issn = {2073-4425}, abstract = {The prevalence of diabetes is increasing globally, and this trend is predicted to continue for future decades. Research is needed to uncover new ways to manage diabetes and its co-morbidities. A significant secondary complication of diabetes is kidney disease, which can ultimately result in the need for renal replacement therapy, via dialysis or transplantation. Diabetic kidney disease presents a substantial burden to patients, their families and global healthcare services. This review highlights studies that have harnessed genomic, epigenomic and functional prediction tools to uncover novel genes and pathways associated with DKD that are useful for the identification of therapeutic targets or novel biomarkers for risk stratification. Telomere length regulation is a specific pathway gaining attention recently because of its association with DKD. Researchers are employing both observational and genetics-based studies to identify telomere-related genes associated with kidney function decline in diabetes. Studies have also uncovered novel functions for telomere-related genes beyond the immediate regulation of telomere length, such as transcriptional regulation and inflammation. This review summarises studies that have revealed the potential to harness therapeutics that modulate telomere length, or the associated epigenetic modifications, for the treatment of DKD, to potentially slow renal function decline and reduce the global burden of this disease.}, }
@article {pmid36979904, year = {2023}, author = {Caslini, C and Serna, A}, title = {Telomere Transcription in MLL-Rearranged Leukemia Cell Lines: Increased Levels of TERRA Associate with Lymphoid Lineage and Are Independent of Telomere Length and Ploidy.}, journal = {Biomedicines}, volume = {11}, number = {3}, pages = {}, doi = {10.3390/biomedicines11030925}, pmid = {36979904}, issn = {2227-9059}, abstract = {Telomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and the preservation of the (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL binds to telomeres and regulates TERRA transcription in telomere length homeostasis and response to telomere dysfunction. MLL fusion proteins (MLL-FPs), the product of MLL rearrangements in leukemia, also bind to telomeric chromatin. However, an effect on telomere transcription in MLL-rearranged (MLL-r) leukemia has not yet been evaluated. Here, we show increased UUAGGG repeat-containing RNA levels in MLL-r acute lymphoblastic leukemia (ALL) when compared to non-MLL-r ALL and myeloid leukemia. MLL rearrangements do not affect telomere length and UUAGGG repeat-containing RNA levels correlate with mean telomere length and reflect increased levels of TERRA. Furthermore, high levels of TERRA in MLL-r ALL occur in the presence of telomerase activity and are independent of ploidy, an underestimated source of variation on the overall transcriptome size in a cell. This MLL rearrangement-dependent and lymphoid lineage-associated increase in levels of TERRA supports a sustained telomere transcription by MLL-FPs that correlates with marked genomic stability previously reported in pediatric MLL-r ALL.}, }
@article {pmid36979709, year = {2023}, author = {Cuevas Diaz, P and Nicolini, H and Nolasco-Rosales, GA and Juarez Rojop, I and Tovilla-Zarate, CA and Rodriguez Sanchez, E and Genis-Mendoza, AD}, title = {Telomere Shortening in Three Diabetes Mellitus Types in a Mexican Sample.}, journal = {Biomedicines}, volume = {11}, number = {3}, pages = {}, doi = {10.3390/biomedicines11030730}, pmid = {36979709}, issn = {2227-9059}, abstract = {This study aimed to explore the role of telomere length in three different diabetes types: latent autoimmune diabetes of adulthood (LADA), latent autoimmune diabetes in the young (LADY), and type 2 diabetes mellitus (T2DM). A total of 115 patients were included, 72 (62.61%) had LADA, 30 (26.09%) had T2DM, and 13 (11.30%) had LADY. Telomere length was measured using real-time Polymerase Chain Reaction. For statistical analysis, we used the ANOVA test, X2 test, and the Mann-Whitney U test. Patients with T2DM had higher BMI compared to LADA and LADY groups, with a BMI average of 31.32 kg/m[2] (p = 0.0235). While the LADA group had more patients with comorbidities, there was not a statistically significant difference (p = 0.3164, p = 0.3315, p = 0.3742 for each of the previously mentioned conditions). There was a difference between those patients with T2DM who took metformin plus any other oral antidiabetic agent and those who took metformin plus insulin, the ones who had longer telomeres. LADA patients had shorter telomeres compared to T2DM patients but not LADY patients. Furthermore, T2DM may have longer telomeres thanks to the protective effects of both metformin and insulin, despite the higher BMI in this group.}, }
@article {pmid36979008, year = {2023}, author = {Ferk, F and Mišík, M and Ernst, B and Prager, G and Bichler, C and Mejri, D and Gerner, C and Bileck, A and Kundi, M and Langie, S and Holzmann, K and Knasmueller, S}, title = {Impact of Bariatric Surgery on the Stability of the Genetic Material, Oxidation, and Repair of DNA and Telomere Lengths.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, doi = {10.3390/antiox12030760}, pmid = {36979008}, issn = {2076-3921}, abstract = {Obesity causes genetic instability, which plays a key-role in the etiology of cancer and aging. We investigated the impact of bariatric surgery (BS) on DNA repair, oxidative DNA damage, telomere lengths, alterations of antioxidant enzymes and, selected proteins which reflect inflammation. The study was realized with BS patients (n = 35). DNA damage, base oxidation, BER, and NER were measured before and 1 month and 6 months after surgery with the single-cell gel electrophoresis technique. SOD and GPx were quantified spectrophotometrically, malondealdehyde (MDA) was quantified by HPLC. Telomere lengths were determined with qPCR, and plasma proteome profiling was performed with high-resolution mass spectrophotometry. Six months after the operations, reduction of body weight by 27.5% was observed. DNA damage decreased after this period, this effect was paralleled by reduced formation of oxidized DNA bases, a decline in the MDA levels and of BER and NER, and an increase in the telomere lengths. The activities of antioxidant enzymes were not altered. Clear downregulation of certain proteins (CRP, SAA1) which reflect inflammation and cancer risks was observed. Our findings show that BS causes reduced oxidative damage of DNA bases, possibly as a consequence of reduction of inflammation and lipid peroxidation, and indicate that the surgery has beneficial long-term health effects.}, }
@article {pmid36978826, year = {2023}, author = {Levstek, T and Trebušak Podkrajšek, K}, title = {Telomere Attrition in Chronic Kidney Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, doi = {10.3390/antiox12030579}, pmid = {36978826}, issn = {2076-3921}, abstract = {Telomeres are dynamic DNA nucleoprotein structures located at the end of chromosomes where they maintain genomic stability. Due to the end replication problem, telomeres shorten with each cell division. Critically short telomeres trigger cellular senescence, which contributes to various degenerative and age-related diseases, including chronic kidney diseases (CKDs). Additionally, other factors such as oxidative stress may also contribute to accelerated telomere shortening. Indeed, telomeres are highly susceptible to oxidative damage due to their high guanine content. Here, we provide a comprehensive review of studies examining telomere length (TL) in CKDs to highlight the association between TL and the development and progression of CKDs in humans. We then focus on studies investigating TL in patients receiving kidney replacement therapy. The mechanisms of the relationship between TL and CKD are not fully understood, but a shorter TL has been associated with decreased kidney function and the progression of nephropathy. Interestingly, telomere lengthening has been observed in some patients in longitudinal studies. Hemodialysis has been shown to accelerate telomere erosion, whereas the uremic milieu is not reversed even in kidney transplantation patients. Overall, this review aims to provide insights into the biological significance of telomere attrition in the pathophysiology of kidney disease, which may contribute to the development of new strategies for the management of patients with CKDs.}, }
@article {pmid36973214, year = {2023}, author = {Zhang, KJ and Zhang, ZH}, title = {[Progress in the study of alternative lengthening of telomeres and prognosis of pancreatic neuroendocrine tumors].}, journal = {Zhonghua bing li xue za zhi = Chinese journal of pathology}, volume = {52}, number = {4}, pages = {431-434}, doi = {10.3760/cma.j.cn112151-20220701-00570}, pmid = {36973214}, issn = {0529-5807}, }
@article {pmid36968845, year = {2023}, author = {Zhang, H and Kong, W and Xie, Y and Zhao, X and Luo, D and Chen, S and Pan, Z}, title = {Telomere-related genes as potential biomarkers to predict endometriosis and immune response: Development of a machine learning-based risk model.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1132676}, pmid = {36968845}, issn = {2296-858X}, abstract = {INTRODUCTION: Endometriosis (EM) is an aggressive, pleomorphic, and common gynecological disease. Its clinical presentation includes abnormal menstruation, dysmenorrhea, and infertility, which seriously affect the patient's quality of life. However, the pathogenesis underlying EM and associated regulatory genes are unknown.<br><br>METHODS: Telomere-related genes (TRGs) were uploaded from TelNet. RNA-sequencing (RNA-seq) data of EM patients were obtained from three datasets (GSE5108, GSE23339, and GSE25628) in the GEO database, and a random forest approach was used to identify telomere signature genes and build nomogram prediction models. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the pathways involved in the action of the signature genes. Finally, the CAMP database was used to screen drugs for potential use in EM treatment.<br><br>RESULTS: Fifteen total genes were screened as EM-telomere differentially expressed genes. Further screening by machine learning obtained six genes as characteristic predictive of EM. Immuno-infiltration analysis of the telomeric genes showed that expressions including macrophages and natural killer cells were significantly higher in cluster A. Further enrichment analysis showed that the differential genes were mainly enriched in biological pathways like cell cycle and extracellular matrix. Finally, the Connective Map database was used to screen 11 potential drugs for EM treatment.<br><br>DISCUSSION: TRGs play a crucial role in EM development, and are associated with immune infiltration and act on multiple pathways, including the cell cycle. Telomere signature genes can be valuable predictive markers for EM.}, }
@article {pmid36967999, year = {2023}, author = {Wan, B and Ma, N and Lv, C}, title = {Identifying effects of genetic obesity exposure on leukocyte telomere length using Mendelian randomization.}, journal = {PeerJ}, volume = {11}, number = {}, pages = {e15085}, pmid = {36967999}, issn = {2167-8359}, abstract = {BACKGROUND: Observational studies have shown that obesity is closely associated with leukocyte telomere length (LTL). However, the causal relationship between obesity and LTL remains unclear. This study investigated the causal relationship between obesity and LTL through the Mendelian randomization approach.<br><br>MATERIALS AND METHODS: The genome-wide association study (GWAS) summary data of several studies on obesity-related traits with a sample size of more than 600,000 individuals were extracted from the UK Biobank cohort. The summary-level data of LTL-related GWAS (45 6,717 individuals) was obtained from the IEU Open GWAS database. An inverse-variance-weighted (IVW) algorithm was utilized as the primary MR analysis method. Sensitivity analyses were conducted via MR-Egger regression, IVW regression, leave-one-out test, MR-pleiotropy residual sum, and outlier methods.<br><br>RESULTS: High body mass index was correlated with a short LTL, and the odds ratio (OR) was 0.957 (95% confidence interval [CI] 0.942-0.973, p = 1.17E-07). The six body fat indexes (whole body fat mass, right leg fat mass, left leg fat mass, right arm fat mass, left arm fat mass, and trunk fat mass) were consistently inversely associated with LTL. Multiple statistical sensitive analysis approaches showed that the adverse effect of obesity on LTL was steady and dependable.<br><br>CONCLUSION: The current study provided robust evidence supporting the causal assumption that genetically caused obesity is negatively associated with LTL. The findings may facilitate the formulation of persistent strategies for maintaining LTL.}, }
@article {pmid36966355, year = {2023}, author = {Wang, H and Ni, J and Guo, X and Xue, J and Wang, X}, title = {Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: A comparison of folic acid and 5-methyltetrahydrofolate.}, journal = {Mutagenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/mutage/gead007}, pmid = {36966355}, issn = {1464-3804}, abstract = {Telomere length (TL), which is maintained by hTERT (component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay.Results showed that abnormal TL elongation was observed in FA and 5-MeTHF deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA deficient condition but was significantly elongated under the 5-MeTHF deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.}, }
@article {pmid36960859, year = {2023}, author = {Maggio, J and Cardama, GA and Armando, RG and Balcone, L and Sobol, NT and Gomez, DE and Mengual Gómez, DL}, title = {Key role of PIN1 in telomere maintenance and oncogenic behavior in a human glioblastoma model.}, journal = {Oncology reports}, volume = {49}, number = {5}, pages = {}, doi = {10.3892/or.2023.8528}, pmid = {36960859}, issn = {1791-2431}, abstract = {PIN1 is the only known enzyme capable of recognizing and isomerizing the phosphorylated Serine/Threonine‑Proline motif. Through this mechanism, PIN1 controls diverse cellular functions, including telomere maintenance. Both PIN1 overexpression and its involvement in oncogenic pathways are involved in several cancer types, including glioblastoma (GBM), a lethal disease with poor therapeutic resources. However, knowledge of the role of PIN1 in GBM is limited. Thus, the present work aimed to study the role of PIN1 as a telomere/telomerase regulator and its contribution to tumor biology. PIN1 knockout (KO) LN‑229 cell variant using CRISPR/Cas9 was developed and compared with PIN1 LN‑229 expressing cells. To study the effect of PIN1 absence, status of NF‑κB pathway was evaluated by luciferase reporter gene assay and quantitative PCR. Results revealed that PIN1 deletion in GBM cells diminished the active levels of NF‑κB and decrease the transcription of il‑8 and htert genes. Then, telomere/telomerase related processes were studied by RQ‑TRAP assay and telomere length determination by qPCR, obtaining a reduction both in telomerase activity as in telomere length in PIN1 KO cells. In addition, measurement of SA β‑galactosidase and caspase‑3 activities revealed that loss of PIN1 triggers senescence and apoptosis. Finally, migration, cell cycle progression and tumorigenicity were studied by flow cytometry/western blot, Transwell assay and in vivo experiments, respectively. PIN1 deletion decreased migration as well as cell cycle progression by increasing doubling time and also resulted in the loss of LN‑229 cell ability to form tumors in mice. These results highlight the role of PIN1 in telomere homeostasis and GBM progression, which supports PIN1 as a potential molecular target for the development of novel therapeutic agents for GBM treatment.}, }
@article {pmid36959362, year = {2023}, author = {Mannherz, W and Agarwal, S}, title = {Thymidine nucleotide metabolism controls human telomere length.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {36959362}, issn = {1546-1718}, abstract = {Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR-Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR-Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.}, }
@article {pmid36949104, year = {2023}, author = {Meesters, M and Van Eetvelde, M and Martens, DS and Nawrot, TS and Dewulf, M and Govaere, J and Opsomer, G}, title = {Prenatal environment impacts telomere length in newborn dairy heifers.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {4672}, pmid = {36949104}, issn = {2045-2322}, abstract = {Telomere length is associated with longevity and survival in multiple species. In human population-based studies, multiple prenatal factors have been described to be associated with a newborn's telomere length. In the present study, we measured relative leukocyte telomere length in 210 Holstein Friesian heifers, within the first ten days of life. The dam's age, parity, and milk production parameters, as well as environmental factors during gestation were assessed for their potential effect on telomere length. We found that for both primi- and multiparous dams, the telomere length was 1.16% shorter for each day increase in the calf's age at sampling (P = 0.017). The dam's age at parturition (P = 0.045), and the median temperature-humidity index (THI) during the third trimester of gestation (P = 0.006) were also negatively associated with the calves' TL. Investigating multiparous dams separately, only the calf's age at sampling was significantly and negatively associated with the calves' TL (P = 0.025). Results of the present study support the hypothesis that in cattle, early life telomere length is influenced by prenatal factors. Furthermore, the results suggest that selecting heifers born in winter out of young dams might contribute to increased longevity in dairy cattle.}, }
@article {pmid36947528, year = {2023}, author = {Topiwala, A and Nichols, TE and Williams, LZJ and Robinson, EC and Alfaro-Almagro, F and Taschler, B and Wang, C and Nelson, CP and Miller, KL and Codd, V and Samani, NJ and Smith, SM}, title = {Telomere length and brain imaging phenotypes in UK Biobank.}, journal = {PloS one}, volume = {18}, number = {3}, pages = {e0282363}, doi = {10.1371/journal.pone.0282363}, pmid = {36947528}, issn = {1932-6203}, abstract = {Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91-0.96), but not stroke or Parkinson's disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.}, }
@article {pmid36946056, year = {2023}, author = {Zhou, Z and Lo, CKM and Chan, KL and Chung, RSY and Pell, JP and Minnis, H and Shiels, PG and Ip, P and Ho, FK}, title = {Child maltreatment and telomere length in middle and older age: retrospective cohort study of 141 748 UK Biobank participants.}, journal = {The British journal of psychiatry : the journal of mental science}, volume = {}, number = {}, pages = {1-5}, doi = {10.1192/bjp.2023.33}, pmid = {36946056}, issn = {1472-1465}, abstract = {BACKGROUND: There is evidence that child maltreatment is associated with shorter telomere length in early life.<br><br>AIMS: This study aims to examine if child maltreatment is associated with telomere length in middle- and older-age adults.<br><br>METHOD: This was a retrospective cohort study of 141 748 UK Biobank participants aged 37-73 years at recruitment. Leukocyte telomere length was measured with quantitative polymerase chain reaction, and log-transformed and scaled to have unit standard deviation. Child maltreatment was recalled by participants. Linear regression was used to analyse the association.<br><br>RESULTS: After adjusting for sociodemographic characteristics, participants with three or more types of maltreatment presented with the shortest telomere lengths (&#x3b2; = -0.05, 95% CI -0.07 to -0.03; P < 0.0001), followed by those with two types of maltreatment (&#x3b2; = -0.02, 95% CI -0.04 to 0.00; P = 0.02), referent to those who had none. When adjusted for depression and post-traumatic stress disorder, the telomere lengths of participants with three or more types of maltreatment were still shorter (&#x3b2; = -0.04, 95% CI -0.07 to -0.02; P = 0.0008). The telomere lengths of those with one type of maltreatment were not significantly different from those who had none. When mutually adjusted, physical abuse (&#x3b2; = -0.05, 95% CI -0.07 to -0.03; P < 0.0001) and sexual abuse (&#x3b2; = -0.02, 95% CI -0.04 to 0.00; P = 0.02) were independently associated with shorter telomere length.<br><br>CONCLUSIONS: Our findings showed that child maltreatment is associated with shorter telomere length in middle- and older-aged adults, independent of sociodemographic and mental health factors.}, }
@article {pmid36944821, year = {2023}, author = {Herrera-Moreno, JF and Prada, D and Baccarelli, AA}, title = {Early Environment and Telomeres: a Long-Term Toxic Relationship.}, journal = {Current environmental health reports}, volume = {}, number = {}, pages = {}, pmid = {36944821}, issn = {2196-5412}, abstract = {PURPOSE OF REVIEW: Telomere length (TL) shortening is a hallmark of biological aging. While studies have extensively focused on the impact of environmental exposures on TL in older populations, consistent evidence indicates that prenatal environmental exposures to air pollutants, polycyclic aromatic hydrocarbons, metals, and endocrine-disrupting chemicals influence TL shortening. Here, we summarize evidence linking prenatal environmental exposures with children's TL and discuss potential long-term effects.<br><br>RECENT FINDINGS: Current evidence shows that prenatal environmental exposures alter TL and identify pregnancy as a critical window of susceptibility for telomere damage in children. However, results vary across studies, possibly depending on the source, exposure time window, and stage evaluated. Additional research is needed to investigate whether early TL alterations mediate long-term health effects of offspring. Prenatal environmental exposures induce early childhood changes in TL. Based on known links between TL and biological aging, these alterations may have long-term impact on individuals' health throughout life.}, }
@article {pmid36943406, year = {2022}, author = {Connor, A and Starnino, L and Busque, L and Tardif, JC and Bourgoin, V and Dubé, MP and Busseuil, D and D'Antono, B}, title = {Childhood maltreatment and leukocyte telomere length in men and women with chronic illness: an evaluation of moderating and mediating influences.}, journal = {Psychological medicine}, volume = {}, number = {}, pages = {1-11}, doi = {10.1017/S0033291722003543}, pmid = {36943406}, issn = {1469-8978}, abstract = {BACKGROUND: Childhood maltreatment can result in lifelong psychological and physical sequelae, including coronary artery disease (CAD). Mechanisms leading to increased risk of illness may involve emotional dysregulation and shortened leukocyte telomere length (LTL).<br><br>METHODS: To evaluate whether (1) childhood maltreatment is associated with shorter LTL among older adults with CAD or other chronic illnesses; (2) sex and/or CAD status influence these results; and (3) symptoms of anxiety, depression, and stress moderate or mediate the association between childhood maltreatment and LTL, men and women (N = 1247; aged 65 &#xb1; 7.2 years) with and without CAD completed validated questionnaires on childhood maltreatment, symptoms of depression, anxiety, and perceived stress. LTL was measured using quantitative polymerase chain reaction. Analyses included bivariate correlations, hierarchical regressions, and moderation/mediation analyses, controlling for sociodemographic and lifestyle variables.<br><br>RESULTS: Childhood maltreatment was associated with significantly shorter LTL (r = -0.059, p = 0.038, b = -0.016, p = 0.005). This relation was not moderated by depression, anxiety, nor perceived stress, though there was mitigated evidence for absence of a maltreatment-LTL relation in men with CAD. Stress perception (but not anxiety or depression) partially mediated the relation between childhood maltreatment and LTL [Indirect effect, b = -0.0041, s.e. = 0.002, 95% CI (-0.0085 to -0.0002)].<br><br>CONCLUSIONS: Childhood maltreatment was associated with accelerated biological aging independently of patient characteristics. Emotional dysregulation resulting in chronic stress may contribute to this process. Whether stress management or other interventions may help prevent or slow premature aging in those who have suffered maltreatment requires study.}, }
@article {pmid36943300, year = {2023}, author = {Wang, B and Shi, X and Gao, J and Liao, R and Fu, J and Bai, J and Cui, H}, title = {SCARECROW maintains the stem cell niche in Arabidopsis roots by ensuring telomere integrity.}, journal = {Plant physiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/plphys/kiad181}, pmid = {36943300}, issn = {1532-2548}, abstract = {Stem cells are the ultimate source of cells for various tissues and organs, and thus are essential for postembryonic plant growth and development. SCARECROW (SCR) is a plant-specific transcription regulator well known for its role in stem-cell renewal in plant roots, but the mechanism by which SCR exerts this function remains unclear. To address this question, we carried out a genetic screen for mutants that no longer express SCR in the stem-cell niche of Arabidopsis (Arabidopsis thaliana) roots and characterized one of these mutants. Molecular genetics methods allowed us to pinpoint the causal mutation in this mutant in TELOMERIC PATHWAYS IN ASSOCIATION WITH STN 1 (TEN1), encoding a factor that protects telomere ends. Interestingly, TEN1 expression was dramatically reduced in the scr mutant. Telomerase, as well as STN1 and CONSERVED TELOMERE MAINTENANCE COMPONENT 1 (CTC1), components of the same protein complex as TEN1, were also dramatically downregulated in scr. Loss of STN1, CTC1, and telomerase caused defects in root stem cells. These results together suggest that SCR maintains root stem cells by promoting expression of genes that ensure genome integrity. Supporting this conclusion, we demonstrated that the scr mutant accumulates more DNA damage than wild-type Arabidopsis and that this problem is aggravated after exposure to zeocin, a DNA damage reagent. Finally, we identified two previously uncharacterized motifs in TEN1 and provide evidence that a conserved amino acid residue in one of the motifs is indispensable for TEN1 function. SCR thus provides a connection between genome integrity and stem-cell maintenance in Arabidopsis roots.}, }
@article {pmid36940725, year = {2023}, author = {Rose, AM and Goncalves, T and Cunniffe, S and Geiller, HEB and Kent, T and Shepherd, S and Ratnaweera, M and O'Sullivan, RJ and Gibbons, RJ and Clynes, D}, title = {Induction of the alternative lengthening of telomeres pathway by trapping of proteins on DNA.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkad150}, pmid = {36940725}, issn = {1362-4962}, support = {/AMS_/Academy of Medical Sciences/United Kingdom ; }, abstract = {Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this is achieved through the alternative lengthening of telomeres (ALT) pathway. Whilst loss of ATRX is a near universal feature of ALT-cancers, it is insufficient in isolation. As such, other cellular events must be necessary - but the exact nature of the secondary events has remained elusive. Here, we report that trapping of proteins (such as TOP1, TOP2A and PARP1) on DNA leads to ALT induction in cells lacking ATRX. We demonstrate that protein-trapping chemotherapeutic agents, such as etoposide, camptothecin and talazoparib, induce ALT markers specifically in ATRX-null cells. Further, we show that treatment with G4-stabilising drugs cause an increase in trapped TOP2A levels which leads to ALT induction in ATRX-null cells. This process is MUS81-endonuclease and break-induced replication dependent, suggesting that protein trapping leads to replication fork stalling, with these forks being aberrantly processed in the absence of ATRX. Finally, we show ALT-positive cells harbour a higher load of genome-wide trapped proteins, such as TOP1, and knockdown of TOP1 reduced ALT activity. Taken together, these findings suggest that protein trapping is a fundamental driving force behind ALT-biology in ATRX-deficient malignancies.}, }
@article {pmid36934410, year = {2023}, author = {D'Aronco, G and Ferraro, P and Sassano, V and Dagostino, C and Biancotto, M and Palumbo, E and Presot, E and Russo, A and Bianchi, V and Rampazzo, C}, title = {SAMHD1 restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase-positive cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {37}, number = {4}, pages = {e22883}, doi = {10.1096/fj.202300122R}, pmid = {36934410}, issn = {1530-6860}, abstract = {SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain-containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular dNTP pools, which support genome integrity. In SAMHD1 deficient fibroblasts isolated from Aicardi-Goutières Syndrome (AGS) patients, all four DNA precursors are increased and markedly imbalanced with the largest effect on dGTP, a key player in the modulation of telomerase processivity. Here, we present data showing that SAMHD1, by restricting the dGTP pool, contributes to telomere maintenance in hTERT-immortalized human fibroblasts from AGS patients as well as in telomerase positive cancer cell lines. Only in cells expressing telomerase, the lack of SAMHD1 causes excessive lengthening of telomeres and telomere fragility, whereas primary fibroblasts lacking both SAMHD1 and telomerase enter normally into senescence. Telomere lengthening observed in SAMHD1 deficient but telomerase proficient cells is a gradual process, in accordance with the intrinsic property of telomerase of adding only a few tens of nucleotides for each cycle. Therefore, only a prolonged exposure to high dGTP content causes telomere over-elongation. hTERT-immortalized AGS fibroblasts display also high fragility of chromosome ends, a marker of telomere replication stress. These results not only demonstrate the functional importance of dGTP cellular level but also reveal the critical role played by SAMHD1 in restraining telomerase processivity and safeguarding telomere stability.}, }
@article {pmid36933050, year = {2023}, author = {Brown, JC and Sturgeon, K and Sarwer, DB and Troxel, AB and DeMichele, AM and Denlinger, CS and Schmitz, KH}, title = {The effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {36933050}, issn = {1573-7217}, abstract = {PURPOSE: Cancer and its treatments accelerate biological aging. This analysis tested the hypothesis that exercise and diet reduce oxidative stress and prevent telomere shortening in breast cancer survivors.<br><br>METHODS: In a 2&#xa0;&#xd7;&#xa0;2 factorial design, 342 breast cancer survivors who were insufficiently physically active and had overweight or obesity at enrollment were randomized to one of four treatment groups for 52&#xa0;weeks: control, exercise alone, diet alone, or exercise plus diet. The endpoints of this analysis were the change from baseline to week 52 in 8-iso-prostaglandin F2&#x3b1; (8-iso-PGF2&#x3b1;) and lymphocyte telomere length.<br><br>RESULTS: Baseline telomere length was shorter than age-adjusted normative values (median difference:&#x2009;-&#x2009;1.8 kilobases; 95% CI&#x2009;-&#x2009;2.4,&#x2009;-&#x2009;1.1); equivalent to 21&#xa0;years (95% CI 17, 25) of accelerated chronological aging. Compared to control, exercise alone did not change 8-iso-PGF2&#x3b1; [9.9%; 95% confidence interval (CI)&#x2009;-&#x2009;1.0, 20.8] or telomere length (13.8%; 95% CI&#x2009;-&#x2009;15.6, 43.3). Compared to control, diet alone was associated with reduced 8-iso-PGF2&#x3b1; (-&#x2009;10.5%; 95% CI&#x2009;-&#x2009;19.5,&#x2009;-&#x2009;1.5) but did not change telomere length (12.1%; 95% CI&#xa0;-&#x2009;17.2, 41.3). Compared to control, exercise plus diet was associated with reduced 8-iso-PGF2&#x3b1; (-&#x2009;9.8%; 95% CI&#x2009;-&#x2009;18.7,&#x2009;-&#x2009;0.9) but did not change telomere length (-&#x2009;8.5%; 95% CI&#x2009;-&#x2009;32.1, 15.2). Change in 8-iso-PGF2&#x3b1; did not correlate with change in telomere length (r&#x2009;=&#x2009;0.07; 95% CI&#x2009;-&#x2009;0.07, 0.20).<br><br>CONCLUSION: In breast cancer survivors, diet alone or exercise plus diet were associated with reduced oxidative stress but did not change telomere length. This analysis may inform future trials that aim to optimize healthy aging in cancer survivors.}, }
@article {pmid36933034, year = {2023}, author = {Meng, Q and Shao, B and Zhao, D and Fu, X and Wang, J and Li, H and Zhou, Q and Gao, T}, title = {Loss of SUN1 function in spermatocytes disrupts the attachment of telomeres to the nuclear envelope and contributes to non-obstructive azoospermia in humans.}, journal = {Human genetics}, volume = {}, number = {}, pages = {}, pmid = {36933034}, issn = {1432-1203}, abstract = {One of the most severe forms of infertility in humans, caused by gametogenic failure, is non-obstructive azoospermia (NOA). Approximately, 20-30% of men with NOA may have single-gene mutations or other genetic variables that cause this disease. While a range of single-gene mutations associated with infertility has been identified in prior whole-exome sequencing (WES) studies, current insight into the precise genetic etiology of impaired human gametogenesis remains limited. In this paper, we described a proband with NOA who experienced hereditary infertility. WES analyses identified a homozygous variant in the SUN1 (Sad1 and UNC84 domain containing 1) gene [c. 663C > A: p.Tyr221X] that segregated with infertility. SUN1 encodes a LINC complex component essential for telomeric attachment and chromosomal movement. Spermatocytes with the observed mutations were incapable of repairing double-strand DNA breaks or undergoing meiosis. This loss of SUN1 functionality contributes to significant reductions in KASH5 levels within impaired chromosomal telomere attachment to the inner nuclear membrane. Overall, our results identify a potential genetic driver of NOA pathogenesis and provide fresh insight into the role of the SUN1 protein as a regulator of prophase I progression in the context of human meiosis.}, }
@article {pmid36932659, year = {2023}, author = {Wang, H and Ni, J and Guo, X and Xue, J and Wang, X}, title = {Effects of folate on telomere length and chromosome stability of human fibroblasts and melanoma cells in vitro: A comparison of folic acid and 5-methyltetrahydrofolate.}, journal = {Mutagenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/mutage/gead004}, pmid = {36932659}, issn = {1464-3804}, abstract = {Telomere length (TL), which is maintained by hTERT (component of telomerase) and/or TRF1/TRF2 (core components of shelterin) via different mechanisms, is essential for chromosomal stability and cell survival. Folates comprise a group of essential B9 vitamin that involve in DNA synthesis and methylation. This study aimed to evaluate the effects of folic acid (FA) and 5-methyltetrahydrofolate (5-MeTHF) on TL, chromosome stability, and cell survival of telomerase-negative BJ and telomerase-positive A375 cells in vitro. BJ and A375 cells were cultured in modified medium with FA or 5-MeTHF (22.6 or 2260 nM) for 28 days. TL and mRNA expression were determined by RT-qPCR. Chromosome instability (CIN) and cell death were measured by CBMN-Cyt assay.Results showed that abnormal TL elongation was observed in FA and 5-MeTHF deficient BJ cells. The TL of A375 cells showed no obvious alterations under the FA deficient condition but was significantly elongated under the 5-MeTHF deficient condition. In both BJ and A375 cells, FA and 5-MeTHF deficiency caused decreased TRF1, TRF2, and hTERT expression, increased CIN and cell death; while a high concentration of 5-MeTHF induced elongated TL, elevated CIN, increased TRF1 and TRF2 expression and decreased hTERT expression, when compared with the FA counterpart. These findings concluded that folate deficiency induced TL instability in both telomerase-negative and positive cells, and FA was more efficient in maintaining TL and chromosome stability compared with 5-MeTHF.}, }
@article {pmid36932145, year = {2023}, author = {Adegunsoye, A and Newton, CA and Oldham, JM and Ley, B and Lee, CT and Linderholm, AL and Chung, JH and Garcia, N and Zhang, D and Vij, R and Guzy, R and Jablonski, R and Bag, R and Voogt, RS and Ma, SF and Sperling, AI and Raghu, G and Martinez, FJ and Strek, ME and Wolters, PJ and Garcia, CK and Pierce, BL and Noth, I}, title = {Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {1489}, pmid = {36932145}, issn = {2041-1723}, abstract = {Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran-Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = -0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79-2.72; Black, HR = 2.22, 95% CI = 1.05-4.66; Hispanic, HR = 3.40, 95% CI = 1.88-6.14; and Asian, HR = 2.11, 95% CI = 0.55-8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.}, }
@article {pmid36922555, year = {2023}, author = {Pepke, ML and Kvalnes, T and Wright, J and Araya-Ajoy, YG and Ranke, PS and Boner, W and Monaghan, P and Sæther, BE and Jensen, H and Ringsby, TH}, title = {Longitudinal telomere dynamics within natural lifespans of a wild bird.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {4272}, pmid = {36922555}, issn = {2045-2322}, abstract = {Telomeres, the nucleotide sequences that protect the ends of eukaryotic chromosomes, shorten with each cell division and telomere loss may be influenced by environmental factors. Telomere length (TL) decreases with age in several species, but little is known about the sources of genetic and environmental variation in the change in TL (∆TL) in wild animals. In this study, we tracked changes in TL throughout the natural lifespan (from a few months to almost 9 years) of free-living house sparrows (Passer domesticus) in two different island populations. TL was measured in nestlings and subsequently up to four times during their lifetime. TL generally decreased with age (senescence), but we also observed instances of telomere lengthening within individuals. We found some evidence for selective disappearance of individuals with shorter telomeres through life. Early-life TL positively predicted later-life TL, but the within-individual repeatability in TL was low (9.2%). Using genetic pedigrees, we found a moderate heritability of ∆TL (h[2] = 0.21), which was higher than the heritabilities of early-life TL (h[2] = 0.14) and later-life TL measurements (h[2] = 0.15). Cohort effects explained considerable proportions of variation in early-life TL (60%), later-life TL (53%), and ∆TL (37%), which suggests persistent impacts of the early-life environment on lifelong telomere dynamics. Individual changes in TL were independent of early-life TL. Finally, there was weak evidence for population differences in ∆TL that may be linked to ecological differences in habitat types. Combined, our results show that individual telomere biology is highly dynamic and influenced by both genetic and environmental variation in natural conditions.}, }
@article {pmid36911306, year = {2023}, author = {Wolf, SE and Zhang, S and Clotfelter, ED}, title = {Experimental ectoparasite removal has a sex-specific effect on nestling telomere length.}, journal = {Ecology and evolution}, volume = {13}, number = {3}, pages = {e9861}, pmid = {36911306}, issn = {2045-7758}, abstract = {Parasites are a strong selective force that can influence fitness-related traits. The length of chromosome-capping telomeres can be used to assess the long-term costs of parasitism, as telomere loss accelerates in response to environmental stressors and often precedes poorer survival prospects. Here, we explored the sex-specific effects of ectoparasite removal on morphology and telomere length in nestling tree swallows (Tachycineta bicolor). To do so, we experimentally removed blow fly (Protocalliphora spp.) larvae from nests using Permethrin, a broad-spectrum insecticide. Compared to water-treated controls, insecticide treatment of nests had a sex-biased effect on blood telomere length: ectoparasite removal resulted in significantly longer telomeres in males but not females. While this treatment did not influence nestling body mass, it was associated with reduced feather development regardless of sex. This may reflect a relaxed pressure to fledge quickly in the absence of parasites, or alternatively, could be a negative side effect of permethrin on morphology. Exploring robust sex-specific telomere dynamics in response to early-life environmental pressures such as parasitism will shed light on sexual dimorphism in adult life histories and aging.}, }
@article {pmid36910209, year = {2023}, author = {Liu, J and Zhao, S and Li, Z and Zhang, Z and Zhao, B and Guan, G and Yin, H and Luo, J}, title = {Activation of telomerase activity and telomere elongation of host cells by Theileria annulata infection.}, journal = {Frontiers in microbiology}, volume = {14}, number = {}, pages = {1128433}, pmid = {36910209}, issn = {1664-302X}, abstract = {Theileria annulata-transformed cells share many phenotypes with cancer cells, including uncontrolled proliferation, immortalization, and dissemination. Telomeres are DNA-protein complex at the end of eukaryotic chromosomes that function to maintain genome stability and cell replicative capacity. Telomere length maintenance is primarily dependent on telomerase activity. In up to 90% of human cancer cells, telomerase is reactivated through expression of its catalytic subunit TERT. However, the effect of T. annulata infection on telomere and telomerase activity in bovine cells has not yet been described. In the present study, we confirmed that telomere length and telomerase activity are upregulated after T. annulata infection in three types of cell lines. This change depends on the presence of parasites. After eliminating Theileria from cells with antitheilerial drug buparvaquone, telomerase activity and the expression level of bTERT were decreased. In addition, inhibition of bHSP90 by novobiocin led to decreased AKT phosphorylation levels and telomerase activity, indicating that the bHSP90-AKT complex is a potent factor modulates telomerase activity in T. annulata-infected cells.}, }
@article {pmid36902458, year = {2023}, author = {Shepelev, N and Dontsova, O and Rubtsova, M}, title = {Post-Transcriptional and Post-Translational Modifications in Telomerase Biogenesis and Recruitment to Telomeres.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, doi = {10.3390/ijms24055027}, pmid = {36902458}, issn = {1422-0067}, abstract = {Telomere length is associated with the proliferative potential of cells. Telomerase is an enzyme that elongates telomeres throughout the entire lifespan of an organism in stem cells, germ cells, and cells of constantly renewed tissues. It is activated during cellular division, including regeneration and immune responses. The biogenesis of telomerase components and their assembly and functional localization to the telomere is a complex system regulated at multiple levels, where each step must be tuned to the cellular requirements. Any defect in the function or localization of the components of the telomerase biogenesis and functional system will affect the maintenance of telomere length, which is critical to the processes of regeneration, immune response, embryonic development, and cancer progression. An understanding of the regulatory mechanisms of telomerase biogenesis and activity is necessary for the development of approaches toward manipulating telomerase to influence these processes. The present review focuses on the molecular mechanisms involved in the major steps of telomerase regulation and the role of post-transcriptional and post-translational modifications in telomerase biogenesis and function in yeast and vertebrates.}, }
@article {pmid36894693, year = {2023}, author = {Spegg, V and Panagopoulos, A and Stout, M and Krishnan, A and Reginato, G and Imhof, R and Roschitzki, B and Cejka, P and Altmeyer, M}, title = {Phase separation properties of RPA combine high-affinity ssDNA binding with dynamic condensate functions at telomeres.}, journal = {Nature structural &amp; molecular biology}, volume = {}, number = {}, pages = {}, pmid = {36894693}, issn = {1545-9985}, abstract = {RPA has been shown to protect single-stranded DNA (ssDNA) intermediates from instability and breakage. RPA binds ssDNA with sub-nanomolar affinity, yet dynamic turnover is required for downstream ssDNA transactions. How ultrahigh-affinity binding and dynamic turnover are achieved simultaneously is not well understood. Here we reveal that RPA has a strong propensity to assemble into dynamic condensates. In solution, purified RPA phase separates into liquid droplets with fusion and surface wetting behavior. Phase separation is stimulated by sub-stoichiometric amounts of ssDNA, but not RNA or double-stranded DNA, and ssDNA gets selectively enriched in RPA condensates. We find the RPA2 subunit required for condensation and multi-site phosphorylation of the RPA2 N-terminal intrinsically disordered region to regulate RPA self-interaction. Functionally, quantitative proximity proteomics links RPA condensation to telomere clustering and integrity in cancer cells. Collectively, our results suggest that RPA-coated ssDNA is contained in dynamic RPA condensates whose properties are important for genome organization and stability.}, }
@article {pmid36890798, year = {2023}, author = {Moustakli, E and Zikopoulos, A and Sakaloglou, P and Bouba, I and Sofikitis, N and Georgiou, I}, title = {Functional association between telomeres, oxidation and mitochondria.}, journal = {Frontiers in reproductive health}, volume = {5}, number = {}, pages = {1107215}, pmid = {36890798}, issn = {2673-3153}, abstract = {Prior research has substantiated the vital role of telomeres in human fertility. Telomeres are prerequisites for maintaining the integrity of chromosomes by preventing the loss of genetic material following replication events. Little is known about the association between sperm telomere length and mitochondrial capacity involving its structure and functions. Mitochondria are structurally and functionally distinct organelles that are located on the spermatozoon's midpiece. Mitochondria produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), which is necessary for sperm motility and generate reactive oxygen species (ROS). While a moderate concentration of ROS is critical for egg-sperm fusion, and fertilization, excessive ROS generation is primarily related to telomere shortening, sperm DNA fragmentation, and alterations in the methylation pattern leading to male infertility. This review aims to highlight the functional connection between mitochondria biogenesis and telomere length in male infertility, as mitochondrial lesions have a damaging impact on telomere length, leading both to telomere lengthening and reprogramming of mitochondrial biosynthesis. Furthermore, it aims to shed light on how both inositol and antioxidants can positively affect male fertility.}, }
@article {pmid36890680, year = {2023}, author = {Chen, Z and Shen, Y and He, J and Shen, Y and Zhu, W and Wu, X and Xiao, M}, title = {Longer leukocyte telomere length increases cardiovascular mortality in type 2 diabetes patients.}, journal = {Journal of diabetes}, volume = {}, number = {}, pages = {}, doi = {10.1111/1753-0407.13376}, pmid = {36890680}, issn = {1753-0407}, abstract = {AIMS: Leukocyte telomere length (LTL), as a biomarker of biological aging, is associated with the prevalence and complications of diabetes. This study aims to investigate the associations between LTL and all-cause and cause-specific mortality in patients with type 2 diabetes.<br><br>METHODS: All participants with baseline LTL records were included from the National Health and Nutrition Examination Survey 1999-2002. Death status and its causes were ascertained for National Death Index based on International Classification of Diseases, Tenth Revision code. Cox proportional hazards regression models were established to estimate the hazard ratios (HRs) of LTL associating with all-cause and cause-specific mortality.<br><br>RESULTS: The study enrolled 804 diabetic patients with the mean follow-up of 14.9&#x2009;&#xb1;&#x2009;2.59&#x2009;years. There were 367 (45.6%) all-cause deaths, 80 (10.0%) cardiovascular deaths, and 42 (5.2%) cancer-related deaths. Longer LTL was associated with reduced all-cause mortality, whereas this association disappeared after adjusting for other variables. Compared with the lowest tertiles of LTL, the multivariable-adjusted hazard ratio of cardiovascular mortality was 2.11 (95% confidence interval [CI] 1.31-3.39; p&#x2009;<&#x2009;.05) in the highest tertiles. In terms of cancer mortality, the highest tertile was negatively correlated with the risk of cancer mortality (HR 0.58 [95% CI 0.37, 0.91], p&#x2009;<&#x2009;.05).<br><br>CONCLUSION: In conclusion, LTL was independently associated with the risk of cardiovascular mortality in patients with type 2 diabetes and was negatively correlated with the risk of cancer mortality. Telomere length may be a predictor of cardiovascular mortality in diabetes.}, }
@article {pmid36883676, year = {2023}, author = {Becher, OJ}, title = {A new path to alternative lengthening of telomeres?.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noad054}, pmid = {36883676}, issn = {1523-5866}, }
@article {pmid36880214, year = {2023}, author = {Yang, C and Wu, X and Chen, S and Xiang, B}, title = {Association between telomere length and hepatocellular carcinoma risk: A Mendelian randomization study.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.5702}, pmid = {36880214}, issn = {2045-7634}, abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer threatening the public health globally. Although HCC has been associated with the telomere length (TL), the causal relationship between them is not well understood. Therefore, we attempted to explore the linear causal relationship between TL and HCC through Mendelian randomization (MR) analysis among Asian and European populations.<br><br>METHODS: The summary statistics of TL-associated single nucleotide polymorphisms (SNPs) were obtained from a genome-wide association study (GWAS) in the Asian population (N = 23,096). The data of TL-associated SNPs in the European population (N&#xa0;=&#xa0;472,174) and the GWAS summary statistics of HCC in the Asian population (1866 cases, 195,745 controls) as well as the European population (168 cases, 372,016 controls) were downloaded from the public GWAS database. Two-sample MR was performed using inverse variance weighting (IVW), weighted median estimate, MR-Egger regression, weighted-mode estimate, and simple-mode estimate methods. Sensitivity analysis was performed to text the primary results' robustness.<br><br>RESULTS: Nine SNPs associated with TL in Asian populations and 98 SNPs in European populations were selected as instrumental variables. No linear causal relationship between heritable TL and the HCC risk was recorded in the Asian (IVW analysis odds ratio [OR]&#xa0;=&#xa0;1.023, 95% confidence interval [CI] 0.745, 1.405, p&#xa0;=&#xa0;0.887) and European populations (IVW analysis OR&#xa0;=&#xa0;0.487, 95% CI 0.180, 1.320, p&#xa0;=&#xa0;0.157). Other methods also achieved similar outcomes. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy.<br><br>CONCLUSIONS: No linear causal association was recorded between heritable TL and HCC in Asian and European populations.}, }
@article {pmid36879937, year = {2023}, author = {Kumari, R and Suneja, A and Mehndiratta, M and Guleria, K and Malik, R}, title = {Maternal Serum Vitamin E Levels and its Association with Cord Blood Telomere Length and Mitochondrial DNA Copy Number in Preterm Premature Rupture of Membranes.}, journal = {Journal of obstetrics and gynaecology of India}, volume = {73}, number = {1}, pages = {9-14}, pmid = {36879937}, issn = {0971-9202}, abstract = {BACKGROUND AND OBJECTIVE: Oxidative stress is one of the pathophysiological factors of pPROM and Vit. E being antioxidant may have preventive role. Study was conducted to estimate maternal serum vitamin E levels and cord blood oxidative stress markers in pPROM cases.<br><br>METHODS: This was a case-control study including 40 pPROM cases and 40 controls. Maternal serum vitamin E levels were measured at recruitment. Cord blood was collected at delivery for estimation of telomere length and mtDNA copy number as oxidative stress markers. Levels were compared using student's t test or Mann Whitney test. For correlation Pearson coefficient was used.<br><br>RESULTS: Maternal serum vitamin E levels were normal in pPROM cases. Cord blood telomere length was more in pPROM than controls (428.99&#x2009;&#xb1;&#x2009;290.65 vs 322.35&#x2009;&#xb1;&#x2009;180.33) (p value 0.05). Cord blood mtDNA copy number was more in pPROM than controls (516.46&#x2009;&#xb1;&#x2009;443.55 vs 384.77&#x2009;&#xb1;&#x2009;328.27) (p value 0.13) though it was not significant. mtDNA copy number had negative correlation with Vit. E levels but it was statistically not significant (p value 0.49). There was no association of vitamin E levels with telomere length (p value 0.95).<br><br>INTERPRETATION AND CONCLUSION: pPROM was not associated with vitamin E deficiency. There was insignificant oxidative stress in cord blood as measured by mtDNA copy number but cord blood telomere length measurement did not detect any oxidative stress in pPPROM cases.}, }
@article {pmid36876055, year = {2023}, author = {Goldstein, AM and Qin, R and Chu, EY and Elder, DE and Massi, D and Adams, DJ and Harms, PW and Robles-Espinoza, CD and Newton-Bishop, JA and Bishop, DT and Harland, M and Holland, EA and Cust, AE and Schmid, H and Mann, GJ and Puig, S and Potrony, M and Alos, L and Nagore, E and Millán-Esteban, D and Hayward, NK and Broit, N and Palmer, JM and Nathan, V and Berry, EG and Astiazaran-Symonds, E and Yang, XR and Tucker, MA and Landi, MT and Pfeiffer, RM and Sargen, MR}, title = {Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.}, journal = {JAAD international}, volume = {11}, number = {}, pages = {43-51}, pmid = {36876055}, issn = {2666-3287}, abstract = {BACKGROUND: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.<br><br>OBJECTIVE: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.<br><br>METHODS: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in &#x2265;25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist.<br><br>RESULTS: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n&#xa0;=&#xa0;139 melanomas), POT1 carriers (OR&#xa0;=&#xa0;225.1, 95% confidence interval: 51.7-980.5; P&#xa0;<&#xa0;.001) and individuals with TERF2IP, ACD, and TERT variants (OR&#xa0;=&#xa0;82.4, 95% confidence interval: 21.3-494.6; P&#xa0;<&#xa0;.001) had increased odds of spitzoid morphology.<br><br>LIMITATIONS: Findings may not be generalizable to nonfamilial melanoma cases.<br><br>CONCLUSION: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.}, }
@article {pmid36873417, year = {2023}, author = {Sha, Z and Hou, T and Zhou, T and Dai, Y and Bao, Y and Jin, Q and Ye, J and Lu, Y and Wu, L}, title = {Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1093255}, pmid = {36873417}, issn = {2297-055X}, abstract = {BACKGROUND: Atrial fibrillation (AF) is an age-related disease, while telomeres play a central role in aging. But the relationship between AF and telomere length (LTL) is still controversial. This study aims to examine the potential causal association between AF and LTL by using Mendelian randomization (MR).<br><br>METHODS: Bidirectional two-sample MR, expression and protein quantitative trait loci (eQTL and pQTL)-based MR were performed using genetic variants from United Kingdom Biobank, FinnGen, and a meta-analysis study, which comprised nearly 1 million participants in the Atrial Fibrillation Study and 470,000 participants in the Telomere Length Study. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, complementary analysis approaches and sensitivity analysis were applied.<br><br>RESULTS: The forward MR revealed a significant causal estimate for the genetically predicted AF with LTL shortening [IVW: odds ratio (OR)&#x2009;=&#x2009;0.989, p&#x2009;=&#x2009;0.007; eQTL-IVW: OR&#x2009;=&#x2009;0.988, p&#x2009;=&#x2009;0.005; pQTL-IVW: OR&#x2009;=&#x2009;0.975, p&#x2009;<&#x2009;0.005]. But in the reverse MR analysis, genetically predicted LTL has no significant correlation with AF (IVW: OR&#x2009;=&#x2009;0.995, p&#x2009;=&#x2009;0.916; eQTL-IVW: OR&#x2009;=&#x2009;0.999, p&#x2009;=&#x2009;0.995; pQTL-IVW: OR&#x2009;=&#x2009;1.055, p&#x2009;=&#x2009;0.570). The FinnGen replication data yielded similar findings. Sensitivity analysis ensured the stability of the results.<br><br>CONCLUSION: The presence of AF leads to LTL shortening rather than the other way around. Aggressive intervention for AF may delay the telomere attrition.}, }
@article {pmid36871092, year = {2023}, author = {Deręgowska, A and Pępek, M and Solarska, I and Machnicki, MM and Pruszczyk, K and Dudziński, M and Niesiobędzka-Krężel, J and Seferyńska, I and Sawicki, W and Wnuk, M and Stokłosa, T}, title = {The interplay between telomeric complex members and BCR::ABL1 oncogenic tyrosine kinase in the maintenance of telomere length in chronic myeloid leukemia.}, journal = {Journal of cancer research and clinical oncology}, volume = {}, number = {}, pages = {}, pmid = {36871092}, issn = {1432-1335}, abstract = {PURPOSE: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by recurrent genetic aberration in leukemic stem cells, namely Philadelphia chromosome caused by reciprocal translocation t(9;22)(q34;q11). In our study, we analyzed the telomeric complex expression and function in the molecular pathogenesis of CML.<br><br>METHODS: We employed CD34+&#x2009;primary leukemic cells, comprising both leukemic stem and progenitor cell populations, isolated from peripheral blood or bone marrow of CML patients in chronic and blastic phase to analyze the telomere length and telomeric-associated proteins.<br><br>RESULTS: The reduction in telomere length during disease progression was correlated with increased expression of BCR::ABL1 transcript and the dynamic changes were neither associated with the enzymatic activity of telomerase nor with gene copy number and expression of telomerase subunits. Increased expression of BCR::ABL1 was positively correlated with expression of TRF2, RAP1, TPP1, DKC1, TNKS1, and TNKS2 genes.<br><br>CONCLUSIONS: The dynamics of telomere length changes in CD34+&#x2009;CML cells is dependent on the expression level of BCR::ABL, which promotes the expression of certain shelterins including RAP1 and TRF2, as well as TNKS, and TNKS2, and results in telomere shortening regardless of telomerase activity. Our results may allow better understanding of the mechanisms responsible for the genomic instability of leukemic cells and CML progression.}, }
@article {pmid36868694, year = {2023}, author = {Chakraborty, A and Roy, S and Hande, MP and Banerjee, B}, title = {Telomere attrition and genomic instability in unexplained recurrent pregnancy loss in humans: A preliminary study.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {886}, number = {}, pages = {503580}, doi = {10.1016/j.mrgentox.2022.503580}, pmid = {36868694}, issn = {1879-3592}, abstract = {Genome instability is defined as an elevated rate of DNA damage and mutations as a result of exposure to potential direct and indirect mutagens. This current investigation was designed to elucidate the genomic instability among couples experiencing unexplained recurrent pregnancy loss (uRPL). A cohort of 1272 individuals with history of unexplained RPL with normal karyotype was retrospectively screened for levels of intracellular ROS production, baseline genomic instability and telomere functionality. The experimental outcome was compared with 728 fertile control individuals. In this study, it was perceived that individuals with uRPL exhibited higher intracellular oxidative stress, along with higher basal levels of genomic instability as compared with the fertile controls. This observation elucidates the role of genomic instability as well as involvement of telomeres in cases of uRPL. It was also observed that higher oxidative stress might be associated with DNA damage and telomere dysfunction resulting in genomic instability among subjects with unexplained RPL. This study highlighted the assessment of genomic instability status in individuals experiencing uRPL.}, }
@article {pmid36864251, year = {2023}, author = {Maresca, C and Dello Stritto, A and D'Angelo, C and Petti, E and Rizzo, A and Vertecchi, E and Berardinelli, F and Bonanni, L and Sgura, A and Antoccia, A and Graziani, G and Biroccio, A and Salvati, E}, title = {PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {234}, pmid = {36864251}, issn = {2399-3642}, abstract = {Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.}, }
@article {pmid36860927, year = {2023}, author = {Sun, H and Chen, G and Guo, B and Lv, S and Yuan, G}, title = {Potential clinical treatment prospects behind the molecular mechanism of alternative lengthening of telomeres (ALT).}, journal = {Journal of Cancer}, volume = {14}, number = {3}, pages = {417-433}, pmid = {36860927}, issn = {1837-9664}, abstract = {Normal somatic cells inevitably experience replicative stress and senescence during proliferation. Somatic cell carcinogenesis can be prevented in part by limiting the reproduction of damaged or old cells and removing them from the cell cycle [1, 2]. However, Cancer cells must overcome the issues of replication pressure and senescence as well as preserve telomere length in order to achieve immortality, in contrast to normal somatic cells [1, 2]. Although telomerase accounts for the bulk of telomere lengthening methods in human cancer cells, there is a non-negligible portion of telomere lengthening pathways that depend on alternative lengthening of telomeres (ALT) [3]. For the selection of novel possible therapeutic targets for ALT-related disorders, a thorough understanding of the molecular biology of these diseases is crucial [4]. The roles of ALT, typical ALT tumor cell traits, the pathophysiology and molecular mechanisms of ALT tumor disorders, such as adrenocortical carcinoma (ACC), are all summarized in this work. Additionally, this research compiles as many of its hypothetically viable but unproven treatment targets as it can (ALT-associated PML bodies (APB), etc.). This review is intended to contribute as much as possible to the development of research, while also trying to provide a partial information for prospective investigations on ALT pathways and associated diseases.}, }
@article {pmid36859557, year = {2023}, author = {Chen, J and Wu, S and Wu, Y and Zhuang, P and Zhang, Y and Jiao, J}, title = {Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice.}, journal = {European journal of nutrition}, volume = {}, number = {}, pages = {}, pmid = {36859557}, issn = {1436-6215}, abstract = {PURPOSE: Previous evidence indicated anti-ageing potential of docosahexaenoic acid (DHA), but the underlying mechanism remains unclear. We investigated protective effect of DHA on telomere attrition and lipid disturbance in male mice with premature ageing caused by telomerase deficiency.<br><br>METHODS: Wild-type (WT) and fourth-generation telomerase-deficient (G4 Terc[-/-], Terc knockout, KO) male mice (C57BL/6, 2&#xa0;months old) were fed control diet (WT-C and KO-C groups) or DHA-enriched diet containing 0.80% DHA by weight (WT-DHA and KO-DHA groups) for 10&#xa0;months. The ageing phenotypes and metabolic level [carbon dioxide emission, oxygen consumption, and respiratory exchange ratio (RER)] were assessed at the end of the experiment. Telomere length in various tissues and the hepatic gene and protein expression for regulating lipid synthesis and lipolysis were measured. Data were tested using one- or two-factor ANOVA.<br><br>RESULTS: In KO male mice, DHA prevented weight loss, corrected high RER, and reduced fat loss. Telomere shortening was reduced by 22.3%, 25.5%, and 13.5% in heart, liver, and testes of the KO-DHA group compared with those in the KO-C group. The KO-DHA group exhibited higher gene transcription involved in glycerol-3-phosphate pathway [glycerol-3-phosphate acyltransferase (Gpat)], lower gene expression of &#x3b2;-oxidation [carnitine palmitoyltransferase 1a (Cpt1a)], and upregulation of proteins in lipid synthesis [mammalian target of rapamycin complex 1 (mTORC1) and sterol responsive element binding protein 1 (SREBP1)] in liver than the KO-C group.<br><br>CONCLUSION: Long-term DHA intervention attenuates telomere attrition and promotes lipid synthesis via the tuberous sclerosis complex 2 (TSC2)-mTORC1-SREBP1 pathway in KO male mice.}, }
@article {pmid36855016, year = {2023}, author = {Chen, X and Hao, Z and Pan, H and Liu, W and Lu, L and Zhang, M and He, X and Yi, H and Tang, S}, title = {Relationship between common telomere length-related genetic variations, telomere length and risk of anti-tuberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated RUCAM.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/fcp.12885}, pmid = {36855016}, issn = {1472-8206}, abstract = {OBJECTIVE: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL and risk of ATDH in Eastern Chinese anti-tuberculosis treatment patients.<br><br>METHODS: A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs).<br><br>RESULTS: The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median=1.239 vs. 1.481, P=0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median=1.544 vs. 1.356 vs. 1.337, P=0.026) and rs2853677 (AA vs. AG vs. GG, median=1.511 vs. 1.544 vs. 1.159, P=0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR=1.725, 95%CI: 1.021-2.913, P=0.042).<br><br>CONCLUSIONS: This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.}, }
@article {pmid36852686, year = {2023}, author = {Zhang, H and Lai, X and Fang, Q and Ma, L and Liu, M and Yang, H and Guo, W and He, M and Yang, L and Zhang, X}, title = {Independent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke.}, journal = {Stroke}, volume = {}, number = {}, pages = {}, doi = {10.1161/STROKEAHA.122.041126}, pmid = {36852686}, issn = {1524-4628}, }
@article {pmid36851065, year = {2023}, author = {Wu, X and Li, P and Tao, J and Chen, X and Zhang, A}, title = {Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats.}, journal = {Toxics}, volume = {11}, number = {2}, pages = {}, doi = {10.3390/toxics11020191}, pmid = {36851065}, issn = {2305-6304}, abstract = {Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.}, }
@article {pmid36849001, year = {2023}, author = {Liu, S and Nong, W and Ji, L and Zhuge, X and Wei, H and Luo, M and Zhou, L and Chen, S and Zhang, S and Lei, X and Huang, H}, title = {The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases.}, journal = {Experimental gerontology}, volume = {}, number = {}, pages = {112132}, doi = {10.1016/j.exger.2023.112132}, pmid = {36849001}, issn = {1873-6815}, abstract = {Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.}, }
@article {pmid36847305, year = {2023}, author = {Levy, MA and Tian, J and Gandelman, M and Cheng, H and Tsapekos, M and Crego, SR and Maddela, R and Sinnott, R}, title = {A Multivitamin Mixture Protects against Oxidative Stress-Mediated Telomere Shortening.}, journal = {Journal of dietary supplements}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/19390211.2023.2179153}, pmid = {36847305}, issn = {1939-022X}, abstract = {Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. Telomeres shorten with each cell division; hence telomere length is associated with aging and longevity. Numerous lifestyle factors have been identified that impact the rate of telomere shortening; high vitamin consumption has been associated with longer telomere length, whereas oxidative stress is associated with telomere shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins and a blend of polyphenolic compounds, could reduce telomere shortening consequent to an oxidative stress (10 uM H2O2 for 8 weeks) in a primary fibroblast cell culture model. Under conditions of oxidative stress, the median and 20[th] percentile telomere length were significantly greater (p < 0.05), and the percentage of critically short telomeres (<3000 bp) was significantly less (p < 0.05) in cells treated with the multivitamin mixture at 4, 15 and 60 ug/ml compared to control (0 ug/ml). Median and 20[th] percentile telomere shortening rate was also reduced under the same conditions (p < 0.05). Taken together, these findings demonstrate that the multivitamin mixture protects against oxidative stress-mediated telomere shortening in cell culture, findings which may have implications in human health.}, }
@article {pmid36847070, year = {2023}, author = {Pepke, ML and Ringsby, TH and Eisenberg, DTA}, title = {The evolution of early-life telomere length, pace-of-life and telomere-chromosome length dynamics in birds.}, journal = {Molecular ecology}, volume = {}, number = {}, pages = {}, doi = {10.1111/mec.16907}, pmid = {36847070}, issn = {1365-294X}, abstract = {Telomeres, the short DNA sequences that protect chromosome ends, are an ancient molecular structure, which is highly conserved across most eukaryotes. Species differ in their telomere lengths, but the causes of this variation are not well understood. Here, we demonstrate that mean early-life telomere length is an evolutionary labile trait across 57 bird species (representing 35 families in 12 orders) with the greatest trait diversity found among passerines. Among these species, telomeres are significantly shorter in fast-lived than in slow-lived species, suggesting that telomere length may have evolved to mediate trade-offs between physiological requirements underlying the diversity of pace-of-life strategies in birds. This association was attenuated when excluding studies that may include interstitial telomeres in the estimation of mean telomere length. Curiously, within some species, larger individual chromosome size predicts longer telomere lengths on that chromosome, leading to the hypothesis that telomere length also covaries with chromosome length across species. We show that longer mean chromosome length or genome size tends to be associated with longer mean early-life telomere length (measured across all chromosomes) within a phylogenetic framework constituting up to 31 bird species. These associations were strengthened when excluding highly influential outliers. However, sensitivity analyses suggested that they were susceptible to sample size effects and not robust to the exclusion of studies that may include interstitial telomeres. Combined, our analyses generalize patterns previously found within a few species and provide potential adaptive explanations for the 10-fold variation in telomere lengths observed among birds.}, }
@article {pmid36843839, year = {2023}, author = {Zhang, X and Zhang, C and Zhou, D and Zhang, T and Chen, X and Ren, J and He, C and Meng, F and Zhou, Q and Yang, Q and Dai, C and Lin, G and Zeng, S and Leng, L}, title = {Telomeres cooperate in zygotic genome activation by affecting DUX4/Dux transcription.}, journal = {iScience}, volume = {26}, number = {3}, pages = {106158}, pmid = {36843839}, issn = {2589-0042}, abstract = {Zygotic genome activation (ZGA) is initiated once the genome chromatin state is organized in the newly formed zygote. Telomeres are specialized chromatin structures at the ends of chromosomes and are reset during early embryogenesis, while the details and significance of telomere changes in preimplantation embryos remain unclear. We demonstrated that the telomere length was shortened in the minor ZGA stage and significantly elongated in the major ZGA stage of human and mouse embryos. Expression of the ZGA pioneer factor DUX4/Dux was negatively correlated with the telomere length. ATAC sequencing data revealed that the chromatin accessibility peaks on the DUX4 promoter region (i.e., the subtelomere of chromosome 4q) were transiently augmented in human minor ZGA. Reduction of telomeric heterochromatin H3K9me3 in the telomeric region also synergistically activated DUX4 expression with p53 in human embryonic stem cells. We propose herein that telomeres regulate the expression of DUX4/Dux through chromatin remodeling and are thereby involved in ZGA.}, }
@article {pmid36834938, year = {2023}, author = {Martel-Martel, A and Corchete, LA and Martí, M and Vidal-Tocino, R and Hurtado, E and Álvaro, E and Jiménez, F and Jiménez-Toscano, M and Balaguer, F and Sanz, G and López, I and Hernández-Villafranca, S and Ballestero, A and Vivas, A and Melone, S and Pastor, C and Brandáriz, L and Gómez-Marcos, MA and Cruz-Hernández, JJ and Perea, J and González-Sarmiento, R}, title = {Telomere Length as a New Risk Marker of Early-Onset Colorectal Cancer.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, doi = {10.3390/ijms24043526}, pmid = {36834938}, issn = {1422-0067}, abstract = {Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (hTERT, TERC, DKC1, TERF1, TERF2, TERF2IP, TINF2, ACD, and POT1) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb; p < 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of hTERT (rs79662648), POT1 (rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354), TERF2 (rs251796 and rs344152214), and TERF2IP (rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.}, }
@article {pmid36834592, year = {2023}, author = {Fujiwara-Tani, R and Takagi, T and Mori, S and Kishi, S and Nishiguchi, Y and Sasaki, T and Ikeda, M and Nagai, K and Bhawal, UK and Ohmori, H and Fujii, K and Kuniyasu, H}, title = {Short Telomere Lesions with Dysplastic Metaplasia Histology May Represent Precancerous Lesions of Helicobacter pylori-Positive Gastric Mucosa.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, doi = {10.3390/ijms24043182}, pmid = {36834592}, issn = {1422-0067}, abstract = {Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients.}, }
@article {pmid36834587, year = {2023}, author = {Deng, S and Yang, M and Su, J and Cui, N and Wu, S and Zhang, G and Wang, L and Hou, Y and Chai, Y and Yu, B}, title = {Heat-Killed Staphylococcus aureus Induces Bone Mass Loss through Telomere Erosion.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, doi = {10.3390/ijms24043179}, pmid = {36834587}, issn = {1422-0067}, abstract = {The mechanism of systemic osteoporosis caused by chronic infection is not completely clear, and there is a lack of reasonable interventions for this disease. In this study, heat-killed S. aureus (HKSA) was applied to simulate the inflammation caused by the typical clinical pathogen and to explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of HKSA caused bone loss in mice. Further exploration found that HKSA caused cellular senescence, telomere length shortening, and telomere dysfunction-induced foci (TIF) in limb bones. As a well-known telomerase activator, cycloastragenol (CAG) significantly alleviated HKSA-induced telomere erosion and bone loss. These results suggested that telomere erosion in bone marrow cells is a possible mechanism of HKSA-induced bone loss. CAG may protect against HKSA-induced bone loss by alleviating telomere erosion in bone marrow cells.}, }
@article {pmid36833352, year = {2023}, author = {Fattet, AJ and Chaillot, M and Koscinski, I}, title = {Telomere Length, a New Biomarker of Male (in)Fertility? A Systematic Review of the Literature.}, journal = {Genes}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/genes14020425}, pmid = {36833352}, issn = {2073-4425}, abstract = {Male factors are suspected in around half cases of infertility, of which up to 40% are diagnosed as idiopathic. In the context of a continuously increased resort to ART and increased decline of semen parameters, it is of greatest interest to evaluate an additional potential biomarker of sperm quality. According to PRISMA guidelines, this systematic review of the literature selected studies evaluating telomere length in sperm and/or in leukocytes as a potential male fertility biomarker. Twenty-two publications (3168 participants) were included in this review of experimental evidence. For each study, authors determined if there was a correlation between telomere length and semen parameters or fertility outcomes. Of the 13 studies concerning sperm telomere length (STL) and semen parameters, ten found an association between short STL and altered parameters. Concerning the impact of STL on ART results, the data are conflicting. However, eight of the 13 included studies about fertility found significantly longer sperm telomeres in fertile men than in infertile men. In leukocytes, the seven studies reported conflicting findings. Shorter sperm telomeres appear to be associated with altered semen parameters or male infertility. Telomere length may be considered as a new molecular marker of spermatogenesis and sperm quality, and thus is related to male fertility potential. However, additional studies are needed to define the place of the STL in the assessment of individual fertility.}, }
@article {pmid36833275, year = {2023}, author = {Barnes, RP and Thosar, SA and Opresko, PL}, title = {Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road.}, journal = {Genes}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/genes14020348}, pmid = {36833275}, issn = {2073-4425}, support = {R35ES030396/NH/NIH HHS/United States ; K99ES033771/NH/NIH HHS/United States ; R01CA207342/NH/NIH HHS/United States ; }, abstract = {Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in a visible phenotype in metaphase cells termed "telomere fragility". A mechanism cells employ to mitigate replication stress, including at telomeres, is DNA synthesis in mitosis (MiDAS). While these phenomena are both observed in mitotic cells, the relationship between them is poorly understood; however, a common link is DNA replication stress. In this review, we will summarize what is known to regulate telomere fragility and telomere MiDAS, paying special attention to the proteins which play a role in these telomere phenotypes.}, }
@article {pmid36831502, year = {2023}, author = {Pauleck, S and Sinnott, JA and Zheng, YL and Gadalla, SM and Viskochil, R and Haaland, B and Cawthon, RM and Hoffmeister, A and Hardikar, S}, title = {Association of Telomere Length with Colorectal Cancer Risk and Prognosis: A Systematic Review and Meta-Analysis.}, journal = {Cancers}, volume = {15}, number = {4}, pages = {}, doi = {10.3390/cancers15041159}, pmid = {36831502}, issn = {2072-6694}, abstract = {(1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82-1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2-4 overall HR (95% CI) = 1.41 (0.26-7.59) and 0.82 (0.69-0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed.}, }
@article {pmid36831134, year = {2023}, author = {Hernández-Álvarez, D and Rosado-Pérez, J and Gavia-García, G and Arista-Ugalde, TL and Aguiñiga-Sánchez, I and Santiago-Osorio, E and Mendoza-Núñez, VM}, title = {Aging, Physical Exercise, Telomeres, and Sarcopenia: A Narrative Review.}, journal = {Biomedicines}, volume = {11}, number = {2}, pages = {}, doi = {10.3390/biomedicines11020598}, pmid = {36831134}, issn = {2227-9059}, abstract = {Human aging is a gradual and adaptive process characterized by a decrease in the homeostatic response, leading to biochemical and molecular changes that are driven by hallmarks of aging, such as oxidative stress (OxS), chronic inflammation, and telomere shortening. One of the diseases associated with the hallmarks of aging, which has a great impact on functionality and quality of life, is sarcopenia. However, the relationship between telomere length, sarcopenia, and age-related mortality has not been extensively studied. Moderate physical exercise has been shown to have a positive effect on sarcopenia, decreasing OxS and inflammation, and inducing protective effects on telomeric DNA. This results in decreased DNA strand breaks, reduced OxS and IA, and activation of repair pathways. Higher levels of physical activity are associated with an apparent increase in telomere length. This review aims to present the current state of the art of knowledge on the effect of physical exercise on telomeric maintenance and activation of repair mechanisms in sarcopenia.}, }
@article {pmid36830739, year = {2023}, author = {Ueno, M}, title = {Exploring Genetic Interactions with Telomere Protection Gene pot1 in Fission Yeast.}, journal = {Biomolecules}, volume = {13}, number = {2}, pages = {}, doi = {10.3390/biom13020370}, pmid = {36830739}, issn = {2218-273X}, abstract = {The regulation of telomere length has a significant impact on cancer risk and aging in humans. Circular chromosomes are found in humans and are often unstable during mitosis, resulting in genome instability. Some types of cancer have a high frequency of a circular chromosome. Fission yeast is a good model for studying the formation and stability of circular chromosomes as deletion of pot1 (encoding a telomere protection protein) results in rapid telomere degradation and chromosome fusion. Pot1 binds to single-stranded telomere DNA and is conserved from fission yeast to humans. Loss of pot1 leads to viable strains in which all three fission yeast chromosomes become circular. In this review, I will introduce pot1 genetic interactions as these inform on processes such as the degradation of uncapped telomeres, chromosome fusion, and maintenance of circular chromosomes. Therefore, exploring genes that genetically interact with pot1 contributes to finding new genes and/or new functions of genes related to the maintenance of telomeres and/or circular chromosomes.}, }
@article {pmid36829978, year = {2023}, author = {Péntek, S and Várnagy, &#xc1; and Farkas, B and Mauchart, P and Gödöny, K and Varjas, T and Kőszegi, T and Kaltenecker, P and Jakabfi-Csepregi, R and Kovács, K and Bódis, J and Sulyok, E}, title = {Telomere Length and Telomerase Activity of Granulosa Cells and Follicular Fluid in Women Undergoing In Vitro Fertilization.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, doi = {10.3390/antiox12020419}, pmid = {36829978}, issn = {2076-3921}, abstract = {This study aimed to evaluate the interrelationship between telomere length, telomerase activity and oxidative DNA damage in patients undergoing in vitro fertilization (IVF). This single-center, observational clinical study comprised 102 unselected, consecutive patients with various infertility diagnoses. Granulosa cells (GCs) and follicular fluid (FF) were analyzed simultaneously for telomere functions and for the marker of oxidative DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG). An Absolute Human Telomere Lengths Quantification qPCR Assay kit and Telomerase Activity Quantification qPCR Assay kit (Nucleotestbio, Budapest, Hungary), as well as an 8-OHdG ELISA kit (Abbexa Ltd., Cambridge, United Kingdom) were used for analyses. Similar telomere lengths were found in GCs and FF, however telomerase activity was markedly depressed, while 8-OHdG levels were markedly elevated in FF compared with those in GCs (p < 0.01). Telomere lengths were independent of telomerase activity both in GCs and FF. However, GC 8-OHdG was inversely related to telomerase activity in GCs and FF (p < 0.05). Importantly, 8-OHdG levels both in GCs and FF had significant negative impact on the number of the retrieved and MII oocytes (p < 0.01), whereas FF 8-OHdG was negatively related further to the number of fertilized oocytes and blastocysts (p < 0.01). In conclusion, we could not confirm the direct association of telomere function and reproductive potential. However, oxidative DNA damage, as mainly reflected by 8-OHdG, adversely affected early markers of IVF outcome and clinical pregnancies.}, }
@article {pmid36826621, year = {2023}, author = {Stock, AJ and Ayyar, S and Kashyap, A and Wang, Y and Yanai, H and Starost, MF and Tanaka-Yano, M and Bodogai, M and Sun, C and Wang, Y and Gong, Y and Puligilla, C and Fang, EF and Bohr, VA and Liu, Y and Beerman, I}, title = {Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {36826621}, issn = {2509-2723}, support = {Intramural Funding/AG/NIA NIH HHS/United States ; }, abstract = {Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert[-/-]) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert[-/-] mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert[-/-] hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert[-/-] transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.}, }
@article {pmid36811398, year = {2023}, author = {Eastwood, JR and Dupoué, A and Delhey, K and Verhulst, S and Cockburn, A and Peters, A}, title = {When does early-life telomere length predict survival? A case study and meta-analysis.}, journal = {Molecular ecology}, volume = {}, number = {}, pages = {}, doi = {10.1111/mec.16894}, pmid = {36811398}, issn = {1365-294X}, abstract = {Suboptimal conditions during development can shorten telomeres, the protective DNA caps on the end of chromosomes. Shorter early-life telomere length (TL) can indicate reduced somatic maintenance, leading to lower survival and shorter lifespan. However, despite some clear evidence, not all studies show a relationship between early-life TL and survival or lifespan, which may be due to differences in biology or study design (e.g., survival period measured). In superb fairy-wrens (Malurus cyaneus), we assessed whether early-life TL predicts mortality across different life-history stages (fledgling, juvenile, adult). However, in contrast to a similar study on a congener, early-life TL did not predict mortality across any life stage in this species. We then performed a meta-analysis including 32 effect sizes from 23 studies (15 birds and 3 mammals) to quantify the effect of early-life TL on mortality whilst taking into consideration potential sources of biological and methodological variation. Overall, the effect of early-life TL on mortality was significant, corresponding to a 15% reduction in mortality risk with each standard deviation increase in TL. However, the effect became weaker when correcting for publication bias. Contrary to our predictions, there was no evidence that effects of early-life TL on mortality varied with species lifespan or the period over which survival was measured. However, negative effects of early-life TL on mortality risk were pervasive throughout life. These results imply that effects of early-life TL on mortality are more likely context-dependent rather than age-dependent, although substantial power and publication bias issues highlight the need for more research.}, }
@article {pmid36810772, year = {2023}, author = {Strzyz, P}, title = {From shortening telomeres to replicative crisis.}, journal = {Nature reviews. Molecular cell biology}, volume = {}, number = {}, pages = {}, pmid = {36810772}, issn = {1471-0080}, }
@article {pmid36809211, year = {2023}, author = {Li, Z and Cai, K and Sun, Y and Zhou, D and Yan, J and Luo, S and Huang, G and Gao, Y and Li, W}, title = {Folic acid protects against age-associated apoptosis and telomere attrition of neural stem cells in senescence-accelerated mouse prone 8.}, journal = {Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme}, volume = {}, number = {}, pages = {}, doi = {10.1139/apnm-2022-0111}, pmid = {36809211}, issn = {1715-5320}, abstract = {Folic acid (FA) could improve cognitive performances and attenuate brain cell injury in the aging brain, FA supplementation is also associated with inhibiting neural stem cells (NSCs) apoptosis. However, its role in age-associated telomere attrition remains unclear. We hypothesized that FA supplementation attenuates age-associated apoptosis of NSCs via alleviating telomere attrition in senescence-accelerated mouse prone 8 (SAMP8). In this study, 4-month-old male SAMP8 mice were assigned equal numbers to four different diet groups (n=15). Fifteen age-matched senescence-accelerated mouse resistant 1 (SAMR1) (Con-R) were used as the standard aging control group, feeding the FA-normal diet. After folic acid treatment 6-month, all mice were sacrificed. NSCs apoptosis, proliferation, oxidative damage and telomere length have been evaluated by immunofluorescence and Q-fluorescent in situ hybridization. The results showed that FA supplementation inhibited age-associated NSCs apoptosis and prevented telomere attrition in the cerebral cortex of SAMP8 mice. Importantly, this effect might be interpreted by the decreased levels of oxidative damage. In conclusion, we demonstrate it may be one of the mechanisms that FA inhibiting age-associated NSCs apoptosis by alleviating telomere length shortening.}, }
@article {pmid36805596, year = {2023}, author = {Turkalo, TK and Maffia, A and Schabort, JJ and Regalado, SG and Bhakta, M and Blanchette, M and Spierings, DCJ and Lansdorp, PM and Hockemeyer, D}, title = {A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {939}, pmid = {36805596}, issn = {2041-1723}, abstract = {Alternative Lengthening of Telomeres (ALT) is an aberrant DNA recombination pathway which grants replicative immortality to approximately 10% of all cancers. Despite this high prevalence of ALT in cancer, the mechanism and genetics by which cells activate this pathway remain incompletely understood. A major challenge in dissecting the events that initiate ALT is the extremely low frequency of ALT induction in human cell systems. Guided by the genetic lesions that have been associated with ALT from cancer sequencing studies, we genetically engineered primary human pluripotent stem cells to deterministically induce ALT upon differentiation. Using this genetically defined system, we demonstrate that disruption of the p53 and Rb pathways in combination with ATRX loss-of-function is sufficient to induce all hallmarks of ALT and results in functional immortalization in a cell type-specific manner. We further demonstrate that ALT can be induced in the presence of telomerase, is neither dependent on telomere shortening nor crisis, but is rather driven by continuous telomere instability triggered by the induction of differentiation in ATRX-deficient stem cells.}, }
@article {pmid36805537, year = {2023}, author = {Han, MH and Lee, EH and Park, HH and Choi, SH and Koh, SH}, title = {Relationship between telomere shortening and early subjective depressive symptoms and cognitive complaints in older adults.}, journal = {Aging}, volume = {15}, number = {}, pages = {}, doi = {10.18632/aging.204533}, pmid = {36805537}, issn = {1945-4589}, abstract = {Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.}, }
@article {pmid36799570, year = {2023}, author = {}, title = {ZBP1 Mediates Replicative Crisis through Telomere-to-Mitochondria Signaling.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1}, doi = {10.1158/2159-8290.CD-RW2023-026}, pmid = {36799570}, issn = {2159-8290}, abstract = {ZBP1 is a major regulator of replicative crisis, which activates an innate immune response.}, }
@article {pmid36798520, year = {2022}, author = {Li, Y and Yang, S and Liao, M and Zheng, Z and Li, M and Wei, X and Liu, M and Yang, L}, title = {Association between genetically predicted leukocyte telomere length and non-scarring alopecia: A two-sample Mendelian randomization study.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1072573}, pmid = {36798520}, issn = {1664-3224}, abstract = {BACKGROUND: The most commonly acknowledged non-scarring alopecia are androgenetic alopecia (AGA) and alopecia areata (AA). Previous studies have revealed various risk factors associated with alopecia. However, the relationship between leukocyte telomere length (LTL) and non-scarring alopecia remains unclear.<br><br>METHODS: A two-sample Mendelian randomization (MR) analysis was performed to evaluate the causality between genetically predicted LTL and the risk of non-scarring alopecia. MR analyses were performed using the inverse variance-weighted (IVW) method and complemented with other MR methods.<br><br>RESULTS: The summary statistics of the genome-wide association studies (GWAS) for AGA and AA were obtained from the FinnGen biobank, which included 119,185 and 211,428 individuals, respectively. A total of 126 single nucleotide polymorphisms (SNPs) with genome-wide significance were selected as the instrumental variables for LTL. The MR analyses suggested a causal relationship between LTL and AGA, and the risk of AGA increased by 3.19 times as the genetically predicted LTL was shortened by one standard deviation in log transformed form under the IVW method (OR&#xa0;=&#xa0;4.19, 95% CI&#xa0;=&#xa0;1.20-14.61, p&#xa0;=&#xa0;0.024). The other MR methods also demonstrated a similar trend of the effect of LTL on AGA. There was no causal relationship between LTL and AA (p&#xa0;>&#xa0;0.05). Sensitivity analyses further demonstrated that the current results were less likely to be affected by confounders and bias.<br><br>CONCLUSION: Our results suggested a potential causal relationship between LTL and AGA, and shortened LTL was associated with an increased risk of AGA.}, }
@article {pmid36798426, year = {2023}, author = {Li, F and Wang, Y and Hwang, I and Jang, JY and Xu, L and Deng, Z and Yu, EY and Cai, Y and Wu, C and Han, Z and Huang, YH and Huang, X and Zhang, L and Yao, J and Lue, NF and Lieberman, PM and Ying, H and Paik, J and Zheng, H}, title = {Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.02.10.528023}, pmid = {36798426}, abstract = {Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.}, }
@article {pmid36797576, year = {2023}, author = {Han, M and Liu, S and Ji, JR and Wu, YF and Chang, KW and Zhang, JY and Wei, JN}, title = {[Interaction of polycyclic aromatic hydrocarbon DNA adducts and telomere length on missed abortion].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {57}, number = {2}, pages = {193-199}, doi = {10.3760/cma.j.cn112150-20220322-00274}, pmid = {36797576}, issn = {0253-9624}, abstract = {Objective: To analyze the contribution and interaction of polycyclic aromatic hydrocarbons (PAH)-DNA adducts and changes of telomere length (TL) on missed abortion. Methods: From March to December 2019, patients with missed abortion in the First Hospital of Shanxi Medical University and pregnant women with normal pregnancy but voluntary abortion in the same department during the same period were selected and divided into a case group and a control group. Questionnaire was used to investigate the general situation and the pregnancy situation of the subjects. The abortion villi were collected and the content of PAH-DNA adducts and TL was detected. Logistic regression model was used to analyze the associated factors of missed abortion. R epiR package and Mediation package were used to analyze the effect and relationship between PAH-DNA adducts and TL on missed abortion. Results: The age of the subjects was(29.92±5.69)years old. The M(Q1,Q3)of PAH-DNA adducts was 453.75(404.61, 504.72) pg/ml. The M(Q1,Q3)of TL was 1.21(0.77, 1.72). The content of PAH-DNA adducts in the case group was higher than that in the control group (Z=-2.10, P=0.036), while the TL was lower than that in the control group (Z=-4.05, P<0.001). Multivariate logistic regression showed that low, medium and high levels of PAH-DNA adducts (OR=3.17,95%CI:1.41-7.14;OR=2.85,95%CI:1.25-6.52;OR=2.46,95%CI:1.07-5.64), and long, medium and short levels of TL (OR=2.50,95%CI:1.11-5.63;OR=3.32,95%CI:1.45-7.56;OR=3.22,95%CI:1.42-7.26) were all risk factors for missed abortion. The medium level of PAH-DNA adducts had a 2.76-fold higher risk of shortened TL than those with the lowest level, and no mediating role of TL was found. The stratified analysis showed that when the TL level was longer (>1.21), the low and high levels of PAH-DNA adducts were associated with missed abortion (all P<0.05); when the TL level was shorter (<1.21), the medium level of PAH-DNA adducts was associated with abortion (P=0.025). At lower levels of PAH-DNA adducts, no effect of TL on missed abortion was observed, while, at higher levels, TL was strongly associated with missed abortion (OR=7.50,95%CI:1.95-28.82;OR=6.04,95%CI:1.54-23.65;OR=9.05,95%CI:2.34-35.04). The interaction analysis found that the AP was 0.72 (95%CI: 0.46-0.99), and the SI was 5.21 (95%CI: 2.30-11.77). Conclusion: The high level of PAH-DNA adducts and shortened TL may increase the risk of missed abortion, and there may be a positive additive interaction between the two factors on missed abortion.}, }
@article {pmid36797493, year = {2023}, author = {Rautiainen, M and Nurk, S and Walenz, BP and Logsdon, GA and Porubsky, D and Rhie, A and Eichler, EE and Phillippy, AM and Koren, S}, title = {Telomere-to-telomere assembly of diploid chromosomes with Verkko.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {36797493}, issn = {1546-1696}, abstract = {The Telomere-to-Telomere consortium recently assembled the first truly complete sequence of a human genome. To resolve the most complex repeats, this project relied on manual integration of ultra-long Oxford Nanopore sequencing reads with a high-resolution assembly graph built from long, accurate PacBio high-fidelity reads. We have improved and automated this strategy in Verkko, an iterative, graph-based pipeline for assembling complete, diploid genomes. Verkko begins with a multiplex de Bruijn graph built from long, accurate reads and progressively simplifies this graph by integrating ultra-long reads and haplotype-specific markers. The result is a phased, diploid assembly of both haplotypes, with many chromosomes automatically assembled from telomere to telomere. Running Verkko on the HG002 human genome resulted in 20 of 46 diploid chromosomes assembled without gaps at 99.9997% accuracy. The complete assembly of diploid genomes is a critical step towards the construction of comprehensive pangenome databases and chromosome-scale comparative genomics.}, }
@article {pmid36779965, year = {2023}, author = {Bountziouka, V and Hansell, AL and Nelson, CP and Codd, V and Samani, NJ}, title = {Large-Scale Analysis of the Association between Air Pollutants and Leucocyte Telomere Length in the UK Biobank.}, journal = {Environmental health perspectives}, volume = {131}, number = {2}, pages = {27701}, pmid = {36779965}, issn = {1552-9924}, mesh = {*Air Pollutants ; Biological Specimen Banks ; Telomere ; United Kingdom ; Leukocytes ; }, }
@article {pmid36778189, year = {2023}, author = {Yue, J and Chen, Q and Wang, Y and Zhang, L and Ye, C and Wang, X and Cao, S and Lin, Y and Huang, W and Xian, H and Qin, H and Wang, Y and Zhang, S and Wu, Y and Wang, S and Yue, Y and Liu, Y}, title = {Telomere-to-telomere and gap-free reference genome assembly of the kiwifruit Actinidia chinensis.}, journal = {Horticulture research}, volume = {10}, number = {2}, pages = {uhac264}, pmid = {36778189}, issn = {2662-6810}, abstract = {Kiwifruit is an economically and nutritionally important fruit crop with extremely high contents of vitamin C. However, the previously released versions of kiwifruit genomes all have a mass of unanchored or missing regions. Here, we report a highly continuous and completely gap-free reference genome of Actinidia chinensis cv. 'Hongyang', named Hongyang v4.0, which is the first to achieve two de novo haploid-resolved haplotypes, HY4P and HY4A. HY4P and HY4A have a total length of 606.1 and 599.6 Mb, respectively, with almost the entire telomeres and centromeres assembled in each haplotype. In comparison with Hongyang v3.0, the integrity and contiguity of Hongyang v4.0 is markedly improved by filling all unclosed gaps and correcting some misoriented regions, resulting in ~38.6-39.5 Mb extra sequences, which might affect 4263 and 4244 protein-coding genes in HY4P and HY4A, respectively. Furthermore, our gap-free genome assembly provides the first clue for inspecting the structure and function of centromeres. Globally, centromeric regions are characterized by higher-order repeats that mainly consist of a 153-bp conserved centromere-specific monomer (Ach-CEN153) with different copy numbers among chromosomes. Functional enrichment analysis of the genes located within centromeric regions demonstrates that chromosome centromeres may not only play physical roles for linking a pair of sister chromatids, but also have genetic features for participation in the regulation of cell division. The availability of the telomere-to-telomere and gap-free Hongyang v4.0 reference genome lays a solid foundation not only for illustrating genome structure and functional genomics studies but also for facilitating kiwifruit breeding and improvement.}, }
@article {pmid36776610, year = {2023}, author = {Cai, Y and Zhong, YD and Zhang, H and Lu, PL and Liang, YY and Hu, B and Wu, H}, title = {Association between dietary vitamin C and telomere length: A cross-sectional study.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1025936}, pmid = {36776610}, issn = {2296-861X}, abstract = {BACKGROUND: Currently, telomere length is known to reflect the replication potential and longevity of cells, and many studies have reported that telomere length is associated with age-related diseases and biological aging. Studies have also shown that vitamin C acts as an oxidant and free radical scavenger to protect cells from oxidative stress and telomere wear, thus achieving anti-aging effects. At present, there are few and incomplete studies on the relationship between vitamin C and telomere length, so this study aims to explore the relationship between vitamin C and telomere length.<br><br>METHODS: This study used cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) database from 1999 to 2002, a total of 7,094 participants were selected from all races in the United States. Male participants accounted for 48.2% and female participants accounted for 51.8%. The correlation between vitamin C and telomere length was assessed using a multiple linear regression model, and the effect of dietary vitamin C on telomere length was obtained after adjusting for confounding factors such as age, gender, race, body mass index (BMI), and poverty income ratio (PIR).<br><br>RESULTS: This cross-sectional study showed that vitamin C was positively correlated with telomere length, with greater dietary vitamin C intake associated with longer telomeres (&#x3b2; = 0.03, 95% CI: 0.01-0.05, P = 0.003).<br><br>CONCLUSION: This study shows that vitamin C intake is positively correlated with human telomere length, which is of guiding significance for our clinical guidance on people's health care, but our study need to be confirmed by more in-depth and comprehensive other research results.}, }
@article {pmid36767300, year = {2023}, author = {Pasha, Q and Rain, M and Tasnim, S and Kanipakam, H and Thinlas, T and Mohammad, G}, title = {The Telomere-Telomerase System Is Detrimental to Health at High-Altitude.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {3}, pages = {}, pmid = {36767300}, issn = {1660-4601}, mesh = {Humans ; Altitude ; *Telomerase/genetics ; Case-Control Studies ; *Altitude Sickness/genetics ; Biomarkers ; Telomere/genetics ; }, abstract = {The hypobaric-hypoxia environment at high-altitude (HA, >2500 m) may influence DNA damage due to the production of reactive molecular species and high UV radiation. The telomere system, vital to chromosomal integrity and cellular viability, is prone to oxidative damages contributing to the severity of high-altitude disorders such as high-altitude pulmonary edema (HAPE). However, at the same time, it is suggested to sustain physical performance. This case-control study, comprising 210 HAPE-free (HAPE-f) sojourners, 183 HAPE-patients (HAPE-p) and 200 healthy highland natives (HLs) residing at ~3500 m, investigated telomere length, telomerase activity, and oxidative stress biomarkers. Fluidigm SNP genotyping screened 65 single nucleotide polymorphisms (SNPs) in 11 telomere-maintaining genes. Significance was attained at p ≤ 0.05 after adjusting for confounders and correction for multiple comparisons. Shorter telomere length, decreased telomerase activity and increased oxidative stress were observed in HAPE patients; contrarily, longer telomere length and elevated telomerase activity were observed in healthy HA natives compared to HAPE-f. Four SNPs and three haplotypes are associated with HAPE, whereas eight SNPs and nine haplotypes are associated with HA adaptation. Various gene-gene interactions and correlations between/among clinical parameters and biomarkers suggested the presence of a complex interplay underlining HAPE and HA adaptation physiology. A distinctive contribution of the telomere-telomerase system contributing to HA physiology is evident in this study. A normal telomere system may be advantageous in endurance training.}, }
@article {pmid36759506, year = {2023}, author = {Falcinelli, M and Dell'Omo, G and Grassi, E and Mariella, E and Leto, SM and Scardellato, S and Lorenzato, A and Arena, S and Bertotti, A and Trusolino, L and Bardelli, A and d'Adda di Fagagna, F}, title = {Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).}, journal = {Cell death &amp; disease}, volume = {14}, number = {2}, pages = {96}, pmid = {36759506}, issn = {2041-4889}, mesh = {Humans ; X-linked Nuclear Protein/genetics/metabolism ; *Intellectual Disability ; Telomere Homeostasis/genetics ; *alpha-Thalassemia ; Co-Repressor Proteins/genetics/metabolism ; *Telomerase/genetics/metabolism ; Mutation/genetics ; Cell Line ; Telomere/genetics/metabolism ; Organoids/metabolism ; *Colorectal Neoplasms/genetics ; Molecular Chaperones/genetics/metabolism ; }, abstract = {Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT). ALT is genetically associated with somatic alterations in alpha-thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes. Cells displaying ALT present distinctive features including C-circles made of telomeric DNA, long and heterogenous telomeric tracts, and telomeric DNA co-localized with promyelocytic leukemia (PML) bodies forming so-called ALT-associated PML bodies (APBs). Here, we identified mutations in ATRX and/or DAXX genes in an extensive collection of CRC samples including 119 patient-derived organoids (PDOs) and 232 established CRC cell lines. C-circles measured in CRC PDOs and cell lines showed low levels overall. We also observed that CRC PDOs and cell lines did not display a significant accumulation of APBs or long telomeres with no appreciable differences between wild-type and mutated ATRX/DAXX samples. Overall, our extensive analyses indicate that CRC is not prone to engage ALT, even when carrying genetic lesions in ATRX and/or DAXX, and support the notion that ATRX/DAXX genomic footprints are not reliable predictors of ALT.}, }
@article {pmid36758285, year = {2023}, author = {Vostatek, R and Hohensinner, P and Nopp, S and Haider, P and Englisch, C and Pointner, J and Pabinger, I and Ay, C}, title = {Association of telomere length and mitochondrial DNA copy number, two biomarkers of biological aging, with the risk of venous thromboembolism.}, journal = {Thrombosis research}, volume = {223}, number = {}, pages = {168-173}, doi = {10.1016/j.thromres.2023.01.031}, pmid = {36758285}, issn = {1879-2472}, abstract = {BACKGROUND: Venous thromboembolism (VTE) is the third most common cardiovascular disease and occurs in all age groups, albeit the risk increases considerably with age. Previous research indicates mitochondrial dysfunction and telomere shortening in cardiovascular aging. However, in the context of VTE this has not been investigated in detail.<br><br>AIM: We aimed to explore biomarkers reflecting biological aging (i.e. human mitochondrial DNA copy number (mtDNA) and telomere length) and their association with VTE.<br><br>METHODS: mtDNA and telomere length were measured in a case-control study of 116 patients with a history of VTE and 128 age- and sex-matched healthy individuals from isolated blood using a qPCR-based assay kit. Cases had at least one unprovoked VTE event and were enrolled no earlier than 3&#xa0;months after the last VTE event.<br><br>RESULTS: The mtDNA copy number was significantly lower in VTE cases compared to controls (median [IQR]: 663 per diploid cells [78.75-2204.5] vs. 2832 per diploid cells [724-4350]; p&#xa0;<&#xa0;0.001). After adjustment for age, sex, BMI, and smoking, mtDNA copy number was independently associated with VTE risk (odds ratio per increase in 400 mtDNA per diploid cell: 0.889, 95%CI 0.834-0.947). mtDNA copy numbers were significantly different between women and men (2375 [455-3737] women vs. 893 [152-3154] men; p&#xa0;<&#xa0;0.001). The analysis of telomere length showed no significant difference between patients and healthy controls.<br><br>CONCLUSION: Lower mtDNA levels were found in patients with VTE compared to controls, indicating an association of biological aging with risk of VTE.}, }
@article {pmid36755096, year = {2023}, author = {Nassour, J and Aguiar, LG and Correia, A and Schmidt, TT and Mainz, L and Przetocka, S and Haggblom, C and Tadepalle, N and Williams, A and Shokhirev, MN and Akincilar, SC and Tergaonkar, V and Shadel, GS and Karlseder, J}, title = {Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {36755096}, issn = {1476-4687}, abstract = {Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations[1,2]. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.}, }
@article {pmid36751991, year = {2023}, author = {Marriott, RJ and Murray, K and Budgeon, CA and Codd, V and Hui, J and Arscott, GM and Beilby, JP and Hankey, GJ and Wittert, GA and Wu, FCW and Yeap, BB}, title = {Serum testosterone and sex hormone-binding globulin are inversely associated with leucocyte telomere length in men: a cross-sectional analysis of the UK Biobank Study.}, journal = {European journal of endocrinology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ejendo/lvad015}, pmid = {36751991}, issn = {1479-683X}, abstract = {OBJECTIVE: Older men on average have lower testosterone concentrations compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle to older aged men.<br><br>DESIGN: Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.<br><br>METHODS: Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). LTL was measured using Polymerase Chain Reaction. Multivariable models were used to assess associations of hormones with standardised LTL.<br><br>RESULTS: In 167,706 men, median age 58 years, adjusting for sociodemographic, lifestyle and medical factors total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P&#x2009;<&#x2009;0.001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI&#x2009;=&#x2009;0.02-0.05, P&#x2009;=&#x2009;0.003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI&#x2009;=&#x2009;0.10-0.13, P&#x2009;<&#x2009;0.001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI&#x2009;=&#x2009;0.08-0.12, P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.}, }
@article {pmid36750187, year = {2023}, author = {Burraco, P and Hernandez-Gonzalez, M and Metcalfe, NB and Monaghan, P}, title = {Ageing across the great divide: tissue transformation, organismal growth and temperature shape telomere dynamics through the metamorphic transition.}, journal = {Proceedings. Biological sciences}, volume = {290}, number = {1992}, pages = {20222448}, pmid = {36750187}, issn = {1471-2954}, mesh = {Animals ; Temperature ; *Aging ; *Metamorphosis, Biological ; Larva ; Telomere ; }, abstract = {Telomere attrition is considered a useful indicator of cellular and whole-organism ageing rate. While approximately 80% of animal species undergo metamorphosis that includes extensive tissue transformations (involving cell division, apoptosis, de-differentiation and de novo formation of stem cells), the effect on telomere dynamics is unknown. We measured telomeres in Xenopus laevis developing from larvae to adults under contrasting environmental temperatures. Telomere dynamics were linked to the degree of tissue transformation during development. Average telomere length in gut tissue increased dramatically during metamorphosis, when the gut shortens by 75% and epithelial cells de-differentiate into stem cells. In the liver (retained from larva) and hindlimb muscle (newly formed before metamorphosis), telomeres gradually shortened until adulthood, likely due to extensive cell division. Tail muscle telomere lengths were constant until tail resorption, and those in heart (retained from larva) showed no change over time. Telomere lengths negatively correlated with larval growth, but for a given growth rate, telomeres were shorter in cooler conditions, suggesting that growing in the cold is more costly. Telomere lengths were not related to post-metamorphic growth rate. Further research is now needed to understand whether telomere dynamics are a good indicator of ageing rate in species undergoing metamorphosis.}, }
@article {pmid36747763, year = {2023}, author = {Jones, CY and Williams, CL and Moreno, SP and Morris, DK and Mondello, C and Karlseder, J and Bertuch, AA}, title = {Hyperextended telomeres promote C-circle formation in telomerase positive human cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36747763}, abstract = {Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post TERT -immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.}, }
@article {pmid36747657, year = {2023}, author = {Landa, I and Thornton, CE and Xu, B and Haase, J and Krishnamoorthy, GP and Hao, J and Knauf, JA and Herbert, ZT and Blasco, MA and Ghossein, R and Fagin, JA}, title = {Telomerase reactivation induces progression of mouse Braf [V600E] -driven thyroid cancers without telomere lengthening.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.01.24.525280}, pmid = {36747657}, abstract = {Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert [-123C>T]) and crossed it with thyroid-specific Braf [V600E] -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf [V600E] animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf [V600E] +Tert [-123C>T] and Braf [V600E] +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.}, }
@article {pmid36729832, year = {2023}, author = {Pires, VB and Lohner, N and Wagner, T and Wagner, CB and Wilkens, M and Hajikazemi, M and Paeschke, K and Butter, F and Luke, B}, title = {RNA-DNA hybrids prevent resection at dysfunctional telomeres.}, journal = {Cell reports}, volume = {42}, number = {2}, pages = {112077}, doi = {10.1016/j.celrep.2023.112077}, pmid = {36729832}, issn = {2211-1247}, abstract = {At critically short telomeres, stabilized TERRA RNA-DNA hybrids drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. We report that telomeric RNA-DNA hybrids prevent Exo1-mediated resection when telomeres become non-functional. We used the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature-dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. Telomeric hybrids do not affect the shortening rate of bulk telomeres. We suggest that TERRA hybrids require dynamic regulation to drive HDR at short telomeres; hybrid presence may initiate HDR through replication stress, whereby their removal allows strand resection.}, }
@article {pmid36726239, year = {2023}, author = {Van Ommen, CE and Hsieh, AYY and Albert, AY and Kimmel, ER and Côté, HCF and Maan, EJ and Prior, JC and Pick, N and Murray, MCM and , }, title = {Lower anti-mullerian hormone levels are associated with HIV in reproductive age women and shorter leukocyte telomere length among late reproductive age women.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000003481}, pmid = {36726239}, issn = {1473-5571}, abstract = {OBJECTIVES: We sought to better understand factors associated with ovarian aging in women living with HIV (WLWH).<br><br>DESIGN: HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, Anti-Mullerian hormone (AMH), and HIV.<br><br>METHODS: We included WLWH and HIV-negative women 12-50&#x200a;years of age in the CARMA cohort with &#x2265; 1 study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analysed in peak reproductive (<35&#x200a;years) vs. late reproductive (&#x2265;35&#x200a;years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and &#x394;AMH/year while adjusting for relevant confounders.<br><br>RESULTS: WLWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women <35&#x200a;years and shorter LTL was associated with AMH levels below 2&#x200a;ng/ml among women &#x2265;35&#x200a;years. Longitudinally, &#x394;AMH/year was largely related to initial AMH level among older women, and to age in younger women.<br><br>CONCLUSIONS: Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WLWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counselling around pregnancy planning. In women &#x2265;35, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.}, }
@article {pmid36719921, year = {2023}, author = {Eguchi, A and Gonzalez, AFGS and Torres-Bigio, SI and Koleckar, K and Birnbaum, F and Zhang, JZ and Wang, VY and Wu, JC and Artandi, SE and Blau, HM}, title = {TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {6}, pages = {e2209967120}, doi = {10.1073/pnas.2209967120}, pmid = {36719921}, issn = {1091-6490}, support = {R01 HL126527/HL/NHLBI NIH HHS/United States ; R01 HL130020/HL/NHLBI NIH HHS/United States ; R01 HL123968/HL/NHLBI NIH HHS/United States ; R01 HL146690/HL/NHLBI NIH HHS/United States ; R01 HL159340/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cardiomyopathy, Dilated/genetics ; Cell Survival ; Dystrophin/genetics ; *Heart Failure/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; *Muscular Dystrophy, Duchenne/metabolism ; Myocytes, Cardiac/metabolism ; Telomere/genetics/metabolism ; }, abstract = {Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart but do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that telomere shortening is a hallmark of DMD cardiomyocytes. Here, we test whether prevention of telomere attrition is possible in cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSC-CMs) and if preventing telomere shortening impacts cardiomyocyte function. We observe reduced cell size, nuclear size, and sarcomere density in DMD iPSC-CMs compared with healthy isogenic controls. We find that expression of just one telomere-binding protein, telomeric repeat-binding factor 2 (TRF2), a core component of the shelterin complex, prevents telomere attrition and rescues deficiencies in cell size as well as sarcomere density. We employ a bioengineered platform to micropattern cardiomyocytes for calcium imaging and perform Southern blots of telomere restriction fragments, the gold standard for telomere length assessments. Importantly, preservation of telomere lengths in DMD cardiomyocytes improves their viability. These data provide evidence that preventing telomere attrition ameliorates deficits in cell morphology, activation of the DNA damage response, and premature cell death, suggesting that TRF2 is a key player in DMD-associated cardiac failure.}, }
@article {pmid36717449, year = {2022}, author = {Morgunova, VV and Sokolova, OA and Sizova, TV and Malaev, LG and Babaev, DS and Kwon, DA and Kalmykova, AI}, title = {Dysfunction of Lamin B and Physiological Aging Cause Telomere Instability in Drosophila Germline.}, journal = {Biochemistry. Biokhimiia}, volume = {87}, number = {12}, pages = {1600-1610}, doi = {10.1134/S000629792212015X}, pmid = {36717449}, issn = {1608-3040}, mesh = {Animals ; *Lamin Type B/genetics/metabolism ; *Drosophila/genetics ; Heterochromatin ; Drosophila melanogaster/genetics ; Aging/genetics ; Telomere/genetics/metabolism ; Germ Cells ; }, abstract = {Chromatin spatial organization in the nucleus is essential for the genome functioning and regulation of gene activity. The nuclear lamina and lamina-associated proteins, lamins, play a key role in this process. Lamin dysfunction leads to the decompaction and transcriptional activation of heterochromatin, which is associated with the premature aging syndrome. In many cell types, telomeres are located at the nuclear periphery, where their replication and stability are ensured by the nuclear lamina. Moreover, diseases associated with defects in lamins and telomeres have similar manifestations and resemble physiological aging. Understanding molecular changes associated with aging at the organismal level is especially important. In this study, we compared the effects caused by the mutation in lamin B and physiological aging in the germline of the model organism Drosophila melanogaster. We have shown that the impaired localization of lamin B leads to the heterochromatin decompaction and transcriptional activation of some transposable elements and telomeric repeats. Both DNA damage and activation of homologous recombination in the telomeres were observed in the germ cells of lamin B mutants. The instability of repeat-enriched heterochromatin can be directly related to the genome destabilization, germ cell death, and sterility observed in lamin B mutants. Similar processes were observed in Drosophila germline in the course of physiological aging, which indicates a close link between the maintenance of the heterochromatin stability at the nuclear periphery and mechanisms of aging.}, }
@article {pmid36714994, year = {2023}, author = {Hsu, BY and Cossin-Sevrin, N and Stier, A and Ruuskanen, S}, title = {Prenatal thyroid hormones accelerate postnatal growth and telomere shortening in wild great tits.}, journal = {The Journal of experimental biology}, volume = {}, number = {}, pages = {}, doi = {10.1242/jeb.243875}, pmid = {36714994}, issn = {1477-9145}, abstract = {Early-life environment is known to affect later-life health and disease, which could be mediated by the early-life programming of telomere length, a key hallmark of ageing. According to the fetal programming of telomere biology hypothesis, variation in prenatal exposure to hormones is likely to influence telomere length. Yet the contribution of key metabolic hormones, i.e. thyroid hormones (THs), has been largely ignored. We recently showed that in contrast to predictions, exposure to elevated prenatal THs increased postnatal telomere length in wild collared flycatchers, but the generality of such effect, its underlying proximate mechanisms and consequences on survival have not been investigated. We therefore conducted a comprehensive study evaluating the impact of THs on potential drivers of telomere dynamics (growth, post-natal THs, mitochondria and oxidative stress), telomere length and medium-term survival using wild great tits as a model system. While prenatal THs did not significantly affect telomere length a week after hatching (i.e. day 7), they influenced postnatal telomere shortening (i.e. shorter telomeres at day 14 and the following winter) but not apparent survival. Circulating THs, mitochondrial density or oxidative stress biomarkers were not significantly influenced, whereas TH-supplemented group showed accelerated growth, which may explain the observed delayed effect on telomeres. We discuss several alternative hypotheses that may explain the contrast with our previous findings in flycatchers. Given that shorter telomeres in early life tend to be carried until adulthood and are often associated with decreased survival prospects, the effects of prenatal THs on telomeres may have long-lasting effects on senescence.}, }
@article {pmid36714598, year = {2022}, author = {Yuan, Y and Tan, Y and Qiu, X and Luo, H and Li, Y and Li, R and Yang, X}, title = {Sperm telomere length as a novel biomarker of male infertility and embryonic development: A systematic review and meta-analysis.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1079966}, pmid = {36714598}, issn = {1664-2392}, mesh = {Pregnancy ; Female ; Humans ; Male ; *Semen Analysis ; Semen ; *Infertility, Male/diagnosis/genetics ; Spermatozoa ; Telomere ; Biomarkers ; Observational Studies as Topic ; }, abstract = {BACKGROUND: Telomeres have an essential role in maintaining the integrity and stability of the human chromosomal genome and preserving essential DNA biological functions. Several articles have been published on the association of STL with male semen parameters and clinical pregnancy. The results, however, are either inconclusive or inconsistent. Therefore, this meta-analysis aimed to systematically assess the accuracy and clinical value of sperm telomere length (STL) as a new marker for diagnosing male infertility and predicting the quality of embryonic development.<br><br>METHODS: We performed a comprehensive systematic search for relevant publications in PubMed, the Cochrane Library, Web of Science, Embase, Scopus, and Ovid, from database build to August 2022. All experimental studies exploring the association of STL with male semen quality, male infertility, or embryonic development were included.<br><br>RESULTS: Overall, Twelve prospective observational cohort studies (1700 patients) were eligible for inclusion in the meta-analysis. The meta-analysis showed a positive linear correlation between STL and semen parameters. The optimal cut-off value for STL diagnosing male infertility was 1.0, with a sensitivity and specificity of 80%. Regarding STL and embryonic development, the clinical pregnancy rate was associated with longer STL, and there was no significant difference between the two groups regarding fertilization rate.<br><br>CONCLUSION: Our study showed that STL has good diagnostic and predictive value for male fertility and clinical pregnancy and could be used as a new biomarker for diagnosing male infertility and predicting embryonic development.<br><br>https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022303333.}, }
@article {pmid36707451, year = {2023}, author = {Valdiani, A and Ofoghi, H}, title = {Enzymatic approaches against SARS-CoV-2 infection with an emphasis on the telomere-associated enzymes.}, journal = {Biotechnology letters}, volume = {}, number = {}, pages = {1-13}, pmid = {36707451}, issn = {1573-6776}, abstract = {The pandemic phase of coronavirus disease 2019 (COVID-19) appears to be over in most countries. However, the unexpected behaviour and unstable nature of coronaviruses, including temporary hiatuses, re-emergence, emergence of new variants, and changing outbreak epicentres during the COVID-19 pandemic, have been frequently reported. The mentioned trend shows the fact that in addition to vaccine development, different strategies should be considered to deal effectively with this disease, in long term. In this regard, the role of enzymes in regulating immune responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently attracted much attention. Moreover, several reports confirm the association of short telomeres with sever COVID-19 symptoms. This review highlights the role of several enzymes involved in telomere length (TL) regulation and explains their relevance to SARS-CoV-2 infection. Apparently, inhibition of telomere shortening (TS) through inhibition and/or activation of these enzymes could be a potential target in the treatment of COVID-19, which may also lead to a reduction in disease severity.}, }
@article {pmid36707016, year = {2023}, author = {Szeltner, Z and Ferenc, G and Juhász, T and Kupihár, Z and Váradi, Z and Szüts, D and Kovács, L}, title = {Probing telomereric-like G4 structures with full or partial 2'-deoxy-5-hydroxyuridine substitutions.}, journal = {Biochimie}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.biochi.2023.01.009}, pmid = {36707016}, issn = {1638-6183}, abstract = {Guanine quadruplexes (G4s) are stable four-stranded secondary DNA structures held together by noncanonical G-G base tetrads. We synthesised the nucleoside analogue 2'-deoxy-5-hydroxyuridine (H) and inserted its phosphoramidite into telomeric repeat-type model oligonucleotides. Full and partial substitutions were made, replacing all guanines in all the three tetrads of a three-tier G4 structure, or only in the putative upper, central, or lower tetrads. We characterised these modified structures using CD, UV absorbance spectroscopy, native gel studies, and a capture oligo-based G4 disruption kinetic assay. The strand separation activity of BLM helicase on these substituted structures was also investigated. Two of the partially H-substituted constructs adopted G4-like structures, but displayed lower thermal stabilities compared to unsubstituted G4. The construct modified in its central tetrad remained mostly denatured, but the possibility of a special structure for the fully replaced variant remained open. H substitutions did not interfere with the G4-resolving activity of BLM helicase, but its efficiency was highly influenced by construct topology and even more by the G4 ligand PhenDC3. Our results suggest that the H modification can be incorporated into G quadruplexes, but only at certain positions to maintain G4 stability. The destabilizing effect observed for 2'-deoxy-5-hydroxyuridine indicates that the cytosine deamination product 5-hydroxyuracil and its nucleoside counterpart in RNA (5-hydroxyuridine), might also be destabilizing in cellular DNA and RNA quadruplexes. The kinetic assay employed in this study can be generally employed for a fast comparison of the stabilities of various G4s either in their free or ligand-bound states.}, }
@article {pmid36705478, year = {2023}, author = {}, title = {Heritable Defects in Mitotic and Telomere Function Confer Sarcoma Risk.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1}, doi = {10.1158/2159-8290.CD-RW2023-016}, pmid = {36705478}, issn = {2159-8290}, abstract = {Mitotic and telomere function pathways were identified to play a role in sarcoma susceptibility.}, }
@article {pmid36703827, year = {2022}, author = {Wai, KM and Swe, T and Myar, MT and Aisyah, CR and Hninn, TSS}, title = {Telomeres susceptibility to environmental arsenic exposure: Shortening or lengthening?.}, journal = {Frontiers in public health}, volume = {10}, number = {}, pages = {1059248}, pmid = {36703827}, issn = {2296-2565}, mesh = {*Arsenic/metabolism ; *Telomerase/genetics/metabolism ; Telomere/metabolism ; }, abstract = {Maintaining telomere length plays a crucial role in regulating cellular life span. Telomere lengthening or shortening is one of the important biomarkers which could predict the preceding or present diseases. Meanwhile, the impact of environmental arsenic exposure on telomere length has increasingly concerned. Although previous studies demonstrated the effects of arsenic on telomere length, the findings were unclear on whether telomere shortens or lengthens by arsenic exposure. Thus, this manuscript summarized and discussed the telomere length alteration following arsenic exposure and the possible does-response effect of arsenic on telomere length. The present review suggested that different age groups may respond differently to arsenic exposure, and the dose-response effect of arsenic could be a critical factor in its effect on telomere length. Moreover, speciation analysis of arsenic could be more informative in identifying the effect of arsenic on telomere length.}, }
@article {pmid36702776, year = {2023}, author = {Hoerr, RE and Eng, A and Payen, C and Di Rienzi, SC and Raghuraman, MK and Dunham, MJ and Brewer, BJ and Friedman, KL}, title = {Hotspot of de novo telomere addition stabilizes linear amplicons in yeast grown in sulfate-limiting conditions.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyad010}, pmid = {36702776}, issn = {1943-2631}, abstract = {Evolution is driven by the accumulation of competing mutations that influence survival. A broad form of genetic variation is the amplification or deletion of DNA (≥50 bp) referred to as copy number variation. In humans, copy number variation may be inconsequential, contribute to minor phenotypic differences, or cause conditions such as birth defects, neurodevelopmental disorders, and cancers. To identify mechanisms that drive copy number variation, we monitored the experimental evolution of Saccharomyces cerevisiae populations grown under sulfate-limiting conditions. Cells with increased copy number of the gene SUL1, which encodes a primary sulfate transporter, exhibit a fitness advantage. Previously, we reported interstitial inverted triplications of SUL1 as the dominant rearrangement in a haploid population. Here, in a diploid population, we find instead that small linear fragments containing SUL1 form and are sustained over several generations. Many of the linear fragments are stabilized by de novo telomere addition within a telomere-like sequence near SUL1 (within the SNF5 gene). Using an assay that monitors telomerase action following an induced chromosome break, we show that this region acts as a hotspot of de novo telomere addition and that required sequences map to a region of <250 base pairs. Consistent with previous work showing that association of the telomere-binding protein Cdc13 with internal sequences stimulates telomerase recruitment, mutation of a four-nucleotide motif predicted to associate with Cdc13 abolishes de novo telomere addition. Our study suggests that internal telomere-like sequences that stimulate de novo telomere addition can contribute to adaptation by promoting genomic plasticity.}, }
@article {pmid36702689, year = {2023}, author = {Heaphy, CM and Singhi, AD}, title = {Reprint of: The Diagnostic and Prognostic Utility of Incorporating DAXX, ATRX, and Alternative Lengthening of Telomeres (ALT) to the Evaluation of Pancreatic Neuroendocrine Tumors (PanNETs).}, journal = {Human pathology}, volume = {132}, number = {}, pages = {1-11}, doi = {10.1016/j.humpath.2023.01.004}, pmid = {36702689}, issn = {1532-8392}, mesh = {Humans ; *Neuroendocrine Tumors/diagnosis/genetics/pathology ; Prognosis ; X-linked Nuclear Protein/genetics ; In Situ Hybridization, Fluorescence ; *Intellectual Disability ; *alpha-Thalassemia ; Nuclear Proteins/genetics ; *Pancreatic Neoplasms/diagnosis/genetics/metabolism ; Telomere/pathology ; Co-Repressor Proteins ; Telomere Homeostasis ; Molecular Chaperones ; }, abstract = {Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. Although many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Furthermore, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.}, }
@article {pmid36700322, year = {2023}, author = {Uzuncakmak, SK and Dirican, E and Ozcan, H and Takim, U}, title = {Relation of ATPase6 Mutations and Telomere Length in Schizophrenia Patients.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {21}, number = {1}, pages = {162-170}, doi = {10.9758/cpn.2023.21.1.162}, pmid = {36700322}, issn = {1738-1088}, abstract = {OBJECTIVE: Schizophrenia is a serious mental disorder. Mutations in mitochondrial genes can change energy metabolism. Telomere is a tandem sequence at the end of chromosomes. Shorter telomere length has been shown in schizophrenia. The aim of this study was to determine the relationship between ATPase6 gene mutations and telomere length in schizophrenia patients.<br><br>METHODS: Blood samples of 34 patients and 34 healthy controls were used. In this study conventional PCR, Sanger sequencing technic and real-time PCR were utilized.<br><br>RESULTS: Five different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) in the ATPase6 gene were identified in schizophrenia patients. The most seen mutation was A8860G (94%). Telomere length analysis indicated the relation of ATPase6 gene mutations and telomere length variations (p = 0.001). Patients carrying the A8860G mutation had shorter telomere lengths than patients carrying other mutations. Comparing telomere length between schizophrenia patients and healthy controls revealed that the mean telomere length of schizophrenia patients was shorter than healthy controls (p = 0.006). The demographic analysis demonstrated a significant relationship between marital status and telomere length (p = 0.011). Besides that, the duration of the illness is another factor that impacts telomere length (p = 0.044). There is no significant relation between telomere length and other clinical and demographic characteristics including education status, age, gender, etc.<br><br>CONCLUSION: In conclusion, telomere length and ATPase6 gene mutations have a significant relation. Studies with larger patient populations and investigation of other mitochondrial gene mutations will make the clearer link between telomere length and mitochondrial mutations.}, }
@article {pmid36699384, year = {2022}, author = {Holmes, O and Nones, K and Tang, YH and Loffler, KA and Lee, M and Patch, AM and Dagg, RA and Lau, LMS and Leonard, C and Wood, S and Xu, Q and Pickett, HA and Reddel, RR and Barbour, AP and Grimmond, SM and Waddell, N and Pearson, JV}, title = {qmotif: determination of telomere content from whole-genome sequence data.}, journal = {Bioinformatics advances}, volume = {2}, number = {1}, pages = {vbac005}, pmid = {36699384}, issn = {2635-0041}, abstract = {MOTIVATION: Changes in telomere length have been observed in cancer and can be indicative of mechanisms involved in carcinogenesis. Most methods used to estimate telomere length require laboratory analysis of DNA samples. Here, we present qmotif, a fast and easy tool that determines telomeric repeat sequences content as an estimate of telomere length directly from whole-genome sequencing.<br><br>RESULTS: qmotif shows similar results to quantitative PCR, the standard method for high-throughput clinical telomere length quantification. qmotif output correlates strongly with the output of other tools for determining telomere sequence content, TelSeq and TelomereHunter, but can run in a fraction of the time-usually under a minute.<br><br>qmotif is implemented in Java and source code is available at https://github.com/AdamaJava/adamajava, with instructions on how to build and use the application available from https://adamajava.readthedocs.io/en/latest/.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.}, }
@article {pmid36696951, year = {2023}, author = {Park, S and Kim, SG and Lee, S and Kim, Y and Cho, S and Kim, K and Kim, YC and Han, SS and Lee, H and Lee, JP and Joo, KW and Lim, CS and Kim, YS and Kim, DK}, title = {Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcsm.13174}, pmid = {36696951}, issn = {2190-6009}, abstract = {BACKGROUND: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required.<br><br>METHODS: This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337&#x2009;138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength,&#xa0;and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated.<br><br>RESULTS: Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits.<br><br>CONCLUSIONS: Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.}, }
@article {pmid36691437, year = {2023}, author = {Sabot, D and Lovegrove, R and Stapleton, P}, title = {The association between sleep quality and telomere length: A systematic literature review.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {28}, number = {}, pages = {100577}, pmid = {36691437}, issn = {2666-3546}, abstract = {Several sleep parameters present an elevated risk for processes that contribute to cellular aging. Short sleep duration, sleep apnoea, and insomnia are significantly associated with shorter telomeres, a biological marker of cellular aging. However, there has been no review or analysis of studies that have examined the association between the psychological construct of sleep quality and telomere length. The present study aimed to provide a systematic review of the association between sleep quality and telomere length. A systematic review of English articles was conducted using MEDLINE/PubMed, PsycINFO, Google Scholar, and Web of Science electronic databases, with the final search conducted on 3rd September 2021. Search terms included sleep quality, poor sleep, insomnia, sleep difficulties, sleep issue*, non-restorative sleep, telomere*, cellular aging, and immune cell telomere length. Study eligibility criteria included human participants aged 18 years or older and a reproducible methodology. Study appraisal and synthesis were completed using a systematic search in line with a PICOS approach (P = Patient, problem, or population; I = Intervention, prognostic factor, exposure; C = Comparison, control, or comparator; O = Outcomes; S = Study designs). Twenty-two studies met review inclusion criteria. Qualitative synthesis of the literature indicated insufficient evidence overall to support a significant association between sleep quality and telomere length. Limitations across studies were addressed, such as the assessment of examined constructs. Findings highlight important targets for future research, including the standardised operationalisation of the sleep quality construct and experimental study designs. Research in this area has clinical significance by identifying possible mechanisms that increase the risk for age-related disease and mortality. PROSPERO Registration No.: CRD 42021233139.}, }
@article {pmid36690926, year = {2022}, author = {Kim, JS and Manichaikul, AW and Hoffman, EA and Balte, P and Anderson, MR and Bernstein, EJ and Madahar, P and Oelsner, EC and Kawut, SM and Wysoczanski, A and Laine, AF and Adegunsoye, A and Ma, JZ and Taub, MA and Mathias, RA and Rich, SS and Rotter, JI and Noth, I and Garcia, CK and Barr, RG and Podolanczuk, AJ}, title = {MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.}, journal = {Thorax}, volume = {}, number = {}, pages = {}, pmid = {36690926}, issn = {1468-3296}, support = {K23 HL140199/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.<br><br>METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).<br><br>RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95%&#x2009;CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95%&#x2009;CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.<br><br>CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.}, }
@article {pmid36689342, year = {2023}, author = {Liu, H and Xu, C and Diplas, BH and Brown, A and Strickland, LM and Yao, H and Ling, J and McLendon, RE and Keir, ST and Ashley, DM and He, Y and Waitkus, MS}, title = {Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noad022}, pmid = {36689342}, issn = {1523-5866}, support = {K22 CA258965/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood.<br><br>METHODS: We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo.<br><br>RESULTS: Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis.<br><br>CONCLUSIONS: SMARCAL1 deficiency is permissive to ALT and promote gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anti-cancer therapeutics that target the ALT phenotype.}, }
@article {pmid36689071, year = {2023}, author = {Yin, H and Pickering, JG}, title = {Telomere Length: Implications for Atherogenesis.}, journal = {Current atherosclerosis reports}, volume = {}, number = {}, pages = {}, pmid = {36689071}, issn = {1534-6242}, support = {FDN-143326/CAPMC/CIHR/Canada ; }, abstract = {PURPOSE OF REVIEW: The purpose of the study is to explore the evidence linking telomere length with atherosclerotic ischemic disease.<br><br>RECENT FINDINGS: There has been a recent expansion in strategies for measuring telomere length, including analyzing genome sequence data and capitalizing on genomic loci that associate with telomere length. These, together with more established approaches, have been used to generate a more complete picture of telomere length relationships with ischemic disease. Whereas earlier meta-analyses suggested an association between short leukocyte telomeres and ischemic disease, several recent large population studies now provide particularly compelling data, including an association with cardiovascular mortality. In addition, whether short leukocyte telomeres might be causally related to ischemic disease has been interrogated using Mendelian randomization strategies, which point to shorter leukocyte telomeres as a determining risk factor. Importantly however, the wide, interindividual variability in telomere length still means that a single assessment of leukocyte telomere length in an individual does not reliably report on a biological aging process. In this regard, recent multi-tissue analyses of telomere length dynamics are providing both new mechanistic insights into how telomere length and shortening rates may participate in atherogenesis and risk prediction opportunities. The balance of evidence indicates that short leukocyte telomeres confer a risk for atherosclerotic cardiovascular disease. Moreover, an integrated analysis of telomere lengths in leukocytes and other tissues may provide a window into individualized telomere dynamics, raising new prospects for risk management.}, }
@article {pmid36685927, year = {2022}, author = {Xiao, Y and Xu, D and Jiang, C and Huili, Y and Nie, S and Zhu, H and Fan, G and Guan, X}, title = {Telomere maintenance-related genes are important for survival prediction and subtype identification in bladder cancer.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {1087246}, pmid = {36685927}, issn = {1664-8021}, abstract = {Background: Bladder cancer ranks among the top three in the urology field for both morbidity and mortality. Telomere maintenance-related genes are closely related to the development and progression of bladder cancer, and approximately 60%-80% of mutated telomere maintenance genes can usually be found in patients with bladder cancer. Methods: Telomere maintenance-related gene expression profiles were obtained through limma R packages. Of the 359 differential genes screened, 17 prognostically relevant ones were obtained by univariate independent prognostic analysis, and then analysed by LASSO regression. The best result was selected to output the model formula, and 11 model-related genes were obtained. The TCGA cohort was used as the internal group and the GEO dataset as the external group, to externally validate the model. Then, the HPA database was used to query the immunohistochemistry of the 11 model genes. Integrating model scoring with clinical information, we drew a nomogram. Concomitantly, we conducted an in-depth analysis of the immune profile and drug sensitivity of the bladder cancer. Referring to the matrix heatmap, delta area plot, consistency cumulative distribution function plot, and tracking plot, we further divided the sample into two subtypes and delved into both. Results: Using bioinformatics, we obtained a prognostic model of telomere maintenance-related genes. Through verification with the internal and the external groups, we believe that the model can steadily predict the survival of patients with bladder cancer. Through the HPA database, we found that three genes, namely ABCC9, AHNAK, and DIP2C, had low expression in patients with tumours, and eight other genes-PLOD1, SLC3A2, RUNX2, RAD9A, CHMP4C, DARS2, CLIC3, and POU5F1-were highly expressed in patients with tumours. The model had accurate predictive power for populations with different clinicopathological features. Through the nomogram, we could easily assess the survival rate of patients. Clinicians can formulate targeted diagnosis and treatment plans for patients based on the prediction results of patient survival, immunoassays, and drug susceptibility analysis. Different subtypes help to further subdivide patients for better treatment purposes. Conclusion: According to the results obtained by the nomogram in this study, combined with the results of patient immune-analysis and drug susceptibility analysis, clinicians can formulate diagnosis and personalized treatment plans for patients. Different subtypes can be used to further subdivide the patient for a more precise treatment plan.}, }
@article {pmid36684585, year = {2022}, author = {Semeraro, MD and Beltrami, AP and Kharrat, F and Almer, G and Sedej, S and Renner, W and Gruber, HJ and Curcio, F and Herrmann, M}, title = {The impact of moderate endurance exercise on cardiac telomeres and cardiovascular remodeling in obese rats.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {1080077}, pmid = {36684585}, issn = {2297-055X}, abstract = {INTRODUCTION: Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging.<br><br>METHODS: Ninety-six 4-months old female Sprague-Dawley rats were fed for 10 months normal (ND) or a HFD diet. Half of the animals in each group performed 30 min treadmill-running sessions on 5 consecutive days per week. At study end, cardiomyocyte cross-sectional area (CSA), interstitial collagen content, vascular density, apoptotic and senescent cells, relative telomere length (RTL), and expression of telomerase-reverse transcriptase (Tert) as marker of telomere-related senescence and apoptosis were analyzed.<br><br>RESULTS: Compared to ND, the HFD group developed obesity, higher CSA, lower capillary density and tended to have more apoptotic cardiomyocytes and interstitials cells. Myocardial RTL and the expression of Terf-1 and Terf-2 were comparable in sedentary HFD and ND animals. In the HFD group, regular moderate endurance exercise improved myocardial vascularization, but had no effect on CSA or apoptosis. Notably, the combination of exercise and HFD increased senescence when compared to sedentary ND or HFD, and reduced RTL when compared to exercise ND animals. Exercising HFD animals also showed a trend toward higher Tert expression compared to all other groups. In addition, exercise reduced Terf-1 expression regardless of diet.<br><br>CONCLUSION: HFD-induced obesity showed no effects on myocardial telomeres and induced only mild morphologic alterations. Summarized, long-term moderate endurance exercise partially reverses HFD-induced effects but may even trigger cardiac remodeling in the context of obesity.}, }
@article {pmid36674498, year = {2023}, author = {Dhillon, VS and Deo, P and Thomas, P and Fenech, M}, title = {Low Magnesium in Conjunction with High Homocysteine and Less Sleep Accelerates Telomere Attrition in Healthy Elderly Australian.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674498}, issn = {1422-0067}, mesh = {Humans ; Aged ; *Magnesium ; Australia ; *Vitamin B 12 ; Folic Acid ; Telomere/genetics ; Sleep ; Micronutrients ; Homocysteine ; }, abstract = {The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from South Australia. Plasma micronutrients including magnesium were measured. Each participant provided information about their sleep hours (<7 h or ≥7 h). Lymphocyte telomere length (TL) was measured by real-time qPCR assay. Plasma magnesium level was significantly low in subjects who sleep less than 7 h (p = 0.0002). TL was significantly shorter in people who are low in magnesium and sleep less than 7 h (p = 0.01). Plasma homocysteine (Hcy) is negatively associated with magnesium (r = -0.299; p < 0.0001). There is a significant interaction effect of magnesium and Hcy on sleep duration (p = 0.04) and TL (p = 0.003). Our results suggest that inadequate magnesium levels have an adverse impact on sleep and telomere attrition rate in cognitively normal elderly people, and this may be exacerbated by low levels of vitamin B12 and folate that elevate Hcy concentration.}, }
@article {pmid36674427, year = {2023}, author = {López-Armas, GDC and Ramos-Márquez, ME and Navarro-Meza, M and Macías-Islas, M&#xc1; and Saldaña-Cruz, AM and Zepeda-Moreno, A and Siller-López, F and Cruz-Ramos, JA}, title = {Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number.}, journal = {International journal of molecular sciences}, volume = {24}, number = {2}, pages = {}, pmid = {36674427}, issn = {1422-0067}, mesh = {Humans ; *Multiple Sclerosis, Relapsing-Remitting/genetics ; *Multiple Sclerosis/genetics ; DNA, Mitochondrial/genetics ; DNA Copy Number Variations ; Leukocytes ; Telomere/genetics ; }, abstract = {Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients.}, }
@article {pmid36669753, year = {2023}, author = {Bountziouka, V and Nelson, CP and Wang, Q and Musicha, C and Codd, V and Samani, NJ}, title = {Dietary patterns and practices and leucocyte telomere length: Findings from the UK Biobank.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2023.01.008}, pmid = {36669753}, issn = {2212-2672}, abstract = {BACKGROUND: Shorter telomere length (TL) is associated with risk of several age-related diseases and decreased lifespan, but the extent to which dietary patterns and practices associate with TL is uncertain.<br><br>OBJECTIVE: This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL).<br><br>DESIGN: This was a cross-sectional study.<br><br>PARTICIPANTS: / setting: Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010.<br><br>MAIN OUTCOME MEASURES: LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardised (z-LTL).<br><br>STATISTICAL ANALYSIS: A-priori adherence to the Mediterranean diet was assessed through the MedDietScore. Principal component analysis was used to a-posteriori extract the "Meat" and "Prudent" dietary patterns. Additional dietary practices considered were the self-reported adherence to "Vegetarian" diet, "Eating 5-a-day of fruit and vegetables" and "Abstaining from eggs/dairy/wheat/sugar". Associations between quintiles of dietary patterns or adherence to dietary practices with z-LTL were investigated through multivariable linear regression models (adjusted for demographic, lifestyle and clinical characteristics).<br><br>RESULTS: Adherence to the "Mediterranean" and the "Prudent" patterns, was positively associated with LTL, with an effect magnitude in z-LTL of 0.020SD and 0.014SD, respectively, for the highest vs the lowest quintile of adherence to the pattern (both P<0.05). Conversely, a reversed association between quintile of the "Meat" pattern and LTL was observed, with z-LTL being on average shorter by 0.025SD (P=6.12x10[-05]) for participants in the highest quintile of the pattern compared to the lowest quintile. For adherents to "5-a-day" z-LTL was on average longer by 0.027SD (P=5.36x10[-09]), and for "abstainers", LTL was shorter by 0.016SD (P=2.51x10[-04]). The association of LTL with a vegetarian diet was non-significant after adjustment for demographic, lifestyle and clinical characteristics.<br><br>CONCLUSION: Several dietary patterns and practices, associated with beneficial health effects, are significantly associated with longer LTL. However, the magnitude of the association was small, and any clinical relevance is uncertain.}, }
@article {pmid36658792, year = {2023}, author = {Park, HS and Im, K and Shin, DY and Yoon, SS and Kwon, S and Kim, SW and Lee, DS}, title = {Telomere integrated scoring system of myelodysplastic syndrome.}, journal = {Journal of clinical laboratory analysis}, volume = {}, number = {}, pages = {e24839}, doi = {10.1002/jcla.24839}, pmid = {36658792}, issn = {1098-2825}, abstract = {INTRODUCTION: Recently, multigene target sequencing is widely performed for the purpose of prognostic prediction and application of targeted therapy. Here, we proposed a new scoring system that encompasses gene variations, telomere length, and Revised International Prognostic Scoring System (IPSS-R) together in Asian myelodysplastic syndrome.<br><br>METHODS: We developed a new scoring model of these variables: age&#xa0;&#x2265;&#x2009;65&#x2009;years&#x2009;+&#x2009;IPSS-R score&#x2009;+&#x2009;ASXL1 mutation&#x2009;+&#x2009;TP53 mutation&#x2009;+&#x2009;Telomere length (<5.37). According to this new scoring system, patients were divided into four groups: very good score cutoff (&#x2264;3.0), good (3.0-4.5), poor (4.5-7.0), and very poor (>7.0).<br><br>RESULTS: The median OS was 170.1, 100.4, 46.0, and 12.0&#xa0;months for very good, good, poor, and very poor, retrospectively (p&#x2009;<&#x2009;0.001). Meanwhile, according to the conventional IPSS-R scoring system, the median OS was 141.3, 50.2, 93.0, 36.0, and 16.2&#xa0;months for very low, low, intermediate, high, and very high, retrospectively (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: The newly developed model incorporating molecular variations and TL yielded more clear separations of the survival curves. By adding the presence of gene mutation and telomere length to the existing IPSS-R, its predictive ability can be further improved in myelodysplastic syndrome.}, }
@article {pmid36657619, year = {2023}, author = {Armstrong, E and Boonekamp, J}, title = {Does oxidative stress shorten telomeres in vivo? A meta-analysis.}, journal = {Ageing research reviews}, volume = {85}, number = {}, pages = {101854}, doi = {10.1016/j.arr.2023.101854}, pmid = {36657619}, issn = {1872-9649}, mesh = {Humans ; *Oxidative Stress ; *Aging/genetics ; Telomere ; Telomere Shortening ; }, abstract = {Telomere attrition is considered a hallmark of ageing. Untangling the proximate causes of telomere attrition may therefore reveal important aspects about the ageing process. In a landmark paper in 2002 Thomas von Zglinicki demonstrated that oxidative stress accelerates telomere attrition in cell culture. In the next 20 years, oxidative stress became firmly embedded into modern theories of ageing and telomere attrition. However, a recent surge of in vivo studies reveals an inconsistent pattern questioning the unequivocal role of oxidative stress in telomere length and telomere attrition (henceforth referred to as telomere dynamics), in living organisms. Here we report the results of the first formal meta-analysis on the association between oxidative stress and telomere dynamics in vivo, representing 37 studies, 4969 individuals, and 18,677 correlational measurements. The overall correlation between oxidative stress markers and telomere dynamics was indistinguishable from zero (r = 0.027). This result was independent of the type of oxidative stress marker, telomere dynamic, or taxonomic group. However, telomere measurement method affected the analysis and the subset of TRF-based studies showed a significant overall correlation (r = 0.09), supporting the prediction that oxidative stress accelerates telomere attrition. The correlation was more pronounced in short-lived species and during the adult life phase, when ageing becomes apparent. We then performed an additional meta-analysis of interventional studies (n = 7) manipulating oxidative stress. This revealed a significant effect of treatment on telomere dynamics (d=0.36). Our findings provide new support for the hypothesis that oxidative stress causes telomere attrition in living organisms.}, }
@article {pmid36656928, year = {2023}, author = {Ballinger, ML and Pattnaik, S and Mundra, PA and Zaheed, M and Rath, E and Priestley, P and Baber, J and Ray-Coquard, I and Isambert, N and Causeret, S and van der Graaf, WTA and Puri, A and Duffaud, F and Le Cesne, A and Seddon, B and Chandrasekar, C and Schiffman, JD and Brohl, AS and James, PA and Kurtz, JE and Penel, N and Myklebost, O and Meza-Zepeda, LA and Pickett, H and Kansara, M and Waddell, N and Kondrashova, O and Pearson, JV and Barbour, AP and Li, S and Nguyen, TL and Fatkin, D and Graham, RM and Giannoulatou, E and Green, MJ and Kaplan, W and Ravishankar, S and Copty, J and Powell, JE and Cuppen, E and van Eijk, K and Veldink, J and Ahn, JH and Kim, JE and Randall, RL and Tucker, K and Judson, I and Sarin, R and Ludwig, T and Genin, E and Deleuze, JF and ,  and Haber, M and Marshall, G and Cairns, MJ and Blay, JY and ,  and Thomas, DM and Tattersall, M and Neuhaus, S and Lewis, C and Tucker, K and Carey-Smith, R and Wood, D and Porceddu, S and Dickinson, I and Thorne, H and James, P and Ray-Coquard, I and Blay, JY and Cassier, P and Le Cesne, A and Duffaud, F and Penel, N and Isambert, N and Kurtz, JE and Puri, A and Sarin, R and Ahn, JH and Kim, JE and Ward, I and Judson, I and van der Graaf, W and Seddon, B and Chandrasekar, C and Rickar, R and Hennig, I and Schiffman, J and Randall, RL and Silvestri, A and Zaratzian, A and Tayao, M and Walwyn, K and Niedermayr, E and Mang, D and Clark, R and Thorpe, T and MacDonald, J and Riddell, K and Mar, J and Fennelly, V and Wicht, A and Zielony, B and Galligan, E and Glavich, G and Stoeckert, J and Williams, L and Djandjgava, L and Buettner, I and Osinki, C and Stephens, S and Rogasik, M and Bouclier, L and Girodet, M and Charreton, A and Fayet, Y and Crasto, S and Sandupatla, B and Yoon, Y and Je, N and Thompson, L and Fowler, T and Johnson, B and Petrikova, G and Hambridge, T and Hutchins, A and Bottero, D and Scanlon, D and Stokes-Denson, J and Génin, E and Campion, D and Dartigues, JF and Deleuze, JF and Lambert, JC and Redon, R and Ludwig, T and Grenier-Boley, B and Letort, S and Lindenbaum, P and Meyer, V and Quenez, O and Dina, C and Bellenguez, C and Le Clézio, CC and Giemza, J and Chatel, S and Férec, C and Le Marec, H and Letenneur, L and Nicolas, G and Rouault, K}, title = {Heritable defects in telomere and mitotic function selectively predispose to sarcomas.}, journal = {Science (New York, N.Y.)}, volume = {379}, number = {6629}, pages = {253-260}, doi = {10.1126/science.abj4784}, pmid = {36656928}, issn = {1095-9203}, mesh = {Humans ; *Sarcoma/genetics/metabolism/pathology ; *Soft Tissue Neoplasms/genetics ; Telomere/genetics/metabolism ; Shelterin Complex ; *Melanoma/genetics ; }, abstract = {Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.}, }
@article {pmid36652742, year = {2023}, author = {Lv, BB and Yang, CL and Tan, ZX and Zheng, L and Li, MD and Jiang, YL and Liu, L and Tang, MM and Hua, DX and Yang, J and Xu, DX and Zhao, H and Fu, L}, title = {Association between cadmium exposure and pulmonary function reduction: Potential mediating role of telomere attrition in chronic obstructive pulmonary disease patients.}, journal = {Ecotoxicology and environmental safety}, volume = {251}, number = {}, pages = {114548}, doi = {10.1016/j.ecoenv.2023.114548}, pmid = {36652742}, issn = {1090-2414}, mesh = {Humans ; Cadmium/toxicity ; *Telomerase ; Forced Expiratory Volume ; *Pulmonary Disease, Chronic Obstructive ; Lung ; }, abstract = {BACKGROUND: Environmental cadmium (Cd) exposure is linked to pulmonary function injury in the general population. But, the association between blood Cd concentration and pulmonary function has not been investigated thoroughly in chronic obstructive pulmonary disease (COPD) patients, and the potential mechanisms are unclear.<br><br>METHODS: All eligible 789 COPD patients were enrolled from Anhui COPD cohort. Blood specimens and clinical information were collected. Pulmonary function test was conducted. The subunit of telomerase, telomerase reverse transcriptase (TERT), was determined through enzyme linked immunosorbent assay (ELISA). Blood Cd was measured via inductively coupled-mass spectrometer (ICP-MS).<br><br>RESULTS: Blood Cd was negatively and dose-dependently associated with pulmonary function. Each 1-unit increase of blood Cd was associated with 0.861&#xa0;L decline in FVC, 0.648&#xa0;L decline in FEV1, 5.938 % decline in FEV1/FVC %, and 22.098 % decline in FEV1 % among COPD patients, respectively. Age, current-smoking, self-cooking and higher smoking amount aggravated Cd-evoked pulmonary function decrease. Additionally, there was an inversely dose-response association between Cd concentration and TERT in COPD patients. Elevated TERT obviously mediated 29.53 %, 37.50 % and 19.48 % of Cd-evoked FVC, FEV1, and FEV1 % declines in COPD patients, respectively.<br><br>CONCLUSION: Blood Cd concentration is strongly associated with the decline of pulmonary function and telomerase activity among COPD patients. Telomere attrition partially mediates Cd-induced pulmonary function decline, suggesting an underlying mechanistic role of telomere attrition in pulmonary function decline from Cd exposure in COPD patients.}, }
@article {pmid36651908, year = {2023}, author = {James, EN and Sagi-Kiss, V and Bennett, M and Mycielska, ME and Karen-Ng, LP and Roberts, T and Matta, S and Dokal, I and Bundy, JG and Parkinson, EK}, title = {Dyskeratosis Congenita links telomere attrition to age-related systemic energetics.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glad018}, pmid = {36651908}, issn = {1758-535X}, support = {MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Underlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence associated metabolites in fibroblast conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/ mass spectrometry and liquid chromatography/ mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species (1-3). Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human ageing in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.}, }
@article {pmid36651296, year = {2023}, author = {Storchova, R and Palek, M and Palkova, N and Veverka, P and Brom, T and Hofr, C and Macurek, L}, title = {Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres.}, journal = {Nucleic acids research}, volume = {}, number = {}, pages = {}, doi = {10.1093/nar/gkac1269}, pmid = {36651296}, issn = {1362-4962}, abstract = {Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D localises at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.}, }
@article {pmid36650155, year = {2023}, author = {Tham, CY and Poon, L and Yan, T and Koh, JYP and Ramlee, MK and Teoh, VSI and Zhang, S and Cai, Y and Hong, Z and Lee, GS and Liu, J and Song, HW and Hwang, WYK and Teh, BT and Tan, P and Xu, L and Koh, AS and Osato, M and Li, S}, title = {High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {281}, pmid = {36650155}, issn = {2041-1723}, mesh = {Humans ; *Telomere/genetics ; *Shelterin Complex ; Aging ; }, abstract = {Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.}, }
@article {pmid36649908, year = {2023}, author = {Lambert-Lanteigne, P and Young, A and Autexier, C}, title = {Complex interaction network revealed by mutation of human telomerase 'Insertion in Fingers' and essential N-terminal domains, and the telomere protein TPP1.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {102916}, doi = {10.1016/j.jbc.2023.102916}, pmid = {36649908}, issn = {1083-351X}, abstract = {In the majority of human cancer cells, cellular immortalization depends on the maintenance of telomere length by telomerase. An essential step required for telomerase function is its recruitment to telomeres, which is regulated by the interaction of the telomere protein, TPP1, with the telomerase essential N-terminal (TEN) domain of the human telomerase reverse transcriptase, hTERT. We previously reported that the hTERT 'insertion in fingers domain' (IFD) recruits telomerase to telomeres in a TPP1-dependent manner. Here we use hTERT truncations and the IFD domain containing mutations in conserved residues or premature aging disease-associated mutations to map the interactions between the IFD and TPP1. We find that the hTERT-IFD domain can interact with TPP1. However, deletion of the IFD motif in hTERT lacking the N-terminus and the C-terminal extension does not abolish interaction with TPP1, suggesting the IFD is not essential for hTERT interaction with TPP1. Several conserved residues in the central IFD-TRAP region that we reported regulate telomerase recruitment to telomeres and cell immortalization compromise interaction of the hTERT-IFD domain with TPP1 when mutated. Using a similar approach, we find that the IFD domain interacts with the TEN domain, but is not essential for intramolecular hTERT interactions with the TEN domain. IFD-TEN interactions are not disrupted by multiple amino acid changes in the IFD or TEN, thus highlighting a complex regulation of IFD-TEN interactions as suggested by recent cryo-EM structures of human telomerase.}, }
@article {pmid36649354, year = {2023}, author = {Schneper, LM and Drake, AJ and Dunstan, T and Kotenko, I and Notterman, DA and Piyasena, C}, title = {Characteristics of salivary telomere length shortening in preterm infants.}, journal = {PloS one}, volume = {18}, number = {1}, pages = {e0280184}, pmid = {36649354}, issn = {1932-6203}, mesh = {Infant ; Female ; Humans ; Infant, Newborn ; *Infant, Premature ; *Telomere Shortening ; Gestational Age ; Maternal Age ; Telomere/genetics ; }, abstract = {OBJECTIVE: To examine the association between gestational age, telomere length (TL) and rate of shortening in newborns.<br><br>STUDY DESIGN: Genomic DNA was isolated from buccal samples of 39 term infants at birth and one year and 32 preterm infants at birth, term-adjusted age (40 weeks post-conception) and age one-year corrected for gestational duration. Telomere length was measured by quantitative real-time PCR. Demographic and clinical data were collected during clinic or research visits and from hospital records. Socioeconomic status was estimated using the deprivation category (DEPCAT) scores derived from the Carstairs score of the subject's postal code.<br><br>RESULTS: At birth, preterm infants had longer telomeres than infants born at term. However, there was no difference in telomere length between preterm infants and term infants at one year of age, implying that the rate of telomere shortening was greater in pre-term than term infants. Interestingly, TL at age 40 weeks post-conception in preterm infants was significantly longer than term infant TL at birth, suggesting that time since conception is not the only factor that affects rate of shortening. Several factors, including sex, fetal growth restriction, maternal age, maternal booking body mass index (BMI), mother education level and DEPCAT score, also differed between the preterm and term groups.<br><br>CONCLUSIONS: Preterm infants have longer telomeres than term infants at birth. In the studied cohort, the rate of telomere shortening was greater in the premature group compared with the term infants. This finding agrees with previous studies using cord blood, suggesting that the longer TL in premature infants detected at birth do not persist and demonstrating that use of saliva DNA is acceptable for studies of telomere dynamics in infants. However, that the TL at age 40 weeks post-conception in preterm is longer than term infants at birth suggests that biological factors other than time since conception also affect rate of shortening.}, }
@article {pmid36643758, year = {2023}, author = {Fu, A and Zheng, Y and Guo, J and Grierson, D and Zhao, X and Wen, C and Liu, Y and Li, J and Zhang, X and Yu, Y and Ma, H and Wang, Q and Zuo, J}, title = {Telomere-to-telomere genome assembly of bitter melon (Momordica charantia L. var. abbreviata Ser.) reveals fruit development, composition and ripening genetic characteristics.}, journal = {Horticulture research}, volume = {10}, number = {1}, pages = {uhac228}, pmid = {36643758}, issn = {2662-6810}, abstract = {Momordica charantia L. var. abbreviata Ser. (Mca), known as bitter gourd or bitter melon, is a Momordica variety with medicinal value and belongs to the Cucurbitaceae family. In view of the lack of genomic information on bitter gourd and other Momordica species and to promote Mca genomic research, we assembled a 295.6-Mb telomere-to-telomere (T2T) high-quality Mca genome with six gap-free chromosomes after Hi-C correction. This genome is anchored to 11 chromosomes, which is consistent with the karyotype information, and comprises 98 contigs (N50 of 25.4 Mb) and 95 scaffolds (N50 of 25.4 Mb). The Mca genome harbors 19 895 protein-coding genes, of which 45.59% constitute predicted repeat sequences. Synteny analysis revealed variations involved in fruit quality during the divergence of bitter gourd. In addition, assay for transposase-accessible chromatin by high-throughput sequencing and metabolic analysis showed that momordicosides and other substances are characteristic of Mca fruit pulp. A combined transcriptomic and metabolomic analysis revealed the mechanisms of pigment accumulation and cucurbitacin biosynthesis in Mca fruit peels, providing fundamental molecular information for further research on Mca fruit ripening. This report provides a new genetic resource for Momordica genomic studies and contributes additional insights into Cucurbitaceae phylogeny.}, }
@article {pmid36642039, year = {2023}, author = {Zong, ZQ and Chen, SW and Wu, Y and Gui, SY and Zhang, XJ and Hu, CY}, title = {Ambient air pollution exposure and telomere length: a systematic review and meta-analysis.}, journal = {Public health}, volume = {215}, number = {}, pages = {42-55}, doi = {10.1016/j.puhe.2022.11.022}, pmid = {36642039}, issn = {1476-5616}, mesh = {Child ; Adult ; Female ; Pregnancy ; Humans ; Nitrogen Dioxide/analysis ; Environmental Exposure ; *Air Pollution/analysis ; *Air Pollutants/adverse effects/analysis ; Particulate Matter/adverse effects/analysis ; Telomere/chemistry ; }, abstract = {OBJECTIVE: This study aimed to provide evidence of the associations between pre- and post-birth and adulthood air pollution exposure with telomere length.<br><br>STUDY DESIGN: The databases of PubMed, Embase, and Web of Science were searched up to June 1st, 2022 in order to include relevant observational studies and perform a systematic review and meta-analysis.<br><br>METHODS: The random-effects meta-analysis was grouped by air pollutant and exposure window (pre- and post-birth and adulthood) to evaluate the summary effect estimate. Cochran's Q and I[2] statistics were used to evaluate the heterogeneity among the included studies. The quality of individual studies was evaluated using the national toxicology program/office of health assessment and translation risk of bias rating tool.<br><br>RESULTS: We identified 18 studies, covering 8506 children and 2263 adults from multiple countries. We found moderate evidence that particulate matter less than 2.5&#xa0;&#x3bc;m (PM2.5) exposure during the entire pregnancy (-0.043, 95% CI:&#xa0;-0.067,&#xa0;-0.018), nitrogen dioxide (NO2) exposure during the first trimester (-0.016, 95% confidence interval [CI]:&#xa0;-0.027,&#xa0;-0.005), long-term adulthood PM2.5 exposure were associated with shortening telomere length. Mild to high between-study heterogeneity was observed for the most tested air pollutant-telomere length combinations in different exposure windows.<br><br>CONCLUSIONS: This systematic review and meta-analysis provides the evidence which strongly supports that prenatal PM2.5 and NO2 exposures were related to reduced telomere length, while prenatal sulfur dioxide (SO2) and carbon monoxide (CO) exposures, childhood PM2.5, particulate matter less than 10&#xa0;&#x3bc;m (PM10), NO2 exposures and short-term adulthood PM2.5 and PM10 exposures were not associated with telomere length. Further high-quality studies are needed to elaborate our suggestive associations.}, }
@article {pmid36641077, year = {2023}, author = {Siegel, SR and Ulrich, M and Logue, SF}, title = {Comparison qPCR study for selecting a valid single copy gene for measuring absolute telomere length.}, journal = {Gene}, volume = {860}, number = {}, pages = {147192}, doi = {10.1016/j.gene.2023.147192}, pmid = {36641077}, issn = {1879-0038}, abstract = {Telomere shortening is a well-known biomarker for biological aging. A previous review of the methods used to measure telomere length (TL) noted how challenging it is to compare results from different studies using diverse methodological techniques. The most commonly used high throughput method for measuring average TL is the quantitative PCR (qPCR) method, where there are two protocols available; the relative TL and the absolute TL (aTL) method. All qPCR methods have similarities in that they use two different primer sets to measure the telomere repeat sequence (TTAGGG)n and a single copy gene region to calculate the average TL, (T/S) ratio. The difference between the relative TL and the aTL assay lies with the introduction of duplex oligomer standards to identify TL in kilobase pairs rather than using the traditional relative TL, T/S ratio method. Problems were noted using 36B4 (RPLP0), which was originally used as a suitable single copy gene qPCR assay. A previous aTL publication attempted to replace the 36B4 (RPLP0) single copy gene using the Interferon beta 1 gene (IFNB1) but results showed a lack of agreement with the TL results when compared to the DNAmTL assay. Here, we compare the two single copy gene assays previously used for the aTL assay and offer an alternative IFNB1 single copy gene assay without non-specific priming amplification to provide more consistent diploid copy number determination and a more robust and reproducible assay for measuring absolute TL.}, }
@article {pmid36636341, year = {2023}, author = {Guo, YZ and Zhang, Y and Wang, Q and Yu, J and Wan, QH and Huang, J and Fang, SG}, title = {Alternative telomere maintenance mechanism in Alligator sinensis provides insights into aging evolution.}, journal = {iScience}, volume = {26}, number = {1}, pages = {105850}, pmid = {36636341}, issn = {2589-0042}, abstract = {Lifespan is a life-history trait that undergoes natural selection. Telomeres are hallmarks of aging, and shortening rate predicts species lifespan, making telomere maintenance mechanisms throughout different lifespans a worthy topic for study. Alligators are suitable for the exploration of anti-aging molecular mechanisms, because they exhibit low or even negligible mortality in adults and no significant telomere shortening. Telomerase reverse transcriptase (TERT) expression is absent in the adult Alligator sinensis, as in humans. Selection analyses on telomere maintenance genes indicated that ATM, FANCE, SAMHD1, HMBOX1, NAT10, and MAP3K4 experienced positive selection on A. sinensis. Repressed pleiotropic ATM kinase in A. sinensis suggests their fitness optimum shift. In ATM downstream, Alternative Lengthening of Telomeres (ALT)-related genes were clustered in a higher expression pattern in A. sinensis, which covers 10-15% of human cancers showing no telomerase activities. In summary, we demonstrated how telomere shortening, telomerase activities, and ALT contributed to anti-aging strategies.}, }
@article {pmid36635307, year = {2023}, author = {Romero-Zamora, D and Hayashi, MT}, title = {A non-catalytic N-terminus domain of WRN prevents mitotic telomere deprotection.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {645}, pmid = {36635307}, issn = {2045-2322}, mesh = {Werner Syndrome Helicase/genetics/metabolism ; *Exodeoxyribonucleases/genetics ; *Telomeric Repeat Binding Protein 2 ; RecQ Helicases/genetics/metabolism ; Telomere/genetics/metabolism ; }, abstract = {Telomeric ends form a loop structure (T-loop) necessary for the repression of ATM kinase activation throughout the normal cell cycle. However, cells undergoing a prolonged mitotic arrest are prone to lose the T-loop, resulting in Aurora B kinase-dependent mitotic telomere deprotection, which was proposed as an anti-tumor mechanism that eliminates precancerous cells from the population. The mechanism of mitotic telomere deprotection has not been elucidated. Here, we show that WRN, a RECQ helicase family member, can suppress mitotic telomere deprotection independently of its exonuclease and helicase activities. Truncation of WRN revealed that N-terminus amino acids 168-333, a region that contains a coiled-coil motif, is sufficient to suppress mitotic telomere deprotection without affecting both mitotic Aurora B-dependent spindle checkpoint and ATM kinase activity. The suppressive activity of the WRN[168-333] fragment is diminished in cells partially depleted of TRF2, while WRN is required for complete suppression of mitotic telomere deprotection by TRF2 overexpression. Finally, we found that phosphomimetic but not alanine mutations of putative Aurora B target sites in the WRN[168-333] fragment abolished its suppressive effect. Our findings reveal a non-enzymatic function of WRN, which may be regulated by phosphorylation in cells undergoing mitotic arrest. We propose that WRN enhances the protective function of TRF2 to counteract the hypothetical pathway that resolves the mitotic T-loop.}, }
@article {pmid36634459, year = {2023}, author = {Vulsteke, JB and Smith, V and Bonroy, C and Derua, R and Blockmans, D and De Haes, P and Vanderschueren, S and Lenaerts, JL and Claeys, KG and Wuyts, WA and Verschueren, P and Vanhandsaeme, G and Piette, Y and De Langhe, E and Bossuyt, X}, title = {Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis.}, journal = {Journal of autoimmunity}, volume = {135}, number = {}, pages = {102988}, doi = {10.1016/j.jaut.2022.102988}, pmid = {36634459}, issn = {1095-9157}, abstract = {PURPOSE: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity.<br><br>METHODS: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n&#xa0;=&#xa0;467), other systemic autoimmune rheumatic diseases (n&#xa0;=&#xa0;923), non-rheumatic disease controls (n&#xa0;=&#xa0;187) and healthy controls (n&#xa0;=&#xa0;199).<br><br>RESULTS: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n&#xa0;=&#xa0;3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n&#xa0;=&#xa0;1), homeobox-containing protein 1 (HMBOX1, n&#xa0;=&#xa0;2), regulator of chromosome condensation 1 (RCC1, n&#xa0;=&#xa0;1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n&#xa0;=&#xa0;1), dyskerin (DKC1, n&#xa0;=&#xa0;1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n&#xa0;=&#xa0;1) and nuclear valosin-containing protein-like (NVL, n&#xa0;=&#xa0;2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB.<br><br>CONCLUSION: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.}, }
@article {pmid36627320, year = {2023}, author = {Sohn, I and Shin, C and Baik, I}, title = {Associations of green tea, coffee, and soft drink consumption with longitudinal changes in leukocyte telomere length.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {492}, pmid = {36627320}, issn = {2045-2322}, mesh = {Male ; Humans ; Female ; *Coffee ; *Tea ; Carbonated Beverages ; Leukocytes ; Telomere ; }, abstract = {Whether beverage consumption is associated with longitudinal observation of telomere length remains unclear. We evaluated the association of green tea, coffee, and soft drink consumption with 6-year changes in leukocyte telomere length (LTL). The study included 1952 participants who provided whole blood samples for LTL assays during the baseline (year 2011-2012) and follow-up (year 2017-2018) periods and reported baseline information on consumption of green tea, coffee, and soft drinks. Robust regression analysis was used to analyze the association adjusted for potential confounding variables. In the results, an inverse association between green tea consumption and LTL changes from baseline, which indicate telomere shortening, was found; regression coefficient [95% confidence interval] was - 0.097 [- 0.164, - 0.029] for participants who daily consumed at least 1 cup of green tea compared with non-consumers (p value = 0.006). This association was stronger among women (versus men) and younger participants aged 50-64 years (versus older). However, a positive association between soft drink consumption and LTL shortening was observed among women (p value < 0.05). Coffee consumption was not associated with LTL changes. These findings suggested that green tea consumption may be protective against telomere shortening reflecting biological aging whereas coffee and soft drink consumption may not.}, }
@article {pmid36617609, year = {2023}, author = {Montoya, M and Uchino, BN}, title = {Social support and telomere length: a meta-analysis.}, journal = {Journal of behavioral medicine}, volume = {}, number = {}, pages = {}, pmid = {36617609}, issn = {1573-3521}, support = {R01HL137606/HL/NHLBI NIH HHS/United States ; }, abstract = {Previous studies have shown that lower social support is associated with higher all-cause mortality (Holt-Lunstad et al. in PLoS ONE Medicine 7:e1000316, 2010). While social support has been associated with system-specific biological measures (e.g., cardiovascular), there is the need to elucidate more general biological mechanisms linking social support to health risk across a number of diseases. In this meta-analytic review, the link between social support and telomere length (Cawthon et al. in Lancet 361:393-395, 2003) was conducted based on the updated PRISMA guidelines (Page et al., 2021). Across 17 studies, higher social support was not significantly related to longer telomere length (Zr = 0.010, 95% CI [- 0.028, 0.047], p > 0.05). The confidence interval indicated that the bulk of plausible values were small to null associations. Little evidence for bias was found as shown by funnel plots and Kendall's Tau. Moderator analyses focusing on the measure of support, health of sample, age, type of assay specimen, and gender were not significant. In conclusion, this review showed no significant relationship between social support and telomere length and highlights important future directions.}, }
@article {pmid36612286, year = {2022}, author = {Faugeras, E and Véronèse, L and Jeannin, G and Janicot, H and Bailly, S and Bay, JO and Pereira, B and Cayre, A and Penault-Llorca, F and Cachin, F and Merle, P and Tchirkov, A}, title = {Telomere Status of Advanced Non-Small-Cell Lung Cancer Offers a Novel Promising Prognostic and Predictive Biomarker.}, journal = {Cancers}, volume = {15}, number = {1}, pages = {}, pmid = {36612286}, issn = {2072-6694}, abstract = {Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.}, }
@article {pmid36612269, year = {2022}, author = {García-Martínez, S and González-Gamo, D and Tesolato, SE and Barabash, A and de la Serna, SC and Domínguez-Serrano, I and Dziakova, J and Rivera, D and Torres, AJ and Iniesta, P}, title = {Telomere Length and Telomerase Activity in Subcutaneous and Visceral Adipose Tissues from Obese and Non-Obese Patients with and without Colorectal Cancer.}, journal = {Cancers}, volume = {15}, number = {1}, pages = {}, pmid = {36612269}, issn = {2072-6694}, abstract = {To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index (BMI). Adipose tissues were obtained from 147 patients who had undergone surgery. A total of 66 cases corresponded to CRC patients, and 81 subjects were not affected by cancer. Relative telomere length was established by qPCR, and telomerase activity was determined by a method based on the telomeric repeat amplification protocol. Our results indicated longer telomeres in patients affected by CRC, both in SAT and VAT, when compared to the group of subjects without CRC. Tumor local invasion was associated with telomere length (TL) in SAT. Considering the BMI values, significant differences were found in the TL of both adipose tissues between subjects affected by CRC and those without cancer. Overweight subjects showed the greatest differences, with longer telomeres in the group of CRC patients, and a higher number of cases with telomerase reactivation in the VAT of subjects without cancer. In conclusion, parameters related to telomere function in adipose tissue could be considered as potential biomarkers in the evaluation of CRC and obesity.}, }
@article {pmid36609582, year = {2023}, author = {Rolles, B and Ferreira, MSV and Vieri, M and Rheinwalt, KP and Schmitz, SM and Alizai, PH and Neumann, U and Brümmendorf, TH and Beier, F and Ulmer, TF and Tometten, M}, title = {Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {304}, pmid = {36609582}, issn = {2045-2322}, mesh = {Humans ; *Quality of Life ; Obesity/surgery ; *Bariatric Surgery ; Telomere ; }, abstract = {Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m[2]. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.}, }
@article {pmid36607563, year = {2023}, author = {Troxel, WM and Madrigano, J and Haas, AC and Dubowitz, T and Rosso, AL and Prather, AA and Ghosh-Dastidar, M and Weinstein, AM and Butters, MA and Presto, A and Gary-Webb, TL}, title = {Examining the Cross-sectional Association Between Neighborhood Conditions, Discrimination, and Telomere Length in a Predominantly African American Sample.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {36607563}, issn = {2196-8837}, support = {NHLBI R01 HL131531/HL/NHLBI NIH HHS/United States ; R01-HL131531-S2/HL/NHLBI NIH HHS/United States ; AG072652/AG/NIA NIH HHS/United States ; }, abstract = {Disproportionate exposure to adverse neighborhood conditions and greater discrimination may contribute to health disparities among African Americans (AAs). We examined whether adverse neighborhood conditions, alone or in conjunction with discrimination, associate with shorter leukocyte telomere length among a predominantly AA cohort. The sample included 200 residents from two low-income neighborhoods (96% AA; mean age = 67 years). Perceived neighborhood conditions and discrimination were surveyed in 2018, and objective neighborhood conditions (total crime rate, neighborhood walkability, ambient air pollution (PM2.5, black carbon)) were collected in 2017/2018. Relative telomere length (T/S; ratio of telomeric DNA to a single-gene copy) was assessed from blood samples. Linear regression models estimated the main effects of each neighborhood condition and discrimination and their interactions on the T/S ratio. Less walkable neighborhoods were associated with shorter telomeres. Higher air pollution (PM2.5) was associated with shorter telomeres among those experiencing greater discrimination. Findings highlight the importance of understanding the intersecting influences of historic and contemporary sources of systemic racism and how they contribute to accelerated aging among adults.}, }
@article {pmid36607418, year = {2023}, author = {Hassanpour, H and Farhadi, N and Bahadoran, S and Akbari, MR}, title = {Cardiac telomere attrition following changes in the expression of shelterin genes in pulmonary hypertensive chickens.}, journal = {British poultry science}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/00071668.2022.2163877}, pmid = {36607418}, issn = {1466-1799}, abstract = {1. The alterations of relative telomere length and expression of shelterin genes (TRF1, TRF2, RAP1, POT1, and TPP1) were evaluated from the chickens' right heart ventricle in the early and last stages of cold-induced pulmonary hypertension (PHS) at 21 and 42 d of age.2. The relative telomere length in the right ventricular tissues was significantly shorter in the PHS group of broilers than in the control group at 42 d, but did not statistically change at 21 d of age. There was a significant negative correlation between relative telomere length and RV:TV ratio in the broilers at 42 d of age.3. The relative expression of POT1, RAP1 and TPP1 genes in the right ventricular tissues was significantly lower in the PHS group than in the control group at 21 d. The relative expression of the TRF2 gene was only higher in the PHS group of broilers than control at 42 d. The mRNA level of the TRF2 gene exhibited a significant positive correlation with RV:TV ratio at 42 d.4. It was concluded that most shelterin genes are dysregulated in the early stage of PHS (right ventricular hypertrophy) while telomere attrition occurs only at the last stage (heart dilation/failure).}, }
@article {pmid36605550, year = {2022}, author = {Ask, TF and Sütterlin, S}, title = {Prefrontally modulated vagal neuroimmunomodulation is associated with telomere length.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1063162}, pmid = {36605550}, issn = {1662-4548}, abstract = {BACKGROUND: Accumulated senescent cells are proposed to be one of the main drivers of age-related pathology such as dementia and cancer through disruption of tissue structure and function. We recently proposed the Neuro-Immuno-Senescence Integrative Model (NISIM), which relates prefrontally modulated vagal tone and subsequent balance between vagal and sympathetic input to the spleen to inflammatory responses leading to generation of reactive oxygen species and oxidative telomere damage.<br><br>AIM: In this study, we assess inflammation as a mediator in the relationship between prefrontally modulated vagal tone and leukocyte telomere length (LTL). We also assess the relationship between a recently proposed index of vagal neuroimmunomodulation (vagal tone/inflammation ratio; NIM index) and telomere length.<br><br>METHODS: This study uses participant data from a large nationally representative longitudinal study since 1974 with a total of 45,000 Norwegian residents so far. A sub-sample of 131 participants from which ultrashort recordings (30 s) of vagal tone, c reactive protein, and LTL could be obtained were included in the study. Relationships were analyzed with Pearson's correlations and hierarchical multiple linear regression using either vagal tone and CRP or the NIM index to predict telomere length.<br><br>RESULTS: Vagal tone was a significant positive predictor of telomere length but this was not mediated by c reactive protein, even after controlling for confounders. The NIM index was a significant positive predictor of telomere length, also when controlling for confounders. In a follow-up analysis simultaneously comparing telomere length between groups with high and low values of vagal tone, and between groups with high and low NIM index values, telomere length was only significantly different between NIM index groups.<br><br>CONCLUSION: This is the first study suggesting that prefrontally modulated vagal neuroimmunomodulation is associated with telomere length thus supporting the NISIM. Results indicate that the NIM index is a more sensitive indicator of vagal neuroimmunomodulation than vagal tone and CRP in isolation.}, }
@article {pmid36604719, year = {2023}, author = {Liu, Q and Li, Z and Huang, L and Zhou, D and Fu, J and Duan, H and Wang, Z and Yang, T and Zhao, J and Li, W and Liu, H and Ma, F and Sun, C and Wang, G and Du, Y and Zhang, M and Chen, Y and Huang, G}, title = {Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study.}, journal = {Immunity &amp; ageing : I &amp; A}, volume = {20}, number = {1}, pages = {1}, pmid = {36604719}, issn = {1742-4933}, abstract = {BACKGROUND: Diet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI.<br><br>RESULTS: A population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (&#x3b2;:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (&#x3b2;:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (&#x3b2;: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (&#x3b2;:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk.<br><br>CONCLUSIONS: Higher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.}, }
@article {pmid36603485, year = {2023}, author = {Duan, X and Huang, T and Zhang, D and Wei, Y and Li, L and Yao, W and Cui, L and Zhou, X and Yang, Y and Wang, W and Zhao, J}, title = {Effect and interaction of TNKS genetic polymorphisms and environmental factors on telomere damage in COEs-exposure workers.}, journal = {Ecotoxicology and environmental safety}, volume = {250}, number = {}, pages = {114489}, doi = {10.1016/j.ecoenv.2022.114489}, pmid = {36603485}, issn = {1090-2414}, mesh = {Humans ; *Coke/adverse effects ; DNA Damage ; *Occupational Exposure/adverse effects/analysis ; *Polycyclic Aromatic Hydrocarbons/toxicity/analysis ; Polymorphism, Genetic ; *Tankyrases/genetics ; Telomere/genetics ; }, abstract = {Coke oven emissions (COEs) contain many carcinogenic polycyclic aromatic hydrocarbons (PAHs). Telomere damage is an early biological marker reflecting long-term COEs-exposure. Whereas, whether the genetic variations of telomere-regulated gene TNKS have an effect on the COEs-induced telomere damage is unknown. So we detected the environmental exposure levels, relative telomere length (RTL), and TNKS genetic polymorphisms among 544 COEs-exposure workers and 238 healthy participants. We found that the RTL of the wild homozygous GG genotype in rs1055328 locus was statistically shorter compared with the CG+CC genotype for the healthy participants using covariance analysis(P = 0.008). In the Generalized linear model (GLM) analysis, TNKS rs1055328 GG could accelerate telomere shortening (P = 0.011); and the interaction between TNKS rs1055328 GG and COEs-exposure had an effect on RTL (P = 0.002). In conclusion, this study was the first to discover the role of TNKS rs1055328 locus in COEs-induced telomere damage, and proved that chromosomal damage was a combined consequence of environmental and genetic factors.}, }
@article {pmid36601105, year = {2022}, author = {Hu, J and Song, J and Chen, Z and Yang, J and Shi, Q and Jin, F and Pang, Q and Chang, X and Tian, Y and Luo, Y and Chen, L}, title = {Reverse causal relationship between periodontitis and shortened telomere length: Bidirectional two-sample Mendelian random analysis.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1057602}, pmid = {36601105}, issn = {1664-3224}, mesh = {Humans ; Causality ; *Chronic Periodontitis ; *Genome-Wide Association Study ; Telomere/genetics ; Telomere Shortening ; }, abstract = {BACKGROUND: Observational studies have demonstrated a link between shortened telomere lengths(TL) and chronic periodontitis. However, whether the shortened TL is the cause or the result of periodontitis is unknown.Therefore, our objective was to investigate a bidirectional causal relationship between periodontitis and TL using a two-sample Mendel randomized (MR) study.<br><br>METHODS: A two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) data was used. As the primary analysis, inverse variance weighting (IVW) was employed. To identify pleiotropy, we used leave-one-out analysis, MR-Egger, Weighted median, Simple mode, Weighted mode, and MR pleiotropy residual sum and outlier (MR-PRESSO).<br><br>RESULTS: In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR. No pleiotropy was detected in sensitivity analysis (all P>0.05).<br><br>CONCLUSION: Our MR studies showed a reverse causal relationship, with shorten TL being linked to a higher risk of periodontitis, rather than periodontitis shorten that TL. Future research is needed to investigate the relationship between cell senescence and the disease.}, }
@article {pmid36592269, year = {2023}, author = {Seki, Y and Aczel, D and Torma, F and Jokai, M and Boros, A and Suzuki, K and Higuchi, M and Tanisawa, K and Boldogh, I and Horvath, S and Radak, Z}, title = {No strong association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging.}, journal = {Biogerontology}, volume = {}, number = {}, pages = {}, pmid = {36592269}, issn = {1573-6768}, abstract = {Cellular senescence is greatly accelerated by telomere shortening, and the steps forward in human aging are strongly influenced by environmental and lifestyle factors, whether DNA methylation (DNAm) is affected by exercise training, remains unclear. In the present study, we investigated the relationships between physiological functions, maximal oxygen uptake (VO2max), vertical jump, working memory, telomere length (TL) assessed by RT-PCR, DNA methylation-based estimation of TL (DNAmTL), and DNA methylation-based biomarkers of aging of master rowers (N = 146) and sedentary subjects (N = 95), aged between 37 and 85 years. It was found that the TL inversely correlated with chronological age. We could not detect an association between telomere length and VO2max, vertical jump, and working memory by RT-PCR method, while these physiological test results showed a correlation with DNAmTL. DNAmGrimAge and DNAmPhenoAge acceleration were inversely associated with telomere length assessed by both methods. It appears that there are no strong beneficial effects of exercise or physiological fitness on telomere shortening, however, the degree of DNA methylation is associated with telomere length.}, }
@article {pmid36591268, year = {2022}, author = {Lv, Z and Cui, J and Zhang, J}, title = {Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1065739}, pmid = {36591268}, issn = {1664-3224}, mesh = {Humans ; Biological Specimen Banks ; Biomarkers/blood ; Genome-Wide Association Study ; *Hyperuricemia/blood/genetics/immunology ; *Inflammation/blood/genetics/immunology ; Insulin-Like Growth Factor I ; Interleukin-6 ; *Telomere/genetics/immunology ; Tumor Necrosis Factor-alpha ; United Kingdom ; *Uric Acid/blood/immunology ; *Gout/blood/immunology ; }, abstract = {OBJECTIVE: Hyperuricemia and gout have become gradually more common. The effect of serum urate on organism aging and systematic inflammation is not determined. This study aims to evaluate whether serum urate is causally associated with cellular aging markers and serum inflammation markers.<br><br>METHODS: A Mendelian randomization study was performed on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with a genome-wide significance level were selected as instrumental variables for leukocyte telomere length (LTL), and serum soluble makers of inflammation (CRP, IL-6, TNF-&#x3b1;, and IGF-1). Standard inverse variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods were used for sensitivity analysis.<br><br>RESULTS: An inverse causal association of genetically predicted serum urate levels and LTL was found using IVW method (OR: 0.96, 95%CI 0.95, 0.97; &#x3b2;=-0.040; SE=0.0072; P=4.37&#xd7;10[-8]). The association was also supported by MR results using MR-Egger method and weighted median method. The MR-PRESSO analysis and leave-one-out sensitivity analysis supported the robustness of the combined results. In terms of other aging-related serum biomarkers, there was no evidence supporting a causal effect of serum urate on CRP, IL-6, TNF-&#x3b1;, or IGF-1 levels.<br><br>CONCLUSIONS: Serum urate levels are negatively associated with telomere length but are not associated with serum soluble indicators of inflammation. Telomere length may be a critical marker that reflects urate-related organismal aging and may be a mechanism in the age-related pathologies and mortality caused by hyperuricemia.}, }
@article {pmid36589292, year = {2022}, author = {Al Khleifat, A and Iacoangeli, A and Jones, AR and van Vugt, JJFA and Moisse, M and Shatunov, A and Zwamborn, RAJ and van der Spek, RAA and Cooper-Knock, J and Topp, S and van Rheenen, W and Kenna, B and Van Eijk, KR and Kenna, K and Byrne, R and López, V and Opie-Martin, S and Vural, A and Campos, Y and Weber, M and Smith, B and Fogh, I and Silani, V and Morrison, KE and Dobson, R and van Es, MA and McLaughlin, RL and Vourc'h, P and Chio, A and Corcia, P and de Carvalho, M and Gotkine, M and Panades, MP and Mora, JS and Shaw, PJ and Landers, JE and Glass, JD and Shaw, CE and Basak, N and Hardiman, O and Robberecht, W and Van Damme, P and van den Berg, LH and Veldink, JH and Al-Chalabi, A}, title = {Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1050596}, pmid = {36589292}, issn = {1662-5102}, support = {R01 NS073873/NS/NINDS NIH HHS/United States ; R56 NS073873/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.<br><br>METHODS: Samples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.<br><br>RESULTS: There were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 &#xd7; 10[-12]), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0&#xd7;10[-7]). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0&#xd7;10[-4]).<br><br>DISCUSSION: Although telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.}, }
@article {pmid36586020, year = {2022}, author = {Liu, Y and Song, L and Wu, M and Bi, J and Wang, L and Liu, Q and Xiong, C and Cao, Z and Xu, S and Wang, Y}, title = {Association between rare earth element exposure during pregnancy and newborn telomere length.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {36586020}, issn = {1614-7499}, abstract = {Telomere length (TL) is considered a marker of biological aging and lifetime health, and some epidemiological studies report that the environmental exposures may influence TL at birth. We aimed to investigate the associations between prenatal rare earth elements (REE) exposure and newborn TL. A total of 587 mother-newborn pairs were recruited during 2013 to 2015 in Wuhan, China. Maternal urinary concentrations of REE collected during three trimesters were measured by inductively coupled plasma mass spectrometry. Quantitative real-time polymerase chain reaction was used to measure relative cord blood TL. The trimester-specific associations between prenatal REE exposure and cord blood TL were evaluated using multiple informant models. Weighted quantile sum regression was used to estimate the mixture effect of urinary REE on cord blood TL. After adjustment for potential confounders, per doubling of urinary REE (Dy, Yb, Pr, Nd, and Tm) concentrations (μg/g creatinine) during the second trimester was respectively associated with 1.94% (95% CI 0.19%, 3.72%), 2.10% (95% CI 0.31%, 3.92%), 2.11% (95% CI 0.35%, 3.89%), 2.08% (95% CI 0.01%, 4.20%), and 1.38% (95% CI 0.09%, 2.70%) increase in cord blood TL. Furthermore, exposure to the mixture of REE during the second trimester was also significantly associated with increased cord blood TL (percent change 1.20%, 95% CI 0.30%, 2.11%). However, these associations were not statistically significant in the first and third trimesters. This study provides new evidence on the potential effect of prenatal REE exposure on the initial (newborn) setting of offspring's telomere biology. Further epidemiological studies are warranted to confirm our findings.}, }
@article {pmid36585257, year = {2023}, author = {Mei, Q and Yu, Q and Li, X and Chen, J and Yu, X}, title = {Regulation of telomere silencing by the core histones-autophagy-Sir2 axis.}, journal = {Life science alliance}, volume = {6}, number = {3}, pages = {}, pmid = {36585257}, issn = {2575-1077}, mesh = {*Histones/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Gene Silencing ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/genetics/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics/metabolism ; Sirtuin 2/genetics/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; }, abstract = {Telomeres contain compacted heterochromatin, and genes adjacent to telomeres are subjected to transcription silencing. Maintaining telomere structure integrity and transcription silencing is important to prevent the occurrence of premature aging and aging-related diseases. How telomere silencing is regulated during aging is not well understood. Here, we find that the four core histones are reduced during yeast chronological aging, leading to compromised telomere silencing. Mechanistically, histone loss promotes the nuclear export of Sir2 and its degradation by autophagy. Meanwhile, reducing core histones enhances the autophagy pathway, which further accelerates autophagy-mediated Sir2 degradation. By screening the histone mutant library, we identify eight histone mutants and one histone modification (histone methyltransferase Set1-catalyzed H3K4 trimethylation) that regulate telomere silencing by modulating the core histones-autophagy-Sir2 axis. Overall, our findings reveal core histones and autophagy as causes of aging-coupled loss of telomere silencing and shed light on dynamic regulation of telomere structure during aging.}, }
@article {pmid36582083, year = {2022}, author = {Dondoladze, K and Nikolaishvili, M and Museliani, T and Jikia, G}, title = {EFFECT OF RADIATION ON AGING PROCESSES AND TELOMERE LENGTH.}, journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii}, volume = {27}, number = {}, pages = {107-119}, doi = {10.33145/2304-8336-2022-27-107-119}, pmid = {36582083}, issn = {2313-4607}, mesh = {*Antioxidants ; *Cellular Senescence/genetics ; Oxidative Stress ; Telomere/genetics ; }, abstract = {Telomeres are the ending areas of chromosomes - protective «caps» that ensure the stability of chromosomes. Telomere shortening is one of the most important biological signs of aging and is involved in cellular aging and the «mitotic clock» mechanism. One of the known mechanisms of the impact of radiation on the aging process is damage to telomeres by free radicals. Oxidative stress has a toxic effect on telomere length. The increase in free radicals occurs under the action of both ionizing and nonionizing radiation, although antioxidant mechanisms are often able to neutralize harmful free radicals. Low doses of nonionizing and ionizing radiation even cause the activation of antioxidant systems, however, when the body is exposed to radiation at a high dose or for a long time, or if pathological processes with oxidative stress occur in the body, damage to cells becomes more noticeable, and aging processes accelerate. Maintaining telomere length and a normal rate of aging is important for health. In this review, we want to discuss the role of ionizing and nonionizing radiation in cellular aging, in particular, in the shortening of telomere length.}, }
@article {pmid36579443, year = {2022}, author = {Clé, DV and Catto, LFB and Gutierrez-Rodrigues, F and Donaires, FS and Pinto, AL and Santana, BA and Darrigo, LG and Valera, ET and Koenigkam-Santos, M and Baddini-Martinez, J and Young, NS and Martinez, EZ and Calado, RT}, title = {Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2022.281808}, pmid = {36579443}, issn = {1592-8721}, abstract = {Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial, 17 patients with short telomeres and/or germline pathogenic variants in telomere-biology genes associated with at least one cytopenia and/or radiologic diagnosis of ILD were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-FISH (average increase, 0.87 kb; 95% CI, 0.20-1.55 kb; p=0.01). At 24 months, all 10 evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% CI, 0.24-1.23 kb; p=0.18). Hematologic response was achieved in 8/16 patients (50%) with marrow failure at 12 months, and in 10/16 patients (63%) at 24 months. Seven patients had ILD at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events (AE) were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No AE grade ≥ 4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events. ClinicalTrials.gov Identifier: NCT02055456.}, }
@article {pmid36579149, year = {2022}, author = {Wang, J and Hao, Y and Zhu, Z and Liu, B and Zhang, X and Wei, N and Wang, T and Lv, Y and Xu, C and Ma, M and Zhang, Y and Liu, F}, title = {Causality of telomere length associated with calcific aortic valvular stenosis: A Mendelian randomization study.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {1077686}, pmid = {36579149}, issn = {2296-858X}, abstract = {BACKGROUND: Observational studies have shown that calcific aortic valve stenosis (CAVS) is associated with a shorter telomere length (TL). However, the results of observational studies are often influenced by confounding factors and reverse causal associations; it is unclear whether there is a causal relationship between TL and CAVS. This study aimed to investigate the causal relationship between TL and CAVS.<br><br>MATERIALS AND METHODS: Genome-wide association study (GWAS) data on TL (n = 472,174) and CAVS (n = 311,437) were used to assess the effect of TL on CAVS. All the participants were of European ancestry. Three Mendelian randomization (MR) methods, namely, MR-Egger, weighted median, and inverse variance weighted (IVW), were used to assess the potential causal effect of TL on CAVS. Heterogeneity was assessed using Cochran's Q statistic. Leave-one-out and MR-Egger regression methods were used for sensitivity and pleiotropy analyses. Forward and reverse MR analyses were performed.<br><br>RESULTS: In total, 118 valid and independent TL genetic instrumental variants were extracted from the GWAS dataset. MR analysis showed that TL was negatively associated with CAVS (odds ratios [OR] = 0.727, 95% confidence interval [CI]: 0.565-0.936, and P = 0.013 by weighted median; OR = 0.763, 95% CI: 0.634-0.920, and P = 0.005 by IVW; OR = 0.757, 95% CI: 0.549-1.044, and P = 0.055 by MR-Egger). Sensitivity and pleiotropy analyses showed that the results of this study were relatively stable and that there was no significant pleiotropy. Reverse MR analyses consistently suggested the absence of causal effects of CAVS liability on TL levels.<br><br>CONCLUSION: A causal relationship between the shortening of TL and the development of CAVS in the European population was suggested in this study, and a theoretical basis was provided to investigate the pathogenesis of CAVS.}, }
@article {pmid36575046, year = {2022}, author = {Yang, X and Benny, PA and Cervera-Marzal, E and Wu, B and Lassiter, CB and Astern, J and Garmire, LX}, title = {Placental telomere length shortening is not associated with severe preeclampsia but the gestational age.}, journal = {Aging}, volume = {15}, number = {2}, pages = {353-370}, pmid = {36575046}, issn = {1945-4589}, mesh = {Pregnancy ; Humans ; Female ; *Placenta ; *Pre-Eclampsia/genetics ; Retrospective Studies ; Gestational Age ; Telomere Shortening ; Telomere ; }, abstract = {Variations in telomere length (TL) have been associated with aging, stress, and many diseases. Placenta TL is an essential molecular component influencing the outcome of birth. Previous investigations into the relationship between placenta TL and preeclampsia (PE) have produced conflicting findings. We conducted a retrospective case-control analysis in this study to address the disparity. We used placenta samples from 224 births received from Hawaii Biorepository (HiBR) between 2006 and 2013, comprising 129 healthy full-term controls and 95 severe PE samples. The average absolute placental TL was calculated using the quantitative polymerase chain reaction (qPCR) technique. We utilized multiple linear regressions to associate placental TL with severe PE and other demographic, clinical and physiological data. The outcome demonstrates that the placental TL of severe PE cases did not significantly differ from that of healthy controls. Instead, there is a strong correlation between gestational age and placenta TL shortening. Placental TL also exhibits racial differences: (1) Latino moms' TL is significantly longer than non-Latino mothers' (p=0.009). (2) Caucasian patients with severe PE have shorter TL than non-Caucasian patients (p=0.0037). This work puts the long-standing question of whether severe PE influences placental TL to rest. Placental TL is not related to severe PE but is negatively associated with gestational age and is also affected by race.}, }
@article {pmid36574746, year = {2023}, author = {Van Der Stukken, C and Nawrot, TS and Wang, C and Lefebvre, W and Vanpoucke, C and Plusquin, M and Roels, HA and Janssen, BG and Martens, DS}, title = {The association between ambient particulate matter exposure and the telomere-mitochondrial axis of aging in newborns.}, journal = {Environment international}, volume = {171}, number = {}, pages = {107695}, doi = {10.1016/j.envint.2022.107695}, pmid = {36574746}, issn = {1873-6750}, mesh = {Humans ; Infant, Newborn ; Female ; Pregnancy ; Particulate Matter/analysis ; Tumor Suppressor Protein p53/analysis/pharmacology ; Placenta/chemistry ; Maternal Exposure/adverse effects ; *Air Pollution/adverse effects/analysis ; Aging ; Mitochondria/chemistry ; DNA, Mitochondrial/analysis ; Telomere ; *Air Pollutants/analysis ; }, abstract = {BACKGROUND: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms.<br><br>METHODS: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1&#x3b1; protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms.<br><br>RESULTS: A 5&#xa0;&#xb5;g/m[3] increment in PM2.5 exposure was associated with -11.23&#xa0;% (95&#xa0;% CI: -17.36&#xa0;% to -4.65&#xa0;%, p&#xa0;=&#xa0;0.0012) and -7.34&#xa0;% (95&#xa0;% CI: -11.56&#xa0;% to -2.92&#xa0;%, p&#xa0;=&#xa0;0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96&#xa0;% (95&#xa0;% CI: -18.84&#xa0;% to -6.64&#xa0;%, p&#xa0;<&#xa0;0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5&#xa0;exposure was associated with a 12.42&#xa0;% (95&#xa0;% CI: -1.07&#xa0;% to 27.74&#xa0;%, p&#xa0;=&#xa0;0.059) higher cord plasma p53 protein level and a -3.69&#xa0;% (95&#xa0;% CI: -6.97&#xa0;% to -0.31&#xa0;%, p&#xa0;=&#xa0;0.033) lower cord plasma PGC-1&#x3b1; protein level during the third trimester. Placental TL mediated 65&#xa0;% of the negative and 17&#xa0;% of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively.<br><br>CONCLUSION: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context.}, }
@article {pmid36573392, year = {2022}, author = {Ardestani, SK and Jamali, T and Taravati, A and Behboudi, H and Vaez-Mahdavi, MR and Faghihzadeh, E and Ghazanfari, T}, title = {Changes in hormones, Leukocyte Telomere Length (LTL), and p16[INK4a] expression in SM-exposed individuals in favor of the cellular senescence.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/01480545.2022.2150205}, pmid = {36573392}, issn = {1525-6014}, abstract = {Sulfur mustard (SM) is a chemical warfare agent with well-known severe toxic effects and may cause long-term debilitating injuries. We aimed to evaluate aging and longevity in Iranian SM-exposed survivors using some endocrine and molecular biomarkers for the first time. Dehydroepiandrosterone (DHEA), prolactin (PRL), cortisol, testosterone, and luteinizing hormone (LH) were measured in 289 male SM-veterans and 66 age-matched males using the ELISA method. Leukocyte Telomere Length (LTL) measurement and p16[INK4a] expression were measured in the peripheral blood leukocytes of 55 males who were exposed to SM. We found a significantly lower serum DHEAS level and higher serum PRL level in SM-exposed groups (without any related to the severity of lung injuries) compared to healthy controls, but no significant difference in serum levels of cortisol, testosterone, and LH. The molar ratio of DHEAS/cortisol was significantly higher in controls compared to the SM-exposed individuals especially those with severe lung damage. Some biological parameters of allostatic load score such as DHEAS and DHEAS/cortisol ratio significantly decreased long-term after the SM exposure. Additionally, we found that LTL was shorter in SM-exposed veterans rather than unexposed controls while p16[INK4a] gene expression significantly increased in these groups. It seems that DHEAS, DHEAS/cortisol ratio, LTL, and p16[INK4a] gene expression have changed significantly in favor of cellular senescence in SM-exposed patients. Therefore, it seems that SM exposure increases biological age compared to chronological age in SM-exposed survivors.}, }
@article {pmid36567450, year = {2023}, author = {Matsuda, Y and Ye, J and Yamakawa, K and Mukai, Y and Azuma, K and Wu, L and Masutomi, K and Yamashita, T and Daigo, Y and Miyagi, Y and Yokose, T and Oshima, T and Ito, H and Morinaga, S and Kishida, T and Minamoto, T and Kojima, M and Kaneko, S and Haba, R and Kontani, K and Kanaji, N and Okano, K and Muto-Ishizuka, M and Yokohira, M and Saoo, K and Imaida, K and Suizu, F}, title = {Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis.}, journal = {Journal of the National Cancer Institute}, volume = {115}, number = {2}, pages = {208-218}, pmid = {36567450}, issn = {1460-2105}, mesh = {Humans ; *Carcinoma, Renal Cell ; *Cancer-Associated Fibroblasts/pathology ; In Situ Hybridization, Fluorescence ; Prognosis ; Telomere Shortening ; Telomere ; *Carcinoma, Squamous Cell/pathology ; *Liver Neoplasms/pathology ; *Kidney Neoplasms ; Telomere Homeostasis ; }, abstract = {BACKGROUND: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression.<br><br>METHODS: TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed.<br><br>RESULTS: There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC.<br><br>CONCLUSIONS: Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.}, }
@article {pmid36563016, year = {2022}, author = {D'Angiolo, M and Yue, JX and De Chiara, M and Barré, BP and Panis, MG and Gilson, E and Liti, G}, title = {Telomeres are shorter in wild Saccharomyces cerevisiae isolates than in domesticated ones.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyac186}, pmid = {36563016}, issn = {1943-2631}, abstract = {Telomeres are ribonucleoproteins that cap chromosome-ends and their DNA length is controlled by counteracting elongation and shortening processes. The budding yeast Saccharomyces cerevisiae has been a leading model to study telomere DNA length control and dynamics. Its telomeric DNA is maintained at a length that slightly varies between laboratory strains, but little is known about its variation at the species level. The recent publication of the genomes of over 1000 S. cerevisiae strains enabled us to explore telomere DNA length variation at an unprecedented scale. Here, we developed a bioinformatic pipeline (YeaISTY) to estimate telomere DNA length from whole-genome-sequences and applied it to the sequenced S. cerevisiae collection. Our results revealed broad natural telomere DNA length variation among the isolates. Notably, telomere DNA length is shorter in those derived from wild rather than domesticated environments. Moreover, telomere DNA length variation is associated with mitochondrial metabolism, and this association is driven by wild strains. Overall, these findings reveal broad variation in budding yeast's telomere DNA length regulation, which might be shaped by its different ecological life-styles.}, }
@article {pmid36555658, year = {2022}, author = {Sagris, M and Theofilis, P and Antonopoulos, AS and Tsioufis, K and Tousoulis, D}, title = {Telomere Length: A Cardiovascular Biomarker and a Novel Therapeutic Target.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555658}, issn = {1422-0067}, mesh = {Humans ; *Cardiovascular System ; Telomere Shortening ; *Atherosclerosis/genetics ; Biomarkers ; *Telomerase/genetics ; Telomere/genetics ; }, abstract = {Coronary artery disease (CAD) is a multifactorial disease with a high prevalence, particularly in developing countries. Currently, the investigation of telomeres as a potential tool for the early detection of the atherosclerotic disease seems to be a promising method. Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere length (TL) has been associated with several human disorders and diseases while its attrition rate varies significantly in the population. The rate of TL shortening ranges between 20 and 50 bp and is affected by factors such as the end-replication phenomenon, oxidative stress, and other DNA-damaging agents. In this review, we delve not only into the pathophysiology of TL shortening but also into its association with cardiovascular disease and the progression of atherosclerosis. We also provide current and future treatment options based on TL and telomerase function, trying to highlight the importance of these cutting-edge developments and their clinical relevance.}, }
@article {pmid36536359, year = {2022}, author = {Wong, KK and Cheng, F and Lim, CKP and Tam, CHT and Tutino, G and Yuen, LY and Wang, CC and Hou, Y and Chan, MHM and Ho, CS and Joglekar, MV and Hardikar, AA and Jenkins, AJ and Metzger, BE and Lowe, WL and Tam, WH and Ma, RCW}, title = {Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {490}, pmid = {36536359}, issn = {1741-7015}, support = {R01 HD034243/HD/NICHD NIH HHS/United States ; R01 HD034242/HD/NICHD NIH HHS/United States ; }, mesh = {Male ; Pregnancy ; Female ; Humans ; Adult ; Child ; Longitudinal Studies ; *Diabetes Mellitus, Type 2 ; Sex Characteristics ; Leukocytes ; Insulin/metabolism ; Glucose/metabolism ; Telomere ; }, abstract = {BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.<br><br>METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 &#xb1; 0.4 (mean &#xb1; SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.<br><br>RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (&#x3b2;=-0.046 &#xb1; 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.<br><br>CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.}, }
@article {pmid36533316, year = {2022}, author = {Derenzini, E and Gueli, A and Risso, A and Bruna, R and Gottardi, D and Cignetti, A and Pileri, S and Avvedimento, EV and Tarella, C}, title = {Long telomeres at baseline and male sex are main determinants of telomere loss following chemotherapy exposure in lymphoma patients.}, journal = {Hematological oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/hon.3118}, pmid = {36533316}, issn = {1099-1069}, abstract = {Although chemotherapy (CHT) exposure is an established cause of telomere attrition, determinants of telomere length (TL) dynamics after chemotherapy are poorly defined. In this study, we analyzed granulocyte telomere dynamics in 34 adult lymphoma patients undergoing first-line CHT. TL was measured by southern blot at each CHT cycle and after 1 year from CHT completion. Median age was 59 yrs (range 22-77). Median number of CHT cycles was 6 (range 3-6). The majority of patients (79%, n = 27) experienced TL shortening following CHT exposure. Mean telomere loss was 673 base pairs (bp) by cycle 6. Telomere shortening was an early event as 87% of the total telomere loss (mean 586 bp) occurred by the end of cycle 3, with no significant recovery after 1 year. A significant correlation was observed between baseline TL and total or fractional telomere loss (p < 0.001), with telomere shortening by cycle 3 observed predominantly in male patients with long telomeres at pre-treatment evaluation. Stratifying the analysis by gender and age only young women (<51 years of age) did not show significant telomere shortening following chemotherapy exposure. These findings indicate that gender and baseline TL are major determinants of TL dynamics following chemotherapy exposure in lymphoma patients.}, }
@article {pmid36526187, year = {2023}, author = {Zamora-Camacho, FJ and Burraco, P and Zambrano-Fernández, S and Aragón, P}, title = {Ammonium effects on oxidative stress, telomere length, and locomotion across life stages of an anuran from habitats with contrasting land-use histories.}, journal = {The Science of the total environment}, volume = {862}, number = {}, pages = {160924}, doi = {10.1016/j.scitotenv.2022.160924}, pmid = {36526187}, issn = {1879-1026}, mesh = {Humans ; Animals ; *Ammonium Compounds ; Hydrogen Peroxide ; Life Cycle Stages ; Oxidative Stress ; Ranidae ; Larva ; Antioxidants ; Locomotion ; Ecosystem ; Telomere ; }, abstract = {Understanding the mechanistic implications behind wildlife responses to global changes is a central topic in eco-evolutionary research. In particular, anthropic pollution is known to impact wild populations across the globe, which may have even stronger consequences for species with complex life cycles. Among vertebrates, amphibians represent a paradigmatic example of metamorphosis, and their characteristics make them highly vulnerable to pollution. Here, we tested for differences in the redox status, telomere length, and locomotor performance across life stages of green frogs (Pelophylax perezi) from agrosystem and natural habitats, both constitutively and in response to an experimental ammonium exposure (10 mg/L). We found that larvae from the agrosystem constitutively showed an enhanced redox status (better antioxidant balance against H2O2, lower lipid peroxidation) but shorter telomeres as compared to larvae from the natural environment. The larval redox response to ammonium was, overall, similar in both habitats. In contrast, after metamorphosis, the redox status of individuals from the natural habitat seemed to cope better with ammonium exposure (denoted by lower lipid peroxidation), and differences between habitats in telomere length were no longer present. Intriguingly, while the swimming performance of larvae did not correlate with individual's physiology, metamorphs with lower glutathione reductase activity and longer telomeres had a better jumping performance. This may suggest that locomotor performance is both traded off with the production of reactive oxygen species and potentiated directly by longer telomeres or indirectly by the mechanisms that buffer their shortening. Overall, our study suggests that contrasting land-use histories can drive divergence in physiological pathways linked to individual health and lifespan. Since this pattern was life-stage dependent, divergent habitat conditions can have contrasting implications across the ontogenetic development of species with complex life cycles.}, }
@article {pmid36525974, year = {2023}, author = {Warecki, B and Bast, I and Tajima, M and Sullivan, W}, title = {Connections between sister and non-sister telomeres of segregating chromatids maintain euploidy.}, journal = {Current biology : CB}, volume = {33}, number = {1}, pages = {58-74.e5}, pmid = {36525974}, issn = {1879-0445}, support = {R35 GM139595/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Chromatids/genetics ; Drosophila melanogaster/genetics ; Telomere/genetics ; Anaphase ; DNA ; Chromosome Segregation ; Cell Cycle Proteins/genetics ; *Drosophila Proteins/genetics ; }, abstract = {The complete separation of sister chromatids during anaphase is a fundamental requirement for successful mitosis. Therefore, divisions with either persistent DNA-based connections or lagging chromosome fragments threaten aneuploidy if unresolved. Here, we demonstrate the existence of an anaphase mechanism in normally dividing cells in which pervasive connections between telomeres of segregating chromosomes aid in rescuing lagging chromosome fragments. We observe that in a large proportion of Drosophila melanogaster neuronal stem cell divisions, early anaphase sister and non-sister chromatids remain connected by thin telomeric DNA threads. Normally, these threads are resolved in mid-to-late anaphase via a spatial mechanism. However, we find that the presence of a nearby unrepaired DNA break recruits histones, BubR1 kinase, Polo kinase, Aurora B kinase, and BAF to the telomeric thread of the broken chromosome, stabilizing it. Stabilized connections then aid lagging chromosome rescue. These results suggest a model in which pervasive anaphase telomere-telomere connections that are normally resolved quickly can instead be stabilized to retain wayward chromosome fragments. Thus, the liability of persistent anaphase inter-chromosomal connections in normal divisions may be offset by their ability to maintain euploidy in the face of chromosome damage and genome loss.}, }
@article {pmid36522605, year = {2022}, author = {Wang, C and Gu, Y and Zhou, J and Zang, J and Ling, X and Li, H and Hu, L and Xu, B and Zhang, B and Qin, N and Lv, H and Duan, W and Jiang, Y and He, Y and Jiang, T and Chen, C and Han, X and Zhou, K and Xu, B and Liu, X and Tao, S and Jiang, Y and Du, J and Dai, J and Diao, F and Lu, C and Guo, X and Huo, R and Liu, J and Lin, Y and Xia, Y and Jin, G and Ma, H and Shen, H and Hu, Z}, title = {Leukocyte telomere length in children born following blastocyst-stage embryo transfer.}, journal = {Nature medicine}, volume = {28}, number = {12}, pages = {2646-2653}, pmid = {36522605}, issn = {1546-170X}, mesh = {Pregnancy ; Humans ; Female ; Animals ; Mice ; *Pregnancy Outcome ; *Premature Birth ; Embryo Transfer ; Reproductive Techniques, Assisted ; Blastocyst ; Leukocytes ; Telomere/genetics ; }, abstract = {Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10[-3]) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10[-3]) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10[-4]) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.}, }
@article {pmid36514516, year = {2022}, author = {Akay, GG}, title = {Telomeres and Psychological Stress: Perspective on Psychopathologies.}, journal = {Noro psikiyatri arsivi}, volume = {59}, number = {4}, pages = {330-337}, pmid = {36514516}, issn = {1300-0667}, abstract = {INTRODUCTION: Telomeres are specialized DNA-protein complexes located at the ends of all chromosomes and act as a "molecular clock" to determine the replicative lifespan of the cells. Recent studies indicate that life-long exposure to stress, starting from the prenatal period, causes many diseases to emerge at an early age, and telomeres may be possible mediators in this process. This article aims to review the relationship between the stress-telomere-disease triad and the potential role of telomere dysfunction in psychopathologies in the light of current literature.<br><br>METHODS: A literature search was conducted along the lines of a narrative review. PubMed and Web of Science databases were used to identify all types of articles published from inception to January 2022. After the title/abstract search, articles available in full text and English were selected based on key findings, the applicability of the method used to test the hypothesis, limitations, interpretation of the results, and impact of the results in the field. A total of 73 records were included in this narrative review.<br><br>RESULTS: The fact that some age-related chronic diseases, such as cardiovascular diseases and type 2 diabetes, are seen more frequently and at an earlier age in certain psychopathologies including depression, bipolar disorder, and schizophrenia suggests that these disorders are premature ageing syndromes. Although there are some conflicting results in the literature, in line with this hypothesis, the presence of shortened telomeres reported in these psychopathologies and the impact of lifelong exposure to stress on this process are remarkable.<br><br>CONCLUSION: Many of the studies point to an association and do not tell much about the causality. Hence, the elucidation of the biological processes underlying the relationship between psychological stress, dysfunctional telomeres and complex, common age-related diseases, as well as psychiatric disorders is important and further studies are needed at the cellular level.}, }
@article {pmid36513246, year = {2023}, author = {Ito, J and Kageyama, M and Hara, S and Sato, T and Shirasuna, K and Iwata, H}, title = {Paternal aging impacts mitochondrial DNA content and telomere length in mouse embryos.}, journal = {Mitochondrion}, volume = {68}, number = {}, pages = {105-113}, doi = {10.1016/j.mito.2022.12.002}, pmid = {36513246}, issn = {1872-8278}, mesh = {Male ; Animals ; Cattle ; Mice ; *DNA, Mitochondrial/genetics ; *Telomere/genetics ; Mitochondria/genetics ; Aging/genetics ; Blastocyst ; }, abstract = {Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring.}, }
@article {pmid36513120, year = {2022}, author = {Misino, S and Busch, A and Wagner, CB and Bento, F and Luke, B}, title = {TERRA increases at short telomeres in yeast survivors and regulates survivor associated senescence (SAS).}, journal = {Nucleic acids research}, volume = {50}, number = {22}, pages = {12829-12843}, pmid = {36513120}, issn = {1362-4962}, mesh = {Humans ; *RNA, Long Noncoding/genetics ; *Saccharomyces cerevisiae/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere Shortening ; }, abstract = {Cancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. Many ALT features are conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA TERRA, and its ability to form RNA-DNA hybrids, has been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. We observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to 'normal' senescence, we report that RNA-DNA hybrids slow the rate of SAS, likely through the elongation of critically short telomeres, however decreasing the rate of telomere shortening may contribute to this effect. In summary, TERRA RNA-DNA hybrids regulate telomere dysfunction-induced senescence before and after survivor formation.}, }
@article {pmid36508921, year = {2023}, author = {Nasiri, L and Vaez-Mahdavi, MR and Hassanpour, H and Ghazanfari, T and Kaboudanian Ardestani, S and Askari, N and Mohseni Majd, MA and Rahimlou, B}, title = {Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence.}, journal = {International immunopharmacology}, volume = {114}, number = {}, pages = {109549}, doi = {10.1016/j.intimp.2022.109549}, pmid = {36508921}, issn = {1878-1705}, mesh = {Humans ; Male ; *Mustard Gas/toxicity ; *Chemical Warfare Agents/toxicity ; Telomere Shortening ; Lipofuscin ; *Veterans ; Leukocytes ; Cellular Senescence ; Transforming Growth Factor beta ; }, abstract = {BACKGROUND: Sulfur mustard (SM) is a toxic gas that causes chronic inflammation and oxidative stress leading to cell senescence. This study aimed to evaluate two indicators of biological aging (i.e., serum lipofuscin level and leukocyte telomere length) and assess their relationship based on the severity of SM exposure in the long term.<br><br>METHODS: The study was performed on two groups of male participants. 1) SM-exposed group (exposed to SM once in 1987), 73 volunteers. 2) Non-exposed group, 16 healthy volunteers. The SM-exposed group was categorized into three subgroups based on the severity of SM exposure and body damage (asymptom, mild, and severe). The blood sample was prepared from members of each group. The serum lipofuscin, TGF-&#x3b2;, malondialdehyde (MDA), c-reactive protein (CRP), and leukocyte telomere length (TL) were measured in all participants.<br><br>RESULTS: The MDA level was increased in the SM-exposed group (mean = 39.6 &#xb5;M, SD = 16.5) compared to the non-exposed group (mean = 21.1 &#xb5;M, SD = 10.3) (P < 0.05). The CRP level was also increased in the SM-exposed group (mean = 5.12 mg/l, SD = 3.36) compared to the non-exposed group (mean = 3.51 mg/l, SD = 1.21), while the TGF-&#x3b2; level was decreased (P < 0.05) in the SM-exposed group (mean = 52.6 pg/ml, SD = 18.7) compared to the non-exposed group (mean = 68.9 pg/ml, SD = 13.8). The relative TL was shorter in the SM-exposed group (mean = 0.40, SD = 0.28) than in the non-exposed group (mean = 2.25, SD = 1.41) (P < 0.05). The lipofuscin level was higher in the total SM-exposed group (mean = 1.44 ng/ml, SD = 0.685) than in the non-exposed group (mean = 0.88 ng/ml, SD = 0.449) (P < 0.05). The MDA and CRP levels were increased in the SM-exposed subgroups of asymptom, mild, and severe than the non-exposed group, while TGF-&#x3b2; level and TL were decreased in those subgroups. The lipofuscin level was higher in the SM-exposed subgroups of mild and severe than in the non-exposed group. The regression analysis determined a negative correlation between lipofuscin level and TL. The lipofuscin/TL ratio was higher in the total SM-exposed group (mean = 6.36, SD = 5.342) than in the non-exposed group (mean = 0.51, SD=0.389). This ratio was also higher in the SM-exposed subgroups of asymptom, mild, and severe than in the non-exposed group. The lipofuscin/TL ratio did not differ between mild and severe subgroups.<br><br>CONCLUSION: The delayed toxicity of SM is associated with chronic oxidative stress, continuous inflammatory stimulation, increased lipofuscin, and telomere shortening. Future studies are needed to verify the suitability of serum lipofuscin to telomere length ratio in determining the severity of SM toxicity.}, }
@article {pmid36502996, year = {2023}, author = {Zhang, Y and Liu, J and Li, X and Zhou, G and Sang, Y and Zhang, M and Gao, L and Xue, J and Zhao, M and Yu, H and Zhou, X}, title = {Dietary selenium excess affected spermatogenesis via DNA damage and telomere-related cell senescence and apoptosis in mice.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {171}, number = {}, pages = {113556}, doi = {10.1016/j.fct.2022.113556}, pmid = {36502996}, issn = {1873-6351}, mesh = {Mice ; Male ; Animals ; *Selenium/pharmacology ; Semen ; Spermatogenesis ; Cellular Senescence ; Apoptosis ; DNA Damage ; *Malnutrition ; Telomere ; }, abstract = {Selenium (Se) is a vital microelement for spermatogenesis and male fertility. The aim of this study was to investigate the effects of Se on the male reproductive function and possible mechanisms. Fourty male mice were randomly divided into 0, 0.1, 0.3 and 0.9 mg/kg Se supplementation groups and given with Se dietary intervention for 12 weeks. Our data showed that excessive Se intake damaged the tissue structure of testes and epididymides of the mice, resulting in decreased sperm quality and quantity. Moreover, excessive Se induced oxidative stress, causing DNA damage and activated DNA damage repair factors (Mre11/Rad50/Nbs1), and also disrupted telomere function by shortening telomere length and decreasing TERT expression. Se excess activated the senescence pathway p53/p21/p16, leading to germ cell senescence, and inhibited cell proliferation by suppressing the Sirt1/Foxo1/c-Myc pathway. All of this led to spermatogenic cell apoptosis, thereby causing a decrease of sperm quantity and quality. In conclusion, excessive Se caused reproductive toxicity via inducing telomere dysfunction due to DNA damage, leading to germ cellular senescence and apoptosis in the testes of male mice. Our research provide new proof to explain the underlying mechanism of male reproductive toxicity triggered by excessive Se intake.}, }
@article {pmid36501220, year = {2022}, author = {Toupance, S and Karampatsou, SI and Labat, C and Genitsaridi, SM and Tragomalou, A and Kassari, P and Soulis, G and Hollander, A and Charmandari, E and Benetos, A}, title = {Longitudinal Association of Telomere Dynamics with Obesity and Metabolic Disorders in Young Children.}, journal = {Nutrients}, volume = {14}, number = {23}, pages = {}, pmid = {36501220}, issn = {2072-6643}, mesh = {Adult ; Adolescent ; Child ; Humans ; Child, Preschool ; *Pediatric Obesity/genetics/metabolism ; Telomere ; Telomere Shortening ; Leukocytes/metabolism ; *Diabetes Mellitus, Type 2/genetics/metabolism ; }, abstract = {In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders, such as obesity and diabetes mellitus type 2. These associations could stem from early life interactions between LTL and metabolic disorders. To test this hypothesis, we explored the associations between LTL and metabolic parameters as well as their evolution over time in children with or without obesity at baseline. Seventy-three (n = 73) children attending our Outpatient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence, aged 2-10 years (mean ± SD: 7.6 ± 2.0 years), were followed for 2 to 4 years. Anthropometric, clinical, and biological (including LTL by Southern blot) measurements were performed annually. Baseline LTL correlated negatively with BMI (p = 0.02), fat percentage (p = 0.01), and blood glucose (p = 0.0007). These associations persisted after adjustments for age and sex. No associations were found between LTL attrition during the follow-up period and any of the metabolic parameters. In young children, obesity and metabolic disturbances were associated with shorter telomeres but were not associated with more pronounced LTL attrition. These results suggest that short telomeres contribute to the development of obesity and metabolic disorders very early in life, which can have a major impact on health.}, }
@article {pmid36498467, year = {2022}, author = {Mulet, A and Signes-Costa, J}, title = {Idiopathic Pulmonary Fibrosis and Telomeres.}, journal = {Journal of clinical medicine}, volume = {11}, number = {23}, pages = {}, pmid = {36498467}, issn = {2077-0383}, abstract = {Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology with a highly compromised prognosis and a significant mortality rate within a few years of diagnosis. Despite being idiopathic, it has been shown that telomeric shortening could play an important role in its etiopathogenesis. Mutations in telomere-related genes have been identified, but they are not always present despite telomere shortening. On the other hand, this telomeric shortening has been linked to a worse prognosis of the disease independently of other clinical factors, implying it may serve as a biomarker.}, }
@article {pmid36497103, year = {2022}, author = {Vilkeviciute, A and Gedvilaite, G and Banevicius, M and Kriauciuniene, L and Zaliuniene, D and Dobiliene, O and Liutkeviciene, R}, title = {Relative Leukocyte Telomere Length and Genetic Variants in Telomere-Related Genes and Serum Levels Role in Age-Related Macular Degeneration.}, journal = {Cells}, volume = {11}, number = {23}, pages = {}, pmid = {36497103}, issn = {2073-4409}, mesh = {Humans ; Telomeric Repeat Binding Protein 1/genetics/metabolism ; *Telomerase/genetics/metabolism ; Leukocytes/metabolism ; *Macular Degeneration/genetics ; DNA ; *Tankyrases ; }, abstract = {UNLABELLED: Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development.<br><br>METHODS: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA).<br><br>RESULTS: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group.<br><br>CONCLUSIONS: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD.}, }
@article {pmid36497039, year = {2022}, author = {Farrukh, S and Baig, S and Hussain, R and Imad, R and Khalid, M}, title = {Parental Genetics Communicate with Intrauterine Environment to Reprogram Newborn Telomeres and Immunity.}, journal = {Cells}, volume = {11}, number = {23}, pages = {}, pmid = {36497039}, issn = {2073-4409}, mesh = {Female ; Humans ; Infant, Newborn ; Pregnancy ; Genotype ; Mothers ; *Telomerase/genetics ; *Telomere/genetics ; Telomere Shortening/genetics ; Fathers ; Male ; *Immunity/genetics ; Maternal Inheritance ; Paternal Inheritance ; }, abstract = {Telomeres, markers for cellular senescence, have been found substantially influenced by parental inheritance. It is well known that genomic stability is preserved by the DNA repair mechanism through telomerase. This study aimed to determine the association between parents-newborn telomere length (TL) and telomerase gene (TERT), highlighting DNA repair combined with TL/TERT polymorphism and immunosenescence of the triad. The mother-father-newborn triad blood samples (n = 312) were collected from Ziauddin Hospitals, Pakistan, between September 2021 and June 2022. The telomere length (T/S ratio) was quantified by qPCR, polymorphism was identified by Sanger sequencing, and immunosenescence by flow cytometry. The linear regression was applied to TL and gene association. The newborns had longest TL (2.51 ± 2.87) and strong positive association (R = 0.25, p&amp;nbsp;≤ 0.0001) (transgenerational health effects) with mothers' TL (1.6 ± 2.00). Maternal demographics-socioeconomic status, education, and occupation-showed significant effects on TL of newborns (p < 0.015, 0.034, 0.04, respectively). The TERT risk genotype CC (rs2736100) was predominant in the triad (0.6, 0.5, 0.65, respectively) with a strong positive association with newborn TL (β = 2.91, <0.0011). Further analysis highlighted the expression of KLRG 1+ in T-cells with shorter TL but less frequent among newborns. The study concludes that TERT, parental TL, antenatal maternal health, and immunity have a significantly positive effect on the repair of newborn TL.}, }
@article {pmid36496180, year = {2022}, author = {Nelson, N and Feurstein, S and Niaz, A and Truong, J and Holien, JK and Lucas, S and Fairfax, K and Dickinson, J and Bryan, TM}, title = {Functional genomics for curation of variants in telomere biology disorder associated genes: A systematic review.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {25}, number = {3}, pages = {100354}, doi = {10.1016/j.gim.2022.11.021}, pmid = {36496180}, issn = {1530-0366}, abstract = {PURPOSE: Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations, and they can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatment. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance. This complicates management decisions, delays treatment, and risks nonuptake of potentially curative therapies. Improved application of functional genomic evidence may reduce variants of uncertain significance classifications.<br><br>METHODS: We systematically searched the literature for published functional assays interrogating TBD gene variants. When possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value, and odds of pathogenicity.<br><br>RESULTS: In total, 3131 articles were screened and 151 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation were available for TERT variants only. We recommend that PS3 and BS3 can be applied at a moderate and supportive level, respectively. PS3/BS3 application was limited by a lack of assay standardization and limited inclusion of benign variants.<br><br>CONCLUSION: Further assay standardization and assessment of benign variants are required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.}, }
@article {pmid36485133, year = {2022}, author = {Savage, SA}, title = {Dyskeratosis congenita and telomere biology disorders.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2022}, number = {1}, pages = {637-648}, pmid = {36485133}, issn = {1520-4383}, mesh = {Humans ; Child ; *Dyskeratosis Congenita/genetics/pathology ; Telomere/genetics/pathology ; Germ-Line Mutation ; Bone Marrow Failure Disorders ; *Anemia, Aplastic ; }, abstract = {Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.}, }
@article {pmid36483815, year = {2022}, author = {Picos-Cárdenas, VJ and Beltrán-Ontiveros, SA and Cruz-Ramos, JA and Contreras-Gutiérrez, JA and Arámbula-Meraz, E and Angulo-Rojo, C and Guadrón-Llanos, AM and Leal-León, EA and Cedano-Prieto, DM and Meza-Espinoza, JP}, title = {Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres: A case report.}, journal = {World journal of clinical cases}, volume = {10}, number = {33}, pages = {12440-12446}, pmid = {36483815}, issn = {2307-8960}, abstract = {BACKGROUND: Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance, including TINF2.<br><br>CASE SUMMARY: Here, we report a female patient who presented thrombocytopenia, anemia, reticulate hyperpigmentation, dystrophy in fingernails and toenails, and leukoplakia on the tongue. A histopathological study of the skin showed dyskeratocytes; however, a bone marrow biopsy revealed normal cell morphology. The patient was diagnosed with dyskeratosis congenita, but her family history did not reveal significant antecedents. Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene, namely, NM_001099274.1:c.854delp.(Val285Alafs*32). An analysis of telomere length showed short telomeres relative to the patient's age.<br><br>CONCLUSION: The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.}, }
@article {pmid36481818, year = {2022}, author = {Sieverling, L and Hong, C and Koser, SD and Ginsbach, P and Kleinheinz, K and Hutter, B and Braun, DM and Cortés-Ciriano, I and Xi, R and Kabbe, R and Park, PJ and Eils, R and Schlesner, M and ,  and Brors, B and Rippe, K and Jones, DTW and Feuerbach, L and , }, title = {Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {7574}, doi = {10.1038/s41467-022-32328-7}, pmid = {36481818}, issn = {2041-1723}, }
@article {pmid36473858, year = {2022}, author = {He, F and Yu, Q and Wang, M and Wang, R and Gong, X and Ge, F and Yu, X and Li, S}, title = {SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {7526}, pmid = {36473858}, issn = {2041-1723}, mesh = {*Histones ; *Sesamum ; Autophagy ; }, abstract = {The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.}, }
@article {pmid36469522, year = {2022}, author = {Martinez, D and Lavebratt, C and Millischer, V and de Jesus R de Paula, V and Pires, T and Michelon, L and Camilo, C and Esteban, N and Pereira, A and Schalling, M and Vallada, H}, title = {Shorter telomere length and suicidal ideation in familial bipolar disorder.}, journal = {PloS one}, volume = {17}, number = {12}, pages = {e0275999}, pmid = {36469522}, issn = {1932-6203}, mesh = {Humans ; *Bipolar Disorder/genetics ; Suicidal Ideation ; Telomere/genetics ; Leukocytes ; *Suicide ; Telomere Shortening/genetics ; }, abstract = {Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.}, }
@article {pmid36466397, year = {2022}, author = {Shi, H and Li, X and Yu, H and Shi, W and Lin, Y and Zhou, Y}, title = {Potential effect of dietary zinc intake on telomere length: A cross-sectional study of US adults.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {993425}, pmid = {36466397}, issn = {2296-861X}, abstract = {BACKGROUND: Telomere length, which is related to chronic diseases and premature mortality, is influenced by dietary factors. Zinc is known as a dietary antioxidant micronutrient, however, its impact on telomere length remains unclear.<br><br>OBJECTIVE: We aimed to examine the potential effect of dietary zinc intake on telomere length among middle-aged and older individuals in the US.<br><br>MATERIALS AND METHODS: Our study included 3,793 US participants aged 45 years and older from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES). 24-h dietary recall interviews were employed to evaluate zinc consumption. Leukocyte telomere length was assessed by real-time quantitative polymerase chain reaction (qPCR). We adopted generalized linear models to investigate the effect of dietary zinc intake on telomere length, and subgroup analyses were further applied. We further evaluated the dose-response relationship using restricted cubic spline analysis.<br><br>RESULTS: Among the 3,793 participants, the average telomere length was 0.926 &#xb1; 0.205 (T/S ratio) or 5509.5 &#xb1; 494.9 (bp). After adjusting for major confounders, every 5 mg increment in dietary zinc consumption was related to 0.64% (95% CI: 0.17%, 1.10%) longer telomere length. In the subgroup analyses, significant relationships were found in females (Percentage change: 1.11%; 95% CI: 0.48%, 1.75%), obese (Percentage change: 0.88%; 95% CI: 0.26%, 1.50%), and low energy intake individuals (Percentage change: 0.99%; 95% CI: 0.51%, 1.46%). Additionally, we revealed a positive linear relationship between dietary zinc intake and telomere length (P for non-linearity = 0.636).<br><br>CONCLUSION: Our study revealed that elevated dietary zinc intake was significantly related to longer telomere length among adults aged 45 years and older in the US. And the association was more pronounced in females, obese, and low energy intake individuals.}, }
@article {pmid36466075, year = {2022}, author = {Krasnienkov, DS and Gorodna, OV and Kaminska, TM and Podolskiy, VV and Podolskiy, VV and Nechyporenko, MV and Antypkin, YG and Livshits, LA}, title = {Analysis of Relative Average Length of Telomeres in Leukocytes of Women with COVID-19.}, journal = {Cytology and genetics}, volume = {56}, number = {6}, pages = {526-529}, pmid = {36466075}, issn = {0095-4527}, abstract = {Coronavirus disease (COVID-19) is an acute infectious disease of the respiratory tract caused by a new SARS-CoV-2 coronavirus. A global vaccination program against SARS-CoV-2 continues, and the incidence of COVID-19 worldwide is significantly decreasing. However, among millions of those who survived COVID-19, numerous groups will need assistance due to increased clinical consequences after COVID-19. Currently, there is a need to search for molecular biomarkers for monitoring the onset and progression of post-COVID syndrome. For this purpose, the relative average length of chromosome regions was studied in the groups of women of reproductive age: in the group of patients (n = 64) recovered from COVID-19 and in the control group (n = 42) of women of the same age. The analysis was carried out using a method of multiplex monochrome quantitative real-time PCR on DNA samples isolated from the peripheral blood leukocytes. According to the results of the study, it was established that the relative average length of chromosomes in the peripheral blood leukocytes was statistically significantly lower in the group of patients with COVID-19 than in the control group (p < 0.05). The results obtained allow one to state that the observed shortening of the relative average length of telomeres in the group of patients that recovered from COVID-19 can indicate that SARS-CoV-2 infection can directly cause the erosion of telomeres in the blood cells, particularly, in leukocytes. Thus, the determination of the relative average length of telomeres can be an informative prognostic marker for estimating the risk of the severity of COVID-19 disease and the development of post-COVID syndrome.}, }
@article {pmid36462796, year = {2022}, author = {Zizza, A and Panico, A and Grassi, T and Recchia, V and Grima, P and De Giglio, O and Bagordo, F}, title = {Is telomere length in buccal or salivary cells a useful biomarker of exposure to air pollution? A review.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {883-884}, number = {}, pages = {503561}, doi = {10.1016/j.mrgentox.2022.503561}, pmid = {36462796}, issn = {1879-3592}, mesh = {Adult ; Child ; Humans ; *Air Pollution/adverse effects ; Biomarkers ; Soot ; Telomere ; *Pesticides ; Carbon ; }, abstract = {Telomeres are repetitive DNA-protein sequences located at the end of chromosomes and play an essential role in preserving information in our genome by protecting against end-to-end fusion, nucleolytic degradation, breakage, and inappropriate recombination. The telomeres shorten with aging and this process can be affected by oxidative stress and inflammation. Environmental and occupational factors may contribute to telomere length (TL) shortening, as demonstrated by an increasing number of studies. In particular, air pollution was associated with aging-related health outcomes and molecular alterations, such as telomeric shortening. Leukocytes are widely used for TL measurement. However, buccal and salivary cells have more intimate contact with airborne pollutants and are easier to sample. The objective of this review was to identify whether salivary or buccal TL represents a valid marker for evaluating the effects of pollution on health. The reviewed studies investigated the association between TL and occupational exposure (genotoxic substances in mechanical workers, and pesticides in pesticides applicators), residential traffic exposure (NOx, NO2, PM2.5, PM10, and black carbon), and household air pollution (PM2.5 and black carbon from biomass stoves). The studies involved adults and children. Although few studies have yet been carried out, almost all reported a negative association between salivary or buccal TL and exposure to air pollutants stating that it could be a good indicator of occupational or airborne pollution exposure. However, further research is needed to evaluate the effect of acute versus long-term exposure on salivary or buccal TL as well as the role of confounding factors. Moreover, most of the reviewed studies were conducted on healthy adults, so it is important to deeply investigate how TL is associated with all-cause mortality such as cancer, diabetes, cardiovascular disease, and respiratory disease, how it can be affected during childhood, and which changes over time can be associated with diseases' onset in adulthood.}, }
@article {pmid36461827, year = {2022}, author = {Safaee, MM and Lin, J and Smith, DL and Fury, M and Scheer, JK and Burke, JF and Bravate, C and Lambert, D and Ames, CP}, title = {Association of telomere length with risk of complications in adult spinal deformity surgery: a pilot study of 43 patients.}, journal = {Journal of neurosurgery. Spine}, volume = {}, number = {}, pages = {1-9}, doi = {10.3171/2022.10.SPINE22605}, pmid = {36461827}, issn = {1547-5646}, abstract = {OBJECTIVE: Risk stratification is a critical element of surgical planning. Early tools were fairly crude, while newer instruments incorporate disease-specific elements and markers of frailty. It is unknown if discrepancies between chronological and cellular age can guide surgical planning or treatment. Telomeres are DNA-protein complexes that serve an important role in protecting genomic DNA. Their shortening is a consequence of aging and environmental exposures, with well-established associations with diseases of aging and mortality. There are compelling data to suggest that telomere length can provide insight toward overall health. The authors sought to determine potential associations between telomere length and postoperative complications.<br><br>METHODS: Adults undergoing elective surgery for spinal deformity were prospectively enrolled. Telomere length was measured from preoperative whole blood using quantitative polymerase chain reaction and expressed as the ratio of telomere (T) to single-copy gene (S) abundance (T/S ratio), with higher T/S ratios indicating longer telomere length. Demographic and patient data included age, BMI, and results for the following rating scales: the Adult Spinal Deformity Frailty Index (ASD-FI), Oswestry Disability Index (ODI), Scoliosis Research Society-22r (SRS-22r), American Society of Anesthesiology (ASA) classification, and Charlson Comorbidity Index (CCI). Operative and postoperative complication data (medical or surgical within 90 days) were also collected.<br><br>RESULTS: Forty-three patients were enrolled, including 31 women (53%), with a mean age of 66 years and a mean BMI of 28.5. The mean number of levels fused was 11, with 21 (48.8%) combined anterior-posterior approaches. Twenty-two patients (51.2%) had a medical or surgical complication. Patients with a postoperative complication had a significantly lower T/S ratio (0.712 vs 0.813, p = 0.008), indicating shorter telomere length, despite a mild difference in age compared with patients without a postoperative complication (68 vs 63 years, p = 0.069). Patients with complications also had higher CCI scores than patients without complications (2.3 vs 3.8, p = 0.004). There were no significant differences in sex, BMI, ASD-FI score, ASA class, preoperative ODI and SRS-22r scores, number of levels fused, or use of three-column osteotomies. In a multivariate model including age, frailty, ASA class, use of an anterior-posterior approach, CCI score, and telomere length, the authors found that short telomere length was significantly associated with postoperative complications. Patients whose telomere length fell in the shortest quartile had the highest risk (OR 18.184, p = 0.030).<br><br>CONCLUSIONS: Short telomere length was associated with an increased risk of postoperative complications despite only a mild difference in chronological age. Increasing comorbidity scores also trended toward significance. Larger prospective studies are needed; however, these data provide a compelling impetus to investigate the role of biological aging as a component of surgical risk stratification.}, }
@article {pmid36458548, year = {2023}, author = {Virseda-Berdices, A and Concostrina-Martinez, L and Martínez-González, O and Blancas, R and Resino, S and Ryan, P and Martin-Vicente, M and Brochado-Kith, O and Blanca-López, N and Mallol Poyato, MJ and López Matamala, B and Martín Parra, C and Jiménez-Sousa, M&#xc1; and Fernández-Rodríguez, A}, title = {Relative telomere length impact on mortality of COVID-19: Sex differences.}, journal = {Journal of medical virology}, volume = {95}, number = {1}, pages = {e28368}, pmid = {36458548}, issn = {1096-9071}, mesh = {Humans ; Male ; Female ; Aged ; *Sex Characteristics ; *COVID-19 ; Prognosis ; Telomere Shortening ; Telomere ; }, abstract = {Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio [HR] (aHR) = 3.33; 95% confidence interval [CI] = 1.05-10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23-11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population.}, }
@article {pmid36457292, year = {2022}, author = {Mayer, SE and Guan, J and Lin, J and Hamlat, E and Parker, JE and Brownell, K and Price, C and Mujahid, M and Tomiyama, AJ and Slavich, GM and Laraia, BA and Epel, ES}, title = {Intergenerational effects of maternal lifetime stressor exposure on offspring telomere length in Black and White women.}, journal = {Psychological medicine}, volume = {}, number = {}, pages = {1-12}, doi = {10.1017/S0033291722003397}, pmid = {36457292}, issn = {1469-8978}, support = {R56HL141878/HL/NHLBI NIH HHS/United States ; K12 HD051958/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Although maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers.<br><br>METHOD: Mothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted.<br><br>RESULTS: Neither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers.<br><br>CONCLUSIONS: Race and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.}, }
@article {pmid36447745, year = {2021}, author = {Aiello, A and Accardi, G and Alì, S and Caruso, C and Chen, M and De Vivo, I and Ligotti, ME and Scapagnini, G and Davinelli, S and Candore, G}, title = {Possible Association of Telomere Length With Sleep Duration. A Preliminary Pilot Study in a Sicilian Cohort with Centenarians.}, journal = {Translational medicine @ UniSa}, volume = {24}, number = {1}, pages = {24-29}, pmid = {36447745}, issn = {2239-9747}, abstract = {Telomere length (TL) is considered a biomarker of ageing although this topic is still debated. Also, sleep pattern changes are physiological part of the normal ageing process. In fact, it is widely recognized that sleep duration declines with age, leading to dysregulation of circadian rhythms. The aim of our study was to analyse the possible association of sleep duration with TL in a sample of 135 subjects with ages ranging from 20 to 111 years, recruited from Palermo and neighbouring municipalities in Sicily (Italy). Preliminary data suggest that relative TL (RTL) decreases with age in both men and women. However, at older ages, the difference between men and women tends to narrow. Nonagenarian and centenarian women do not show RTL values significantly different from those observed in adult and old women (40-89 years aged). Moreover, to analyse the relationship between TL and sleep, we stratified sleep duration into greater or lesser than 8-h periods. We found that centenarians, who daily sleep 8 hours or more, have longer RTL than centenarians who sleep fewer than 8 hours. Although the relatively small sample size of centenarians, we provide preliminary evidence that sleep duration may affect the RTL of centenarians. To the best of our knowledge, this is the first study to examine the relationship between centenarians, RTL and sleep duration. Further studies with greater sample size of centenarians are required to replicate and extend these data.}, }
@article {pmid36442845, year = {2022}, author = {Ni, W and Wolf, K and Breitner, S and Zhang, S and Nikolaou, N and Ward-Caviness, CK and Waldenberger, M and Gieger, C and Peters, A and Schneider, A}, title = {Higher Daily Air Temperature Is Associated with Shorter Leukocyte Telomere Length: KORA F3 and KORA F4.}, journal = {Environmental science &amp; technology}, volume = {56}, number = {24}, pages = {17815-17824}, pmid = {36442845}, issn = {1520-5851}, mesh = {Adult ; Humans ; *Air Pollution/analysis ; Temperature ; Cohort Studies ; Leukocytes ; Telomere ; }, abstract = {Higher air temperature is associated with increased age-related morbidity and mortality. To date, short-term effects of air temperature on leukocyte telomere length have not been investigated in an adult population. We aimed to examine the short-term associations between air temperature and leukocyte telomere length in an adult population-based setting, including two independent cohorts. This population-based study involved 5864 participants from the KORA F3 (2004-2005) and F4 (2006-2008) cohort studies conducted in Augsburg, Germany. Leukocyte telomere length was assessed by a quantitative PCR-based method. We estimated air temperature at each participant's residential address through a highly resolved spatiotemporal model. We conducted cohort-specific generalized additive models to explore the short-term effects of air temperature on leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days separately and pooled the estimates by fixed-effects meta-analysis. Our study found that between individuals, an interquartile range (IQR) increase in daily air temperature was associated with shorter leukocyte telomere length at lags 0-1, 2-6, 0-6, and 0-13 days (%change: -2.96 [-4.46; -1.43], -2.79 [-4.49; -1.07], -4.18 [-6.08; -2.25], and -6.69 [-9.04; -4.27], respectively). This meta-analysis of two cohort studies showed that between individuals, higher daily air temperature was associated with shorter leukocyte telomere length.}, }
@article {pmid36440190, year = {2022}, author = {Lan, B and Bai, Y and Chang, X and Zhang, X}, title = {Independent and joint effect of relative telomere length and type 2 diabetes on all-cause mortality in American adults.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1035017}, pmid = {36440190}, issn = {1664-2392}, mesh = {Adult ; Humans ; Male ; United States ; Female ; *Diabetes Mellitus, Type 2/genetics ; Nutrition Surveys ; Telomere/genetics ; Leukocytes ; Proportional Hazards Models ; }, abstract = {OBJECTIVE: The joint effect of leukocyte telomere length (LTL) and type 2 diabetes (T2D) on the risk of all-cause death has been sparsely explored. The study designed to examine the joint effect of T2D and LTL on the probability of death in American adults.<br><br>METHODS: A cohort of 6862 adults with LTL measurements and with or without T2D from the NHANES 1999-2002 with follow-up information until 2015 was studied. Quantitative PCR was used to measure the length of telomeres relative to standard reference DNA (T/S ratio). Individuals were grouped into three tertiles according to the LTL levels, with the first tertile demonstrating the lowest one and used as the reference group. The effects of LTL and T2D status on death were evaluated using Kaplan-Meier curves along with log-rank test. Three Cox proportional hazards models with adjustment for various confounders were used to examine the links between TL and all-cause death possibility using adjusted hazard ratios (HRs).<br><br>RESULTS: Adults in the sample averaged 45.54 years of age, with 49.51% being male. After a median follow-up period of 14.4 years, 1543 (22.5%) individuals died from all cause. The probability of all-cause mortality was higher among individuals with LTL in the highest tertile than individuals in the lowest tertile (aHR = 0.89; 95%CI: 0.77-1.03); however, the difference did not reach the level of statistical significance (P = 0.11). Conversely, the individuals with T2D had a higher probability of death than individuals without (aHR = 1.26; 95%CI: 1.06-1.50; P = 0.0092). When LTL and T2D status were investigated jointly, subjects in the highest TLT tertile and with T2D had the highest probability of mortality compared with their counterparts (aHR = 1.34; 95%CI: 1.07-1.68; P = 0.0101). However, there was no independent effect of low TLT on mortality as demonstrated among individuals with diabetes (aHR = 1.14; 95%CI: 0.95-1.38; P = 0.1662).<br><br>CONCLUSION: The joint effect of TLT and T2D was larger than the sum of the independent effects on the risk of all-cause death. Participants with high TLT and diabetes showed the highest possibility of death compared with other groups.}, }
@article {pmid36437769, year = {2022}, author = {Zhao, G and Guo, D and Li, L and Yang, C and Dong, J}, title = {The Association between Dietary Magnesium Intake and Telomere Length in Adults with Hypertension.}, journal = {The journal of nutrition, health &amp; aging}, volume = {26}, number = {11}, pages = {1010-1015}, doi = {10.1007/s12603-022-1856-y}, pmid = {36437769}, issn = {1760-4788}, mesh = {Male ; Humans ; Female ; Nutrition Surveys ; *Magnesium ; *Hypertension/genetics ; Uric Acid ; Telomere ; }, abstract = {BACKGROUND: Dietary micronutrients are significantly associated with telomere length, as shown in multiple studies. However, no study has investigated the association between magnesium intake and telomere length in adults with hypertension.<br><br>METHODS: Participants were included from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. Dietary magnesium intake was assessed using the 24 - hour recall method and the telomere length of leukocytes was measured using polymerase chain reaction (PCR). A multivariate regression model was then used to assess the association between dietary magnesium intake and telomere length in adults with hypertension.<br><br>RESULTS: Our final analysis included 2199 hypertensive adults (46.79% males) with a mean dietary magnesium intake of 254.82&#xb1;133.47 mg/day. Linear regression, adjusted for race, sex, age, smoking, uric acid, and other variables, showed that every 1 mg increase in dietary magnesium intake was associated with a 0.20 (95% CI: 0.01, 0.39, p = 0.043) longer telomere length in all participants. In the &#x2265;45 years age group, there was a statistically significant association between the telomere length and dietary magnesium (95% CI: 0.16, 0.63, p <0.001).<br><br>CONCLUSIONS: This study suggests that increased magnesium intake is associated with a longer telomere length in hypertensive adults, especially in those &#x2265;45 years of age. However, further research is needed to determine a causal relationship.}, }
@article {pmid36437244, year = {2022}, author = {Maciejewska, N and Olszewski, M and Jurasz, J and Baginski, M and Stasevych, M and Zvarych, V and Folini, M and Zaffaroni, N}, title = {Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres.}, journal = {Cell death &amp; disease}, volume = {13}, number = {11}, pages = {1005}, pmid = {36437244}, issn = {2041-4889}, mesh = {Humans ; *Telomerase ; Telomere ; DNA Damage ; *Lung Neoplasms ; Anthraquinones/pharmacology ; Cell Line, Tumor ; *Bone Neoplasms ; }, abstract = {Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.}, }
@article {pmid36435475, year = {2023}, author = {Tao, HY and He, SM and Zhao, CY and Wang, Y and Sheng, WJ and Zhen, YS}, title = {Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.}, journal = {International journal of biological macromolecules}, volume = {226}, number = {}, pages = {1088-1099}, doi = {10.1016/j.ijbiomac.2022.11.225}, pmid = {36435475}, issn = {1879-0003}, mesh = {Animals ; Mice ; Humans ; Recombinant Fusion Proteins/genetics/pharmacology/metabolism ; *Telomerase/genetics/metabolism ; ErbB Receptors/metabolism ; Down-Regulation ; Telomere Shortening ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; *Immunoconjugates/pharmacology ; Telomere/metabolism ; }, abstract = {OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy.<br><br>METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3&#x223c;AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed.<br><br>RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3&#x223c;AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1&#xa0;nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3&#x223c;AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-&#x3b2; in athymic mice.<br><br>CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.}, }
@article {pmid36427630, year = {2022}, author = {Jenkins, AJ and Syreeni, A and Mutter, S and Januszewski, AS and Groop, PH}, title = {Telomeres in clinical diabetes research - Moving towards precision medicine in diabetes care?.}, journal = {Diabetes research and clinical practice}, volume = {194}, number = {}, pages = {110178}, doi = {10.1016/j.diabres.2022.110178}, pmid = {36427630}, issn = {1872-8227}, mesh = {Humans ; *Precision Medicine ; Telomere/genetics ; Telomere Shortening ; *Diabetes Mellitus/genetics/therapy ; Biomarkers ; }, abstract = {The early prediction of health outcomes for people with diabetes mellitus is desirable, as are adjunct therapies to reduce the related chronic complications and risk of premature death. The length of telomeres, protective caps on chromosome ends, is influenced by genetic and acquired factors, and shorter telomeres have been associated with and predictive of adverse cardiometabolic outcomes. Many studies have shown associations between telomere length in white blood cells (WBC) and diabetes per se and its chronic complications, and some studies show that telomeres do not always progressively shorten in people with diabetes. With the pandemic of diabetes and taking into consideration the calculations of residual risk using existent risk equations, additional tests to stratify subject risk are desirable. In this evolving era of precision medicine for people with diabetes, this 'global biomarker' of WBC telomere length may be useful to help predict health outcomes, to monitor health status, and may be a therapeutic target. We comment on the field of telomere investigations in diabetes, including recommending areas for further clinical research.}, }
@article {pmid36427074, year = {2022}, author = {Goswami, J and MacArthur, TA and Ramachandran, D and Mahony, C and Howick, AS and Price-Troska, T and Thompson, RJ and Spears, GM and Bailey, KR and Patnaik, MS and Passos, JF and Park, MS and Ferrer, A}, title = {Telomere Length of Peripheral Blood Mononuclear Cells is Associated with Discharge Disposition in Older Trauma Patients.}, journal = {Shock (Augusta, Ga.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/SHK.0000000000002059}, pmid = {36427074}, issn = {1540-0514}, abstract = {INTRODUCTION: Little is known regarding peripheral blood mononuclear cell telomere length (PBMC-TL) and response to traumatic injury. The objective of this study was to characterize the role of PBMC-TL in coagulation and clinical outcomes after injury.<br><br>METHODS: Plasma and buffy coats were prospectively collected from trauma patients and healthy volunteers. DNA was purified and PBMC-TL quantified by qPCR. Thrombin generation kinetics were expressed as lag time (LT, minutes), peak height (PH, nM), time to peak (ttPeak, min), and endogenous thrombin potential (ETP, nM*min). Results in median and quartiles [Q1, Q3]. Wilcoxon rank sum testing; p < 0.05 considered significant.<br><br>RESULTS: Forty-two younger patients (21 [20, 22] years, 69% male) and 39 older patients (62 [61, 64] years, 79% male) were included. There was no significant difference in Clinical Frailty Scores between groups. Younger patients had longer total PBMC-TL (0.40 Mb [0.30, 0.49] vs. 0.29 Mb [0.23, 0.33], p < 0.001) and longer average PBMC-TL per chromosome (4.3 kb [3.3, 5.3] vs. 3.2 kb [2.5, 3.7], p < 0.001). When older patients were stratified by 50th percentile of PBMC-TL, there were no differences in thrombin generation; however, those with shorter telomeres were less likely to be discharged home (29% vs. 77%, p = 0.004). Older patients in the bottom quartile of PBMC-TL had shorter LT (2.78 min [2.33, 3.00] vs. 3.33 min [3.24, 3.89], p = 0.030) and were less likely to be discharged home (22% vs. 90%, p = 0.006) than those in the top quartile of PBMC-TL. Multivariable logistic regression models revealed both increased age and shorter PBMC-TL to be independent predictors of discharge disposition other than home.<br><br>CONCLUSION: In older trauma patients, shorter PBMC-TL is associated with accelerated initiation of thrombin generation and lower likelihood of being discharged to home.}, }
@article {pmid36421025, year = {2023}, author = {PerezGrovas-Saltijeral, A and Ochoa-Morales, A and Jara-Prado, A and Velázquez-Cruz, R and Rivera-Paredez, B and Dávila-OrtizdeMontellano, D and Benítez-Alonso, EO and Santamaría-Olmedo, M and Sevilla-Montoya, R and Marfil-Marín, E and Valdés-Flores, M and Martínez-Ruano, L and Camacho-Molina, A and Hidalgo-Bravo, A}, title = {Unraveling the role of relative telomere length and CAG expansion on initial symptoms of juvenile Huntington disease.}, journal = {European journal of neurology}, volume = {30}, number = {3}, pages = {612-621}, doi = {10.1111/ene.15644}, pmid = {36421025}, issn = {1468-1331}, mesh = {Adult ; Humans ; *Huntington Disease/genetics/diagnosis ; Trinucleotide Repeats/genetics ; Telomere ; Age of Onset ; }, abstract = {BACKGROUND AND PURPOSE: Juvenile-onset Huntington disease (JHD) is defined when symptoms initiate before 20 years of age. Mechanisms explaining differences between juvenile and adult onset are not fully understood. Our aim was to analyze the distribution of initial symptoms in a cohort of JHD patients and to explore its relationship with CAG expansion and relative telomere length (RTL).<br><br>METHODS: A total of 84 JHD patients and 54 neurologically healthy age and sex matched individuals were recruited. CAG length was measured by southern blot or triplet repeat primed polymerase chain reaction. RTL was measured using the Cawthon method.<br><br>RESULTS: Psychiatric symptoms were most frequent when considering the entire cohort. When divided into onset before or after 10&#x2009;years, cognitive symptoms were more frequent in the youngest, whilst in the older group psychiatric symptoms prevailed. Motor symptoms were rare in the youngest and epilepsy was observed only in this group as well as a larger CAG expansion. RTL analysis revealed shorter telomeres in JHD patients compared to controls. This difference is not influenced by age, initial symptoms, time of disease or CAG expansion.<br><br>CONCLUSIONS: To the best of our knowledge this is the largest cohort of JHD patients reported. Psychiatric manifestations deserve special attention when JHD is suspected and epilepsy is especially important in the youngest patients. Initial symptoms seem to be influenced by CAG expansion and therefore age of onset. RTL is significantly reduced in JHD patients which can influence the characteristic neurodegeneration of JHD and contribute to the clinical discrepancy between adult and juvenile forms of Huntington disease.}, }
@article {pmid36416860, year = {2023}, author = {Jezek, M and Sun, W and Negesse, MY and Smith, ZM and Orosz, A and Green, EM}, title = {Set1 regulates telomere function via H3K4 methylation-dependent and -independent pathways and calibrates the abundance of telomere maintenance factors.}, journal = {Molecular biology of the cell}, volume = {34}, number = {1}, pages = {ar6}, pmid = {36416860}, issn = {1939-4586}, support = {R01 GM124342/GM/NIGMS NIH HHS/United States ; }, mesh = {Methylation ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Histones/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins/metabolism ; }, abstract = {Set1 is an H3K4 methyltransferase that comprises the catalytic subunit of the COMPASS complex and has been implicated in transcription, DNA repair, cell cycle control, and numerous other genomic functions. Set1 also promotes proper telomere maintenance, as cells lacking Set1 have short telomeres and disrupted subtelomeric gene repression; however, the precise role for Set1 in these processes has not been fully defined. In this study, we have tested mutants of Set1 and the COMPASS complex that differentially alter H3K4 methylation status, and we have attempted to separate catalytic and noncatalytic functions of Set1. Our data reveal that Set1-dependent subtelomeric gene repression relies on its catalytic activity toward H3K4, whereas telomere length is regulated by Set1 catalytic activity but likely independent of the H3K4 substrate. Furthermore, we uncover a role for Set1 in calibrating the abundance of critical telomere maintenance proteins, including components of the telomerase holoenzyme and members of the telomere capping CST (Cdc13-Stn1-Ten1) complex, through both transcriptional and posttranscriptional pathways. Altogether, our data provide new insights into the H3K4 methylation-dependent and -independent roles for Set1 in telomere maintenance in yeast and shed light on possible roles for Set1-related methyltransferases in other systems.}, }
@article {pmid36406126, year = {2022}, author = {Peretz, I and Kupiec, M and Sharan, R}, title = {A comparative analysis of telomere length maintenance circuits in fission and budding yeast.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {1033113}, pmid = {36406126}, issn = {1664-8021}, abstract = {The natural ends of the linear eukaryotic chromosomes are protected by telomeres, which also play an important role in aging and cancer development. Telomere length varies between species, but it is strictly controlled in all organisms. The process of Telomere Length Maintenance (TLM) involves many pathways, protein complexes and interactions that were first discovered in budding and fission yeast model organisms (Saccharomyces cerevisiae, Schizosaccharomyces pombe). In particular, large-scale systematic genetic screens in budding yeast uncovered a network of ≈ 500 genes that, when mutated, cause telomeres to lengthen or to shorten. In contrast, the TLM network in fission yeast remains largely unknown and systematic data is still lacking. In this work we try to close this gap and develop a unified interpretable machine learning framework for TLM gene discovery and phenotype prediction in both species. We demonstrate the utility of our framework in pinpointing the pathways by which TLM homeostasis is maintained and predicting novel TLM genes in fission yeast. The results of this study could be used for better understanding of telomere biology and serve as a step towards the adaptation of computational methods based on telomeric data for human prognosis.}, }
@article {pmid36404192, year = {2023}, author = {Vinayagamurthy, S and Bagri, S and Mergny, JL and Chowdhury, S}, title = {Telomeres expand sphere of influence: emerging molecular impact of telomeres in non-telomeric functions.}, journal = {Trends in genetics : TIG}, volume = {39}, number = {1}, pages = {59-73}, doi = {10.1016/j.tig.2022.10.002}, pmid = {36404192}, issn = {0168-9525}, mesh = {*Telomere/genetics/metabolism ; DNA/metabolism ; *G-Quadruplexes ; Heterochromatin ; }, abstract = {Although the impact of telomeres on physiology stands well established, a question remains: how do telomeres impact cellular functions at a molecular level? This is because current understanding limits the influence of telomeres to adjacent subtelomeric regions despite the wide-ranging impact of telomeres. Emerging work in two distinct aspects offers opportunities to bridge this gap. First, telomere-binding factors were found with non-telomeric functions. Second, locally induced DNA secondary structures called G-quadruplexes are notably abundant in telomeres, and gene regulatory regions genome wide. Many telomeric factors bind to G-quadruplexes for non-telomeric functions. Here we discuss a more general model of how telomeres impact the non-telomeric genome - through factors that associate at telomeres and genome wide - and influence cell-intrinsic functions, particularly aging, cancer, and pluripotency.}, }
@article {pmid36402910, year = {2022}, author = {Roberts, EK and Boss, J and Mukherjee, B and Salerno, S and Zota, A and Needham, BL}, title = {Persistent organic pollutant exposure contributes to Black/White differences in leukocyte telomere length in the National Health and Nutrition Examination Survey.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {19960}, pmid = {36402910}, issn = {2045-2322}, support = {R01 AG033592/AG/NIA NIH HHS/United States ; U24 AG066528/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Adult ; Persistent Organic Pollutants ; *Polychlorinated Biphenyls/toxicity ; Nutrition Surveys ; Cross-Sectional Studies ; White People ; Leukocytes ; *Environmental Pollutants/toxicity ; Telomere/genetics ; }, abstract = {Despite racial disparities in diseases of aging and premature mortality, non-Hispanic Black Americans tend to have longer leukocyte telomere length (LTL), a biomarker of cellular aging, than non-Hispanic White Americans. Previous findings suggest that exposure to certain persistent organic pollutants (POPs) is both racially-patterned and associated with longer LTL. We examine whether Black/White differences in LTL are explained by differences in exposure to 15 POPs by estimating the indirect effect (IE) of self-reported race on LTL that is mediated through nine polychlorinated biphenyls (PCBs), three furans, and three dioxins, as well as their mixtures. Our study population includes 1,251 adults from the 1999-2000 and 2001-2002 cycles of the cross-sectional National Health and Nutrition Examination Survey. We characterized single-pollutant mediation effects by constructing survey-weighted linear regression models. We also implemented various approaches to quantify a global mediation effect of all POPs, including unpenalized linear regression, ridge regression, and examination of three summary exposure scores. We found support for the hypothesis that exposure to PCBs partially mediates Black/White differences in LTL. In single-pollutant models, there were significant IEs of race on LTL through six individual PCBs (118, 138, 153, 170, 180, and 187). Ridge regression (0.013, CI 0.001, 0.023; 26.0% mediated) and models examining summative exposure scores with linear combinations derived from principal components analysis (0.019, CI 0.009, 0.029; 34.8% mediated) and Toxic Equivalency Quotient (TEQ) scores (0.016, CI 0.005, 0.026; 28.8% mediated) showed significant IEs when incorporating survey weights. Exposures to individual POPs and their mixtures, which may arise from residential and occupational segregation, may help explain why Black Americans have longer LTL than their White counterparts, providing an environmental explanation for counterintuitive race differences in cellular aging.}, }
@article {pmid36401358, year = {2022}, author = {Wang, L and Yin, H and Huang, S and Huang, S and Huang, C and Zhang, Z and Liu, H}, title = {Bortezomib induces cellular senescence in A549 lung cancer cells by stimulating telomere shortening.}, journal = {Human &amp; experimental toxicology}, volume = {41}, number = {}, pages = {9603271221124094}, doi = {10.1177/09603271221124094}, pmid = {36401358}, issn = {1477-0903}, mesh = {Humans ; Bortezomib/pharmacology/therapeutic use ; *Lung Neoplasms/drug therapy/genetics ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics ; A549 Cells ; Telomere Shortening ; *Antineoplastic Agents/pharmacology/therapeutic use ; Cell Line, Tumor ; Cellular Senescence ; }, abstract = {Bortezomib (BTZ) is a first-generation proteasome inhibitor with anti-tumor properties for multiple myeloma and mantle cell lymphoma. Increasing evidence has shown that BTZ exhibits toxic effects on diverse tumor cells, including non-small cell lung cancer (NSCLC) cells. However, the mechanism has not been fully evaluated. Here, we examined the regulatory effect of BTZ on cellular senescence, a potent tumor suppressive mechanism, in NSCLC cell lines. SA-β-gal staining assay showed that BTZ caused a significant increase in β-Gal positive A549 cells. BTZ also induced cell cycle arrest on G0/G1 phase in A549 cells. Furthermore, telomerase activity was markedly reduced in A549 cells treated with BTZ. BTZ reduced the expression levels of hTERT, and the key proteins binding to telomeric DNA, including POT1 and TIN2. It also induced the expressions of the cell cycle-associated tumor suppressors p53 and p21 in A549 cells. Moreover, hTERT overexpression abolished the effects of BTZ on A549 cells. These results show that BTZ induced cellular senescence by stimulating telomere shortening. Our results provide experimental data for the potential clinical application of BTZ in NSCLC treatment.}, }
@article {pmid36400982, year = {2023}, author = {Jin, M and Huang, JD}, title = {New mechanism to promote long-term T-cell immunity by telomere transfer from antigen-presenting cells.}, journal = {Cellular &amp; molecular immunology}, volume = {20}, number = {2}, pages = {117-118}, pmid = {36400982}, issn = {2042-0226}, mesh = {*T-Lymphocytes ; *Antigen-Presenting Cells ; Antigen Presentation ; Telomere ; }, }
@article {pmid36399511, year = {2022}, author = {Chen, L and Zhang, C and Ma, W and Huang, J and Zhao, Y and Liu, H}, title = {METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability.}, journal = {Nucleic acids research}, volume = {50}, number = {20}, pages = {11619-11634}, pmid = {36399511}, issn = {1362-4962}, mesh = {*RNA, Long Noncoding/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Shortening ; Homologous Recombination ; DNA ; Telomere Homeostasis ; }, abstract = {Telomeric repeat-containing RNA (TERRA) is a type of long non-coding RNA transcribed from telomeres, and it forms R-loops by invasion into telomeric DNA. Since either an excessive or inadequate number of R-loops leads to telomere instability, the TERRA levels need to be delicately modulated. In this study, we found that m6A modification presents on the subtelomeric regions of TERRA and stabilizes it, and the loss of METTL3 impacts telomere stability. Mechanically, the m6A modification on TERRA is catalyzed by METTL3, recognized and stabilized by the m6A reader YTHDC1. Knockdown of either METTL3 or YTHDC1 enhances TERRA degradation. The m6A-modified TERRA forms R-loops and promotes homologous recombination which is essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells. METTL3 depletion leads to R-loop reduction, telomere shortening and instability. Altogether, these findings reveal that METTL3 protects telomeres by catalyzing m6A modification on TERRA, indicating that inhibition or deletion of METTL3 is potentially a new avenue for ALT cancer therapy.}, }
@article {pmid36399449, year = {2022}, author = {Salih, A and Galazzo, IB and Petersen, SE and Lekadir, K and Radeva, P and Menegaz, G and Altmann, A}, title = {Telomere length is causally connected to brain MRI image derived phenotypes: A mendelian randomization study.}, journal = {PloS one}, volume = {17}, number = {11}, pages = {e0277344}, pmid = {36399449}, issn = {1932-6203}, support = {MR/L016311/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Mendelian Randomization Analysis ; *Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Phenotype ; Telomere ; }, abstract = {Recent evidence suggests that shorter telomere length (TL) is associated with neuro degenerative diseases and aging related outcomes. The causal association between TL and brain characteristics represented by image derived phenotypes (IDPs) from different magnetic resonance imaging (MRI) modalities remains unclear. Here, we use two-sample Mendelian randomization (MR) to systematically assess the causal relationships between TL and 3,935 brain IDPs. Overall, the MR results suggested that TL was causally associated with 193 IDPs with majority representing diffusion metrics in white matter tracts. 68 IDPs were negatively associated with TL indicating that longer TL causes decreasing in these IDPs, while the other 125 were associated positively (longer TL leads to increased IDPs measures). Among them, ten IDPs have been previously reported as informative biomarkers to estimate brain age. However, the effect direction between TL and IDPs did not reflect the observed direction between aging and IDPs: longer TL was associated with decreases in fractional anisotropy and increases in axial, radial and mean diffusivity. For instance, TL was positively associated with radial diffusivity in the left perihippocampal cingulum tract and with mean diffusivity in right perihippocampal cingulum tract. Our results revealed a causal role of TL on white matter integrity which makes it a valuable factor to be considered when brain age is estimated and investigated.}, }
@article {pmid36396857, year = {2023}, author = {Hong, Z and Lin, X and Zhou, Y and Zheng, G and Liao, X and Wei, Q and Zhang, Z and Liang, J}, title = {Lean body mass but not body fat mass is related with leukocyte telomere length in children.}, journal = {International journal of obesity (2005)}, volume = {47}, number = {1}, pages = {67-74}, pmid = {36396857}, issn = {1476-5497}, mesh = {Male ; Female ; Humans ; Child ; Cross-Sectional Studies ; *Body Composition/physiology ; *Bone Density/physiology ; Absorptiometry, Photon ; Telomere ; }, abstract = {OBJECTIVES: The aim of this study was to investigate the relationship between body composition and leukocyte telomere length (LTL) in healthy Chinese children aged 6-11 years.<br><br>METHODS: This cross-sectional study enrolled 406 healthy children (175 girls and 231 boys). The relative telomere length in their peripheral blood leukocytes was determined via quantitative polymerase chain reaction. Dual-energy X-ray absorptiometry was used to determine body fat content and regional fat distribution, appendicular skeletal muscle mass (ASM), bone mineral density (BMD) and bone mineral content (BMC) at the total body (TB) and total body less head (TBLH) levels, and total body lean mass (TBLM) was then determined. ASM/height[2] (ASMI) was also calculated.<br><br>RESULTS: After adjusting for potential covariates, multiple linear regression analyses revealed that neither body fat content nor regional body fat distribution were significantly associated with LTL (&#x3b2;&#x2009;=&#x2009;-8.48&#x2009;&#xd7;&#x2009;10[-6]-1.44&#x2009;&#xd7;&#x2009;10[-1], p&#x2009;=&#x2009;0.227-0.959). However, ASM, ASMI, TB BMC/TB BMD, TBLH BMC/TBLH BMD and TBLM were positively associated with LTL (&#x3b2;&#x2009;=&#x2009;8.95&#x2009;&#xd7;&#x2009;10[-6]-4.95&#x2009;&#xd7;&#x2009;10[-1], p&#x2009;=&#x2009;0.005-0.035). Moreover, analysis of covariance revealed there was a statistically significant dose-dependent positive association between LTL and ASM, TB BMC/BMD, TBLH BMC/BMD, and TBLM (p-trend&#x2009;=&#x2009;0.002-0.025).<br><br>CONCLUSIONS: Skeletal muscle mass and bone mass but not body fat content or distribution were significantly associated with LTL in this pediatric population.}, }
@article {pmid36394537, year = {2022}, author = {Vicari, MR and Bruschi, DP and Cabral-de-Mello, DC and Nogaroto, V}, title = {Telomere organization and the interstitial telomeric sites involvement in insects and vertebrates chromosome evolution.}, journal = {Genetics and molecular biology}, volume = {45}, number = {3 Suppl 1}, pages = {e20220071}, pmid = {36394537}, issn = {1415-4757}, abstract = {Telomere has a central role in chromosomal stability events. Chromosome ends organized in telomere-loop prevent activation of DNA damage response (DDR) mechanisms, thus keeping the chromosome structure organized. On the other hand, free chromosome ends, dysfunctional telomeres, and interstitial telomeric sequences (ITS) can trigger chromosome rearrangements. Here, the telomere organization, function, and maintenance mechanisms, in addition to ITS types and their involvement in chromosome changes, were revisited. Despite a general (TTAGGG)n sequence being present in vertebrate telomeres, insects show more diversification of their telomere motif. The relation between ITS and chromosome rearrangements was observed in insects and vertebrates, demonstrating different types of genome organization and distribution. Some ITS cannot be considered relicts of chromosome rearrangements because probable they were inserted during a double-strand break repair mechanism. On the other hand, the involvement of telomere sequences participating or triggering chromosome rearrangements or organizing satellite DNA components in several species groups is evident. The genomic assembling advances and applying other methodologies over ITS, and their flanking regions, can help to understand the telomere participation in the chromosomal evolution in species groups with highly diversified karyotypes.}, }
@article {pmid36394204, year = {2022}, author = {Yuan, X and Yuan, H and Zhang, N and Liu, T and Xu, D}, title = {Thyroid carcinoma-featured telomerase activation and telomere maintenance: Biology and translational/clinical significance.}, journal = {Clinical and translational medicine}, volume = {12}, number = {11}, pages = {e1111}, pmid = {36394204}, issn = {2001-1326}, mesh = {Humans ; *Telomerase/genetics/metabolism ; *Thyroid Neoplasms/diagnosis/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Biology ; }, abstract = {BACKGROUND: Telomerase is a ribonucleoprotein complex consisting of a catalytic component telomerase reverse transcriptase (TERT), internal RNA template and other co-factors, and its essential function is to synthesize telomeric DNA, repetitive TTAGGG sequences at the termini of linear chromosomes. Telomerase is silent in normal human follicular thyroid cells, primarily due to the TERT gene being tightly repressed. During the development and progression of thyroid carcinomas (TCs), TERT induction and telomerase activation is in general required to maintain telomere length, thereby conferring TC cells with immortal and aggressive phenotypes.<br><br>METHODS: The genomic alterations of the TERT loci including TERT promoter's gain-of-function mutations, copy number gain, fusion and rearrangements, have recently been identified in TCs as mechanisms to induce TERT expression and to activate telomerase. Importantly, numerous studies have consistently shown that TERT promoter mutations and TERT expression occur in all TC subtypes, and are robustly associated with TC malignancy, aggressiveness, treatment failure and poor outcomes. Therefore, the assessment of TERT promoter mutations and TERT expression is highly valuable in TC diagnostics, prognosis, treatment decision, and follow-up design. In addition, the TERT promoter is frequently hypermethylated in TC cells and tumors, which is required to activate TERT transcription and telomerase. Dysregulation of other components in the telomerase complex similarly upregulate telomerase. Moreover, shortened telomeres lead to altered gene expression and metabolism, thereby actively promoting TC aggressiveness. Here we summarize recent findings in TCs to provide the landscape of TC-featured telomere/telomerase biology and discuss underlying implications in TC precision medicine.<br><br>CONCLUSION: Mechanistic insights into telomerase activation and TERT induction in TCs are important both biologically and clinically. The TERT gene aberration and expression-based molecular classification of TCs is proposed, and for such a purpose, the standardization of the assay and evaluation system is required. Moreover, the TERT-based system and 2022 WHO TC classification may be combined to improve TC care.}, }
@article {pmid36385813, year = {2022}, author = {Liu, Y and Ye, X and Wang, Z and Zong, S and Cui, Y}, title = {In Situ Super-Resolution Imaging of Telomeres with DNA-PAINT.}, journal = {ACS omega}, volume = {7}, number = {44}, pages = {40512-40519}, pmid = {36385813}, issn = {2470-1343}, abstract = {Telomeres are located at the ends of chromosomes and play an important role in maintaining the integrity of chromosomes and controlling the cycle of cell division. Studies have shown that abnormal telomere length may lead to the occurrence of some diseases. Therefore, accurate measurement of telomere length will be helpful for the prediction and diagnosis of related diseases. DNA point accumulation for imaging in nanoscale topography (PAINT) is an optical super-resolution technology that relies on the instantaneous binding of the fluorescent DNA imaging strand to the target epitope. Here, we present the first demonstration of DNA-PAINT-based in situ super-resolution imaging of telomeres as well as centromeres. For DNA-PAINT imaging, Cy5-labeled telomere DNA (5'-Cy5-TTTTTCCCTAACCCTAA-3') and Cy3-labeled centromere DNA (5'-Cy3-TTTTTAGCTTCTGTCTAGTTT-3') are utilized as the imager strands. Through an improved permeabilization strategy that we proposed, the imager strands can bind with intracellular telomeres and centromeres with high specificity, realizing super-resolution imaging of telomeres and centromeres. To check the applicability of DNA-PAINT in evaluating telomere length, we conducted an experiment using azidothymidine (AZT)-treated tumor cells as the imaging target. The DNA-PAINT imaging results clearly revealed the telomerase inhibition effect of AZT. Compared with single-molecule localization microscopy (SMLM) with peptide nucleic acid (PNA)-based fluorescence in situ hybridization (FISH), our method has the advantages of low cost, low toxicity, and simple equipment. Such a DNA-PAINT-based imaging strategy holds great potential in measuring telomere length with high accuracy, which would play an important role in the study of telomere-related diseases such as cancer.}, }
@article {pmid36374285, year = {2022}, author = {Kohlrausch, FB and Wang, F and Luo, D and Mahn, R and Keefe, DL}, title = {Telomere fusions as a signal of term placental aging? A pilot study.}, journal = {Reproduction &amp; fertility}, volume = {3}, number = {4}, pages = {L9-L11}, pmid = {36374285}, issn = {2633-8386}, mesh = {Animals ; Humans ; Female ; Pregnancy ; Pilot Projects ; *Placenta ; }, abstract = {The placenta plays an essential role at the beginning of life, nourishing and supporting the fetus, but its life span is limited. In late pregnancy, the placenta develops signs of aging, including inflammation and impaired function, which may complicate pregnancy. Placentas also show another sign of aging - cells with extra or missing chromosomes. Chromosomally abnormal cells could gather in the placenta if they get stranded there and/or if the cells do not separate normally. Chromosome separation goes wrong in aging cells when the DNA sequences, which protect the ends of the chromosomes, erode. When chromosomes lose their protective caps, they fuse which leads to abnormal numbers of chromosomes. In this pilot study, for the first time, we found fusions between the caps in a human placenta when it reaches full term. More studies are needed to decide whether this has an influence on how the placenta works and outcomes of pregnancy.}, }
@article {pmid36372149, year = {2023}, author = {Liu, C and Chen, YJ and Sun, B and Chen, HG and Mustieles, V and Messerlian, C and Sun, Y and Meng, TQ and Lu, WQ and Pan, XF and Xiong, CL and Hou, J and Wang, YX}, title = {Blood trihalomethane concentrations in relation to sperm mitochondrial DNA copy number and telomere length among 958 healthy men.}, journal = {Environmental research}, volume = {216}, number = {Pt 4}, pages = {114737}, doi = {10.1016/j.envres.2022.114737}, pmid = {36372149}, issn = {1096-0953}, mesh = {Humans ; Male ; *Semen Analysis ; Semen/chemistry ; DNA, Mitochondrial ; DNA Copy Number Variations ; Trihalomethanes/toxicity ; Spermatozoa ; Telomere ; *Water Pollutants, Chemical/analysis ; }, abstract = {BACKGROUND: In animal and human studies, exposure to trihalomethanes (THMs) has been associated with reduced semen quality. However, the underlying mechanisms remain poorly understood.<br><br>OBJECTIVE: To investigate the associations of blood THM concentrations with sperm mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) among healthy men.<br><br>METHODS: We recruited 958 men who volunteered as potential sperm donors. A single blood sample was collected from each participant at recruitment and measured for chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM) concentrations. Within a 90-day follow-up, the last semen sample provided by each participant was quantified for sperm mtDNAcn and TL. We used multivariable linear regression models to assess the associations between blood THM concentrations and sperm mtDNAcn and TL. We also performed stratified analyses according to the time intervals between baseline blood THM determinations and semen collection (i.e., 0-9, 10-14, 15-69, or >69 days) to explore potential windows of susceptibility.<br><br>RESULTS: After adjusting for potential confounders, we found inverse associations between quartiles (or categories) of blood TBM, brominated THM (Br-THM, the sum of BDCM, DBCM, and TBM), and total THM (TTHM, the sum of all four THMs) concentrations and sperm mtDNAcn (all P for trend&#x2264;0.03). Besides, we found inverse associations between quartiles of blood TCM, Br-THM, chlorinated THM (Cl-THM, the sum of TCM, BDCM, and DBCM), and TTHM concentrations and sperm TL (all P for trend<0.10). Stratified analyses showed stronger associations between Br-THM concentrations and sperm mtDNAcn determined 15-69 days since baseline exposure determinations, and between blood TCM and TTHM concentrations and sperm TL determined >69 days since baseline exposure determinations.<br><br>CONCLUSION: Exposure to THMs may be associated with sperm mitochondrial and telomeric dysfunction.}, }
@article {pmid36371747, year = {2023}, author = {Yu, HJ and Ho, M and Chau, PH and Geng, L and Fong, DYT}, title = {Salivary telomere length and the risks of prediabetes and diabetes among middle-aged and older adults: findings from the Health and Retirement Study.}, journal = {Acta diabetologica}, volume = {60}, number = {2}, pages = {273-283}, pmid = {36371747}, issn = {1432-5233}, mesh = {Male ; Middle Aged ; Humans ; Aged ; Retirement ; Overweight ; *Prediabetic State/epidemiology/genetics ; Obesity/complications/epidemiology ; *Diabetes Mellitus/epidemiology/genetics ; Telomere Shortening ; Telomere/genetics ; *Cardiovascular Diseases ; }, abstract = {AIM: To assess the association of telomere length (TL) with prediabetes/diabetes and to explore the potential factors affecting TL among individuals with prediabetes/diabetes by weight status.<br><br>METHODS: This study included 3,379 eligible adults (aged 45-85&#xa0;years, males: 42%) from the US Health and Retirement Study in 2008. TL was assayed using quantitative PCR of saliva (T/S ratio). Linear and nonlinear associations between TL and prediabetes/diabetes were assessed using the logistic regression and restricted cubic spline model, respectively, adjusting for TL-plate numbers, age, sex, race, body mass index, lifestyles, diabetes medications, and cardiometabolic parameters (blood pressure, C-reactive protein, and total cholesterol). Multiple linear regression was used for testing any factors associated with TL.<br><br>RESULTS: Among 3,379 participants, 868 (25.7%) had prediabetes with a mean TL of 1.34&#x2009;&#xb1;&#x2009;0.37 (T/S ratio) and 858 (25.4%) had diabetes with a mean TL of 1.36&#x2009;&#xb1;&#x2009;0.43 (T/S ratio). Neither linear nor nonlinear association of TL with prediabetes/diabetes was significant by weight status. Age was negatively associated with TL in both normal-weight (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.002, p&#x2009;=&#x2009;0.025) and overweight/obese (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.002, p&#x2009;=&#x2009;0.006) prediabetes, but non-significant in normal-weight and overweight/obese diabetes. BMI and cardiometabolic parameters were not associated with TL in prediabetes/diabetes by weight status.<br><br>CONCLUSIONS: Salivary TL was not associated with prediabetes/diabetes among the US middle-aged and older adults. Further longitudinal studies are required to establish the link between TL and diabetes development and to identify potential factors affecting TL shortening, particularly in normal-weight diabetic patients.}, }
@article {pmid36370823, year = {2023}, author = {Yasir, S and Thompson, S and Chen, ZE and Knudson, R and Knutson, D and Kloft-Nelson, S and Graham, RP and Jain, D and Simon, SM and Wu, TT and Torbenson, M}, title = {Alternative lengthening of telomeres in primary hepatic neoplasms.}, journal = {Human pathology}, volume = {131}, number = {}, pages = {79-86}, doi = {10.1016/j.humpath.2022.11.003}, pmid = {36370823}, issn = {1532-8392}, support = {P50 CA210964/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Hepatocellular/genetics/pathology ; *Hemangiosarcoma/genetics/pathology ; In Situ Hybridization, Fluorescence ; *Liver Neoplasms/genetics/pathology ; *Cholangiocarcinoma/genetics/pathology ; *Carcinosarcoma/pathology ; Bile Ducts, Intrahepatic/pathology ; *Bile Duct Neoplasms/genetics/pathology ; Telomere/genetics/pathology ; }, abstract = {The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcoma (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumor (N = 2), embryonal sarcoma (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N = 2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.}, }
@article {pmid36364907, year = {2022}, author = {Nonsa-Ard, R and Aneknan, P and Tong-Un, T and Honsawek, S and Leelayuwat, N}, title = {Effects of Irvingia gabonensis Extract on Metabolism, Antioxidants, Adipocytokines, Telomere Length, and Aerobic Capacity in Overweight/Obese Individuals.}, journal = {Nutrients}, volume = {14}, number = {21}, pages = {}, pmid = {36364907}, issn = {2072-6643}, mesh = {Humans ; Adipokines ; Adiponectin ; *Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Dietary Supplements ; Double-Blind Method ; Inflammation/drug therapy ; Obesity/drug therapy ; *Overweight ; Plant Extracts/pharmacology/therapeutic use ; Polyesters/therapeutic use ; Telomere ; }, abstract = {We investigated the effects of Irvingia gabonensis (IG) kernel extract on the metabolism, adiposity indices, redox status, inflammation, adipocytokines, blood leukocyte relative telomere length (RTL), and aerobic capacity of overweight/obese individuals. All participants used the first 12-week phase to monitor body weight. They were then randomly divided into two groups: (1) 300 mg IG or (2) placebo (PLA). Both groups took one tablet per day for 12 weeks. The variables were measured before supplementation and after 3, 6, and 12 weeks of supplementation. RTL and aerobic capacity were measured before and after 12 weeks. Compared with the PLA, the IG increased plasma vitamin C after supplementation at 6 (p < 0.01) and 12 weeks (p < 0.05) and serum adiponectin after 3 weeks (p < 0.05). Compared with before supplementation, plasma malondialdehyde in the IG and serum leptin in the PLA were decreased after 12-week supplementation, without any differences between the groups. There were no differences between groups with respect to metabolism, inflammation, RTL, and aerobic capacity after the supplementation. We suggest that 12-week daily IG supplementation improved plasma vitamin C and adiponectin. The findings show the possible mechanism contributing to the effect of IG supplementation on a reduction in obesity-related complications.}, }
@article {pmid36362235, year = {2022}, author = {Scarabino, D and Veneziano, L and Mantuano, E and Arisi, I and Fiore, A and Frontali, M and Corbo, RM}, title = {Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study.}, journal = {International journal of molecular sciences}, volume = {23}, number = {21}, pages = {}, pmid = {36362235}, issn = {1422-0067}, mesh = {Humans ; *Huntington Disease/diagnosis/genetics ; Follow-Up Studies ; Telomere/genetics ; Leukocytes, Mononuclear ; Leukocytes ; Biomarkers ; }, abstract = {The identification of biomarkers for neurodegenerative disorders such as Huntington's disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39-51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.}, }
@article {pmid36362129, year = {2022}, author = {Nonsa-Ard, R and Aneknan, P and Tong-Un, T and Honsawek, S and Leelayuwat, C and Leelayuwat, N}, title = {Telomere Length Is Correlated with Resting Metabolic Rate and Aerobic Capacity in Women: A Cross-Sectional Study.}, journal = {International journal of molecular sciences}, volume = {23}, number = {21}, pages = {}, pmid = {36362129}, issn = {1422-0067}, mesh = {Humans ; Female ; *Basal Metabolism ; Cross-Sectional Studies ; *Obesity ; Energy Intake ; Telomere ; Body Composition ; }, abstract = {This study investigated the associations between relative telomere length (RTL) and resting metabolic rate (RMR), resting fat oxidation (RFO), and aerobic capacity and whether oxidative stress and inflammation are the underlying mechanisms in sedentary women. We also aimed to determine whether the correlations depend on age and obesity. Sixty-eight normal weight and 66 obese women participated in this study. After adjustment for age, energy expenditure, energy intake, and education level, the RTL of all participants was negatively correlated with absolute RMR (RMRAB) and serum high-sensitivity C-reactive protein (hsCRP) concentration, and positively correlated with maximum oxygen consumption (V˙O2max) (all p < 0.05). After additional adjustment for adiposity indices and fat-free mass (FFM), RTL was positively correlated with plasma vitamin C concentration (p < 0.05). Furthermore, after adjustment for fasting blood glucose concentration, RTL was negatively correlated with age and positively correlated with V˙O2max (mL/kg FFM/min). We found that normal weight women had longer RTL than obese women (p < 0.001). We suggest that RTL is negatively correlated with RMRAB and positively correlated with aerobic capacity, possibly via antioxidant and anti-inflammatory mechanisms. Furthermore, age and obesity influenced the associations. We provide useful information for the management of promotion strategies for health-related physical fitness in women.}, }
@article {pmid36359878, year = {2022}, author = {Reddy, HM and Randall, TA and Cipressa, F and Porrazzo, A and Cenci, G and Frydrychova, RC and Mason, JM}, title = {Identification of the Telomere elongation Mutation in Drosophila.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359878}, issn = {2073-4409}, mesh = {Animals ; *Drosophila/genetics ; *Drosophila melanogaster/genetics ; Gene Products, gag/genetics ; Telomere/genetics ; Mutation/genetics ; }, abstract = {Telomeres in Drosophila melanogaster, which have inspired a large part of Sergio Pimpinelli work, are similar to those of other eukaryotes in terms of their function. Yet, their length maintenance relies on the transposition of the specialized retrotransposons Het-A, TART, and TAHRE, rather than on the activity of the enzyme telomerase as it occurs in most other eukaryotic organisms. The length of the telomeres in Drosophila thus depends on the number of copies of these transposable elements. Our previous work has led to the isolation of a dominant mutation, Tel[1], that caused a several-fold elongation of telomeres. In this study, we molecularly identified the Tel[1] mutation by a combination of transposon-induced, site-specific recombination and next-generation sequencing. Recombination located Tel[1] to a 15 kb region in 92A. Comparison of the DNA sequence in this region with the Drosophila Genetic Reference Panel of wild-type genomic sequences delimited Tel[1] to a 3 bp deletion inside intron 8 of Ino80. Furthermore, CRISPR/Cas9-induced deletions surrounding the same region exhibited the Tel[1] telomere phenotype, confirming a strict requirement of this intron 8 gene sequence for a proper regulation of Drosophila telomere length.}, }
@article {pmid36359738, year = {2022}, author = {Sung, JY and Cheong, JH}, title = {Single Cell Analysis of Gastric Cancer Reveals Non-Defined Telomere Maintenance Mechanism.}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359738}, issn = {2073-4409}, mesh = {Humans ; *Stomach Neoplasms/genetics ; Single-Cell Analysis ; Ubiquitin-Protein Ligases/metabolism ; Telomere/metabolism ; Tumor Necrosis Factor-alpha ; Homeostasis ; }, abstract = {Telomere maintenance mechanisms (TMMs) are important for cell survival and homeostasis. However, most related cancer research studies have used heterogenous bulk tumor tissue, which consists of various single cells, and the cell type properties cannot be precisely recognized. In particular, cells exhibiting non-defined TMM (NDTMM) indicate a poorer prognosis than those exhibiting alternative lengthening of telomere (ALT)-like mechanisms. In this study, we used bioinformatics to classify TMMs by cell type in gastric cancer (GC) in single cells and compared the biological processes of each TMM. We elucidated the pharmacological vulnerabilities of NDTMM type cells, which are associated with poor prognosis, based on molecular mechanisms. We analyzed differentially expressed genes in cells exhibiting different TMMs in two single-cell GC cohorts and the pathways enriched in single cells. NDTMM type cells showed high stemness, epithelial-mesenchymal transition, cancer hallmark activity, and metabolic reprogramming with mitochondrial abnormalities. Nuclear receptor subfamily 4 group A member 1 (NR4A1) activated parkin-dependent mitophagy in association with tumor necrosis factor-alpha (TNFA) to maintain cellular homeostasis without TMM. NR4A1 overexpression affected TNFA-induced GC cell apoptosis by inhibiting Jun N-terminal kinase/parkin-dependent mitophagy. Our findings also revealed that NR4A1 is involved in cell cycle mediation, inflammation, and apoptosis to maintain cell homeostasis, and is a novel potential therapeutic target in recalcitrant GC.}, }
@article {pmid36359275, year = {2022}, author = {Macek, P and Poreba, R and Gac, P and Bogunia-Kubik, K and Dratwa, M and Wieckiewicz, M and Wojakowska, A and Michalek-Zrabkowska, M and Mazur, G and Martynowicz, H}, title = {Genetic Variants of the TERT Gene and Telomere Length in Obstructive Sleep Apnea.}, journal = {Biomedicines}, volume = {10}, number = {11}, pages = {}, pmid = {36359275}, issn = {2227-9059}, abstract = {INTRODUCTION: Obstructive sleep apnea (OSA) is a worldwide breathing disorder that has been diagnosed globally in almost 1 billion individuals aged 30-69 years. It is characterized by repeated upper airway collapses during sleep. Telomerase reverse transcriptase (TERT) is involved in the prevention of telomere shortening. This prospective, observational study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of TERT and the severity of OSA, taking into account hypertension and diabetes prevalence.<br><br>METHODS: A total of 149 patients with OSA were diagnosed using one-night video-polysomnography based on the American Academy of Sleep Medicine guidelines. The TERT SNPs and telomere length (TL) were detected using real-time quantitative polymerase chain reaction.<br><br>RESULTS: Statistical analysis showed that there is no relationship between the rs2853669 and rs2736100 polymorphisms of TERT, and the severity of OSA (p > 0.05). Moreover, no relationship between TL and the severity of OSA was observed. The G allele in the locus of rs2736100 TERT was associated with hypertension prevalence and was more prevalent in hypertensives patients (46.00% vs. 24.49%, p = 0.011). The prevalence of hypertension was higher in patients with the C allele in the locus of rs2853669 than in patients without this allele (50.79% vs. 30.23%, p = 0.010). Moreover, a lower prevalence of diabetes was observed in homozygotes of rs2736100 TERT than in heterozygotes (5.63% vs. 15.38%, p = 0.039).<br><br>CONCLUSION: This study showed no relationship between OSA and TERT SNPs. However, SNPs of the TERT gene (rs2736100 and rs2853669) were found to affect arterial hypertension and diabetes prevalence.}, }
@article {pmid36357941, year = {2022}, author = {Shin, DY and Lim, KM and Park, HS and Kwon, S and Yoon, SS and Lee, DS}, title = {The importance of critically short telomere in myelodysplastic syndrome.}, journal = {Biomarker research}, volume = {10}, number = {1}, pages = {79}, pmid = {36357941}, issn = {2050-7771}, abstract = {A few critically short telomeres trigger genomic instability regardless of average telomere length (TL). Recently, the telomere shortest length assay (TeSLA) was developed to detect critically short telomeres and measure absolute telomeres. Using TeSLA with the internally labeled biotin probe, we measured the TL of bone marrow (BM) aspirates from 52 patients with myelodysplastic syndrome (MDS). A percentage of shortest telomeres (< 1.0 kb (ShTL1.0)) were calculated. ShTL1.0 was correlated to IPSS-R risk (spearman's rho = 0.35 and p = 0.0196), and ShTL1.0 and BM blast (2.61% in < 5% blast, 4.15% in 5-10% blast, and 6.80% in 10-20% blast, respectively, p = 0.0332). Interestingly, MDS patients with a shortest TL ≥ 0.787 kb at the time of diagnosis showed better overall survival (OS) and progression-free survival (PFS) than patients with a shortest TL < 0.787 kb in the multivariate analyses (HR = 0.13 and 0.30, p = 0.011 and 0.048 for OS and PFS, respectively). Our results clearly show the presence and abundance of critically short telomeres in MDS patients. These pathologic telomeres are associated with IPSS-R which is a validated prognostic scoring system in MDS. Furthermore, they are independent prognostic factors for OS in MDS patients. Future prospective studies are needed to validate our results.}, }
@article {pmid36356143, year = {2022}, author = {Chun-On, P and Hinchie, AM and Beale, HC and Gil Silva, AA and Rush, E and Sander, C and Connelly, CJ and Seynnaeve, BKN and Kirkwood, JM and Vaske, OM and Greider, CW and Alder, JK}, title = {TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma.}, journal = {Science (New York, N.Y.)}, volume = {378}, number = {6620}, pages = {664-668}, doi = {10.1126/science.abq0607}, pmid = {36356143}, issn = {1095-9203}, support = {R35 CA209974/CA/NCI NIH HHS/United States ; R01 HL135062/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; *Melanoma/genetics ; Mutation ; *Promoter Regions, Genetic/genetics ; *Shelterin Complex/genetics ; *Skin Neoplasms/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; *Telomere Homeostasis/genetics ; *Telomere-Binding Proteins/genetics ; Transcriptional Activation ; }, abstract = {Overcoming replicative senescence is an essential step during oncogenesis, and the reactivation of TERT through promoter mutations is a common mechanism. TERT promoter mutations are acquired in about 75% of melanomas but are not sufficient to maintain telomeres, suggesting that additional mutations are required. We identified a cluster of variants in the promoter of ACD encoding the shelterin component TPP1. ACD promoter variants are present in about 5% of cutaneous melanoma and co-occur with TERT promoter mutations. The two most common somatic variants create or modify binding sites for E-twenty-six (ETS) transcription factors, similar to mutations in the TERT promoter. The variants increase the expression of TPP1 and function together with TERT to synergistically lengthen telomeres. Our findings suggest that TPP1 promoter variants collaborate with TERT activation to enhance telomere maintenance and immortalization in melanoma.}, }
@article {pmid36352846, year = {2022}, author = {Deng, Y and Li, Q and Zhou, F and Li, G and Liu, J and Lv, J and Li, L and Chang, D}, title = {Telomere length and the risk of cardiovascular diseases: A Mendelian randomization study.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {1012615}, pmid = {36352846}, issn = {2297-055X}, abstract = {BACKGROUND: The causal direction and magnitude of the associations between telomere length (TL) and cardiovascular diseases (CVDs) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between TL and CVDs using Mendelian randomization (MR).<br><br>MATERIALS AND METHODS: In this two-sample MR study, we identified 154 independent TL-associated genetic variants from a genome-wide association study (GWAS) consisting of 472,174 individuals (aged 40-69) in the UK Biobank. Summary level data of CVDs were obtained from different GWASs datasets. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), Mendelian Randomization robust adjusted profile score (MR-RAPS), maximum likelihood estimation, weighted mode, penalized weighted mode methods, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to investigate the associations between TL and CVDs.<br><br>RESULTS: Our findings indicated that longer TL was significantly associated with decreased risk of coronary atherosclerosis [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.75-0.95; P = 4.36E-03], myocardial infarction (OR, 0.72; 95% CI, 0.63-0.83; P = 2.31E-06), ischemic heart disease (OR, 0.87; 95% CI, 0.78-0.97; P = 1.01E-02), stroke (OR, 0.87; 95% CI, 0.79-0.95; P = 1.60E-03), but an increased risk of hypertension (OR, 1.12; 95% CI, 1.02-1.23; P = 2.00E-02). However, there was no significant association between TL and heart failure (OR, 0.94; 95% CI, 0.87-1.01; P = 1.10E-01), atrial fibrillation (OR, 1.01; 95% CI, 0.93-1.11; P = 7.50E-01), or cardiac death (OR, 0.95; 95% CI, 0.82-1.10; P = 4.80E-01). Both raw and outlier corrected estimates from MR-PRESSO were consistent with those of IVW results. The sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, P > 0.05), while Cochran's Q test and MR-Egger suggested different degrees of heterogeneity.<br><br>CONCLUSION: Our MR study suggested that longer telomeres were associated with decreased risk of several CVDs, including coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke, as well as an increased risk of hypertension. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.}, }
@article {pmid36350851, year = {2022}, author = {Geiller, HEB and Harvey, A and Jones, RE and Grimstead, JW and Cleal, K and Hendrickson, EA and Baird, DM}, title = {ATRX modulates the escape from a telomere crisis.}, journal = {PLoS genetics}, volume = {18}, number = {11}, pages = {e1010485}, pmid = {36350851}, issn = {1553-7404}, support = {A18246/A29202/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Humans ; *Telomerase/genetics/metabolism ; Telomere Homeostasis/genetics ; X-linked Nuclear Protein/genetics ; *alpha-Thalassemia/genetics ; Telomere/genetics/metabolism ; *Neoplasms ; }, abstract = {Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells.}, }
@article {pmid36350415, year = {2022}, author = {Bloom, SI and Tucker, JR and Lim, J and Thomas, TG and Stoddard, GJ and Lesniewski, LA and Donato, AJ}, title = {Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions.}, journal = {GeroScience}, volume = {44}, number = {6}, pages = {2741-2755}, pmid = {36350415}, issn = {2509-2723}, support = {T32 HL007576/HL/NHLBI NIH HHS/United States ; R01 AG060395/AG/NIA NIH HHS/United States ; F31 AG076312/AG/NIA NIH HHS/United States ; UL1 TR002538/TR/NCATS NIH HHS/United States ; R44 AG053131/AG/NIA NIH HHS/United States ; R01 AG050238/AG/NIA NIH HHS/United States ; R01 AG048366/AG/NIA NIH HHS/United States ; UL1 TR001067/TR/NCATS NIH HHS/United States ; UL1 TR000105/TR/NCATS NIH HHS/United States ; UL1 RR025764/RR/NCRR NIH HHS/United States ; }, mesh = {*Muscle, Smooth, Vascular ; *Endothelial Cells ; Telomere/genetics ; DNA Damage ; }, abstract = {Aging increases the risk of atherosclerotic cardiovascular disease which is associated with arterial senescence; however, the mechanisms responsible for the development of cellular senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) remain elusive. Here, we study the effect of aging on arterial DNA damage and telomere dysfunction. Aging resulted in greater DNA damage in ECs than VSMCs. Further, telomere dysfunction-associated DNA damage foci (TAF: DNA damage signaling at telomeres) were elevated with aging in ECs but not VMSCs. Telomere length was modestly reduced in ECs with aging and not sufficient to induce telomere dysfunction. DNA damage and telomere dysfunction were greatest in atheroprone regions (aortic minor arch) versus non-atheroprone regions (thoracic aorta). Collectively, these data demonstrate that aging results in DNA damage and telomere dysfunction that is greater in ECs than VSMCs and elevated in atheroprone aortic regions.}, }
@article {pmid36347948, year = {2023}, author = {Bussa, RM and Mora-Plazas, M and Marín, C and Villamor, E}, title = {Vitamin D status and leukocyte telomere length in middle childhood.}, journal = {European journal of clinical nutrition}, volume = {77}, number = {2}, pages = {295-297}, pmid = {36347948}, issn = {1476-5640}, mesh = {Male ; Female ; Humans ; Child ; Child, Preschool ; Cross-Sectional Studies ; *Vitamin D ; *Vitamins ; Leukocytes ; Telomere ; }, abstract = {Short telomere length is associated with chronic diseases and decreased lifespan. Vitamin D and its binding protein (DBP) may maintain telomeres through anti-inflammatory actions, yet the role of vitamin D on telomere length is uncertain, especially in children. We assessed the cross-sectional associations of plasma 25-hydroxy vitamin D (25(OH)D) and DBP with leukocyte telomere length (LTL) in a group of 447 children ages 5-12 years from the Bogotá School Children Cohort. We compared the distribution of age-standardized LTL (z-score) between 25(OH)D categories and between DBP quartiles overall and by sex. Overall, 25(OH)D was not significantly associated with LTL. Nonetheless, among boys, 25(OH)D < 50 nmol/L was related to an adjusted 0.36 shorter LTL z-score (95% CI: -0.71, -0.01; P = 0.046) compared with 25(OH)D ≥ 75 nmol/L. There was no association among girls. DBP was not significantly related to LTL. Intervention studies are warranted to determine whether increasing vitamin D status enhances telomere length.}, }
@article {pmid36347559, year = {2022}, author = {Glousker, G and Lingner, J}, title = {TFIIH moonlighting at telomeres.}, journal = {Genes &amp; development}, volume = {36}, number = {17-18}, pages = {951-953}, pmid = {36347559}, issn = {1549-5477}, mesh = {*Telomeric Repeat Binding Protein 1 ; Telomere/genetics/metabolism ; Telomere Shortening ; Telomere-Binding Proteins/metabolism ; *Telomerase/metabolism ; Shelterin Complex ; }, abstract = {Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking telomerase due to the end replication problem. In addition, recent work uncovered that the bulk of telomeric DNA poses severe hurdles for the semiconservative DNA replication machinery, requiring the assistance of an increasing number of specialized factors that prevent accidental telomere loss or damage events. In this issue of Genes &amp; Development, Yang and colleagues (pp. 956-969) discover that TFIIH, a basic component of the PolII transcription initiation and nucleotide excision repair machinery, facilitates telomere replication. TFIIH is recruited to telomeres by the shelterin component TRF1, taking on at telomeres a moonlighting function.}, }
@article {pmid36347449, year = {2023}, author = {Wu, S and Wu, Y and Chen, J and Zhuang, P and Zhang, Y and Jiao, J}, title = {Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice.}, journal = {The Journal of nutritional biochemistry}, volume = {112}, number = {}, pages = {109202}, doi = {10.1016/j.jnutbio.2022.109202}, pmid = {36347449}, issn = {1873-4847}, mesh = {Female ; Animals ; Male ; Mice ; *Telomerase/genetics/metabolism ; Docosahexaenoic Acids/pharmacology/therapeutic use ; Cellular Senescence ; Aging/genetics ; *Fatty Acids, Omega-3 ; Inflammation ; DNA, Mitochondrial ; Mitochondria/metabolism ; Telomere/metabolism ; }, abstract = {The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple age-related diseases are associated with telomere length. Telomerase is intimately related to inflammation and oxidative stress, but whether the underlying function of n-3 PUFAs on telomere maintenance is based on telomerase activation or related mechanisms remains unclear. Herein, we utilized late-generation (G4) telomerase-deficient (Terc[-/-]) mice to perform a lifelong docosahexaenoic acid (DHA) intervention to determine the potential of DHA in telomere maintenance and health promotion. Unfortunately, DHA failed to prolong mouse longevity in either intrinsic or premature aging. However, intriguingly, lifelong dietary DHA intervention slowed the aging phenotypes and profoundly attenuated telomere attrition in blood leukocytes and multiple tissues, consistent with decreased β-galactosidase activity and other senescence hallmarks with no observed sex differences. Notably, DHA intervention alleviated telomere attrition-induced γ-H2AX accumulation dependent on poly (ADP-ribose) polymerase 1 (PARP1) recruitment, and further regulated mitochondrial dysfunction critically involved in the DNA damage response. Together with the improvement of mitochondria function, the blocked reactive oxygen species (ROS) accumulation and suppression of the nuclear factor-κB (NF-κB)/nucleotide-binding domain-like receptor protein 3 (NLRP3)/caspase-1 pathways partially indicated anti-oxidative and anti-inflammatory effects of DHA. These data revealed a regulatory paradigm involving DHA in the telomere-DNA-mitochondria feedback loop mediated by DNA damage response and inflammation in alleviating senescence, which may hold potential as a translatable intervention in telomere-related diseases during aging.}, }
@article {pmid36345036, year = {2022}, author = {Rodríguez-Fernández, B and Vilor-Tejedor, N and Arenaza-Urquijo, EM and Sánchez-Benavides, G and Suárez-Calvet, M and Operto, G and Minguillón, C and Fauria, K and Kollmorgen, G and Suridjan, I and de Moura, MC and Piñeyro, D and Esteller, M and Blennow, K and Zetterberg, H and De Vivo, I and Molinuevo, JL and Navarro, A and Gispert, JD and Sala-Vila, A and Crous-Bou, M and , }, title = {Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study.}, journal = {Alzheimer's research &amp; therapy}, volume = {14}, number = {1}, pages = {167}, pmid = {36345036}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid ; Mendelian Randomization Analysis ; Endophenotypes ; Biomarkers/cerebrospinal fluid ; Apolipoproteins E/genetics ; Telomere ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; }, abstract = {Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations.}, }
@article {pmid36342193, year = {2023}, author = {Coutelier, H and Ilioaia, O and Le Peillet, J and Hamon, M and D'Amours, D and Teixeira, MT and Xu, Z}, title = {The Polo kinase Cdc5 is regulated at multiple levels in the adaptation response to telomere dysfunction.}, journal = {Genetics}, volume = {223}, number = {1}, pages = {}, pmid = {36342193}, issn = {1943-2631}, support = {FDN-167265//CIHR/Canada ; }, mesh = {*Protein Serine-Threonine Kinases/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Saccharomyces cerevisiae Proteins/genetics/metabolism ; Protein Kinases/genetics ; Phosphorylation ; Saccharomyces cerevisiae/metabolism ; Checkpoint Kinase 2/genetics ; DNA Damage ; Telomere/genetics/metabolism ; }, abstract = {Telomere dysfunction activates the DNA damage checkpoint to induce a cell cycle arrest. After an extended period of time, however, cells can bypass the arrest and undergo cell division despite the persistence of the initial damage, a process called adaptation to DNA damage. The Polo kinase Cdc5 in Saccharomyces cerevisiae is essential for adaptation and for many other cell cycle processes. How the regulation of Cdc5 in response to telomere dysfunction relates to adaptation is not clear. Here, we report that Cdc5 protein level decreases after telomere dysfunction in a Mec1-, Rad53- and Ndd1-dependent manner. This regulation of Cdc5 is important to maintain long-term cell cycle arrest but not for the initial checkpoint arrest. We find that both Cdc5 and the adaptation-deficient mutant protein Cdc5-ad are heavily phosphorylated and several phosphorylation sites modulate adaptation efficiency. The PP2A phosphatases are involved in Cdc5-ad phosphorylation status and contribute to adaptation mechanisms. We finally propose that Cdc5 orchestrates multiple cell cycle pathways to promote adaptation.}, }
@article {pmid36341901, year = {2022}, author = {Fan, G and Song, L and Liu, Q and Wu, M and Bi, J and Xu, L and Xiong, C and Cao, Z and Xu, S and Wang, Y}, title = {Association of maternal folic acid supplementation during pregnancy with newborn telomere length.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {114}, number = {}, pages = {52-56}, doi = {10.1016/j.reprotox.2022.10.006}, pmid = {36341901}, issn = {1873-1708}, mesh = {Humans ; Infant, Newborn ; Female ; Pregnancy ; Cohort Studies ; China ; *Dietary Supplements ; *Folic Acid ; Telomere ; }, abstract = {This study aimed to explore the associations between maternal folic acid (FA) supplementation during different trimesters of pregnancy and newborn telomere length (TL). Data were collected from a birth cohort study of 746 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. After adjustment for potential confounders, maternal FA supplementation after the first trimester and throughout pregnancy were associated with longer newborn TL [β = 0.29, 95 % confidence interval (CI): 0.20, 0.38 and β = 0.24, 95 % CI: 0.16, 0.32, respectively]. No significant association was found between maternal FA supplementation in the first trimester and newborn TL. In conclusion, a possible association between maternal FA supplementation during pregnancy with longer newborn TL was suggested in the present study. This study provides insight into the benefit of newborn TL by maternal FA supplementation during pregnancy.}, }
@article {pmid36338739, year = {2022}, author = {Li, Y and Ma, L}, title = {Relationship between telomere length and the prognosis of breast cancer based on estrogen receptor status: A Mendelian randomization study.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {1024772}, pmid = {36338739}, issn = {2234-943X}, abstract = {OBJECTIVE: To identify the relationship between telomere length and the prognosis of breast cancer with different status of estrogen receptor (ER).<br><br>METHODS: We collected single nucleotide polymorphisms (SNPs) associated with telomere length and breast cancer prognosis from the MRCIEU GWAS database and the dataset of a large meta-analysis conducted by the Breast Cancer Association Consortium (BCAC), respectively. The relationship was identified using inverse-variance weighted (IVW), MR-Egger, weighted median, penalized weighted median, and maximum likelihood methods. IVW, MR-Egger, and MR-PRESSO methods were used to perform sensitivity analysis to assess the accuracy of the results.<br><br>RESULTS: Telomere length was negatively associated with the prognosis of total breast cancer (odds ratio [OR]=1.84, 95% confidence interval [CI]=1.08-3.14, IVW method), especially with ER- breast cancer (OR=1.89, 95% CI=1.11-3.22, IVW method). No similar relationship was found between telomere length and the prognosis of ER+ breast cancer (OR=0.99, 95% CI=0.62-1.58, IVW method). The findings from other methods were consistent with the results shown by the IVW method. The Mendelian randomization assumptions did not appear to be violated. Sensitivity analysis indicated that the result was robust, and no bias was observed in the study.<br><br>CONCLUSION: Telomere length is associated with the prognosis of total breast cancer, especially with ER- breast cancer. There is no significant correlation between telomere length and the prognosis of ER+ breast cancer. These findings add to the evidence that long telomere could predict a poor prognosis of ER- breast cancer.}, }
@article {pmid36334946, year = {2022}, author = {Lansdorp, PM}, title = {Telomeres, Telomerase and Cancer.}, journal = {Archives of medical research}, volume = {53}, number = {8}, pages = {741-746}, doi = {10.1016/j.arcmed.2022.10.004}, pmid = {36334946}, issn = {1873-5487}, mesh = {Animals ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Neoplasms/genetics ; Aging/genetics ; }, abstract = {Telomeres and telomerase play a crucial role in human aging and cancer. Three "drivers" of human aging can be identified. The developmental program encoded in DNA is the primary determinant of lifespan. Faithful execution of the developmental program requires stability of the (epi-)genome which is challenged throughout life by damage to DNA as well as epigenetic 'scars' from error-free DNA repair and stochastic errors made during the establishment and maintenance of the "epigenome". Over time (epi-)mutations accumulate, compromising cellular function and causing (pre-)malignant alterations. Damage to the genome and epigenome can be considered the second "driver" of aging. A third driver of the aging process, important to suppress tumors in long-lived animals, is caused by progressive loss of telomeric DNA. Telomere erosion protects against cancer early in life but limits cell renewal late in life, in agreement with the Antagonistic Pleiotropy theory on the evolutionary origin of aging. Malignant tumors arise when mutations and/or epimutations in cells (clock 2) corrupt the developmental program (clock 1) as well as tumor suppression by telomere erosion (clock 3). In cancer cells clock 3 is typically inactivated by loss of p53 as well as increased expression of telomerase. Taken together, aging in humans can be described by the ticking of three clocks: the clock that directs development, the accumulation of (epi-)mutations over time and the telomere clock that limits the number of cell divisions in normal stem and immune cells.}, }
@article {pmid36332602, year = {2022}, author = {Decottignies, A}, title = {TERRA and RAD51AP1 at the R&amp;D-loop department of ALT telomeres.}, journal = {Molecular cell}, volume = {82}, number = {21}, pages = {3963-3965}, doi = {10.1016/j.molcel.2022.10.006}, pmid = {36332602}, issn = {1097-4164}, mesh = {*Telomere Homeostasis ; Telomere/genetics ; R-Loop Structures ; *RNA, Long Noncoding/genetics ; Chromatin ; }, abstract = {In this issue of Molecular Cell, Kaminski et al. and Yadav et al. demonstrate that RAD51AP1 and TERRA non-coding RNA positively regulate the alternative mechanism of telomere maintenance by promoting D-loop formation and chromatin-directed mechanisms to suppress transcription-collision events during ALT telomere synthesis.}, }
@article {pmid36330920, year = {2022}, author = {Vaurs, M and Audry, J and Runge, KW and Géli, V and Coulon, S}, title = {A proto-telomere is elongated by telomerase in a shelterin-dependent manner in quiescent fission yeast cells.}, journal = {Nucleic acids research}, volume = {50}, number = {20}, pages = {11682-11695}, pmid = {36330920}, issn = {1362-4962}, support = {R01 HL158007/HL/NHLBI NIH HHS/United States ; R01 HL152678/HL/NHLBI NIH HHS/United States ; R01 AG051601/AG/NIA NIH HHS/United States ; }, mesh = {*Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; *Shelterin Complex ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; }, abstract = {Telomere elongation is coupled with genome replication, raising the question of the repair of short telomeres in post-mitotic cells. We investigated the fate of a telomere-repeat capped end that mimics a single short telomere in quiescent fission yeast cells. We show that telomerase is able to elongate this single short telomere during quiescence despite the binding of Ku to the proto-telomere. While Taz1 and Rap1 repress telomerase in vegetative cells, both shelterin proteins are required for efficient telomere extension in quiescent cells, underscoring a distinct mode of telomerase control. We further show that Rad3ATR and Tel1ATM are redundantly required for telomere elongation in quiescence through the phosphorylation of Ccq1 and that Rif1 and its associated-PP1 phosphatases negatively regulate telomerase activity by opposing Ccq1 phosphorylation. The distinct mode of telomerase regulation in quiescent fission yeast cells may be relevant to that in human stem and progenitor cells.}, }
@article {pmid36330807, year = {2022}, author = {Wu, Y and Zhang, Y and Jiao, J}, title = {The relationship between n-3 polyunsaturated fatty acids and telomere: A review on proposed nutritional treatment against metabolic syndrome and potential signaling pathways.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/10408398.2022.2142196}, pmid = {36330807}, issn = {1549-7852}, abstract = {Metabolic syndrome (MetS), a cluster of metabolic abnormalities composed of central obesity, elevated blood pressure, glucose disturbances, hypercholesterolemia and dyslipidaemia, has increasingly become a public health problem in the 21st century worldwide. The dysfunction of telomeres, the repetitive DNA with highly conserved sequences (5'-TTAGGG-3'), is remarkably correlated with organismal aging, even suggesting a causal relationship with metabolic disorders. The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple disorders are associated with telomere length in evidence, which have recently drawn wide attention. However, functional targets and pathways for the associations of n-3 PUFAs and telomere with MetS remain scare. Few studies have summarized the role of n-3 PUFAs in DNA damage repair pathways, anti-inflammatory pathways, and redox balance, linking with telomere biology, and other potential telomere-related signaling pathways. This review aims to (i) elucidate how n-3 PUFAs ameliorate telomere attrition in the context of anti-oxidation and anti-inflammation; (ii) unravel the role of n-3 PUFAs in modulating telomere-related neuron dysfunction and regulating the neuro-endocrine-immunological network in MetS; (iii) epidemiologically implicate the associations of metabolic disorders and n-3 PUFAs with telomere length; and (iv) suggest promising biochemical approaches and advancing methodologies to overcome the inter-variation problem helpful for future research.}, }
@article {pmid36330668, year = {2022}, author = {Monaghan, P and Olsson, M and Richardson, DS and Verhulst, S and Rogers, SM}, title = {Integrating telomere biology into the ecology and evolution of natural populations: Progress and prospects.}, journal = {Molecular ecology}, volume = {31}, number = {23}, pages = {5909-5916}, doi = {10.1111/mec.16768}, pmid = {36330668}, issn = {1365-294X}, mesh = {*Ecology ; *Biological Evolution ; Telomere/genetics ; }, }
@article {pmid36319514, year = {2023}, author = {Beranek, M and Borsky, P and Fiala, Z and Andrys, C and Hamakova, K and Chmelarova, M and Kovarikova, H and Karas, A and Kremlacek, J and Palicka, V and Borska, L}, title = {Telomere length, oxidative and epigenetic changes in blood DNA of patients with exacerbated psoriasis vulgaris.}, journal = {Anais brasileiros de dermatologia}, volume = {98}, number = {1}, pages = {68-74}, pmid = {36319514}, issn = {1806-4841}, mesh = {Female ; Humans ; *Metabolic Syndrome ; 5-Methylcytosine ; Epigenesis, Genetic ; Oxidative Stress/genetics ; RNA/metabolism ; Telomere/genetics/metabolism ; DNA/metabolism ; *Psoriasis/genetics ; }, abstract = {BACKGROUND: The pathogenesis of psoriasis vulgaris involves changes in DNA molecules, genomic instability, telomere attrition, and epigenetic alterations among them. These changes are also considered important mechanisms of aging in cells and tissues.<br><br>OBJECTIVE: This study dealt with oxidation damage, telomere length and methylation status in DNA originating from peripheral blood of 41 psoriatic patients and 30 healthy controls.<br><br>METHODS: Oxidative damage of serum DNA/RNA was determined immunochemically. Real-time PCR was used for the analysis of the telomere length. ELISA technique determined levels of 5-methylcytosine in blood cells' DNA.<br><br>RESULTS: Oxidative damage of serum DNA/RNA was higher in patients than in controls (median, 3758 vs. 2286pg/mL, p<0.001). A higher length of telomeres per chromosome was found in patients whole-cell DNA than in controls (3.57 vs. 3.04 kilobases, p=0.011). A negative correlation of the length of telomeres with an age of the control subjects was revealed (Spearman's rho=-0.420, p=0.028). Insignificantly different levels of 5-methylcytosine in patients and controls were observed (33.20 vs. 23.35%, p=0.234). No influences of sex, smoking, BMI, PASI score, and metabolic syndrome on the methylation status were found.<br><br>STUDY LIMITATIONS: i) A relatively small number of the participants, particularly for reliable subgroup analyses, ii) the Caucasian origin of the participants possibly influencing the results of the parameters determined, and iii) Telomerase activity was not directly measured in serum or blood cells.<br><br>CONCLUSION: The study demonstrated increased levels of oxidized DNA/RNA molecules in the serum of patients with exacerbated psoriasis vulgaris. The results were minimally influenced by sex, the presence of metabolic syndrome, or cigarette smoking. In the psoriatic blood cells' DNA, the authors observed longer telomeres compared to healthy controls, particularly in females. Insignificantly higher global DNA methylation in psoriasis cases compared to the controls indicated marginal clinical importance of this epigenetic test performed in the blood cells' DNA.}, }
@article {pmid36319501, year = {2022}, author = {Ramírez-Sanabria, M and Martínez-Magaña, J and Nicolini-Sánchez, H and Guzmán-Sánchez, R and Genis-Mendoza, AD}, title = {[Association between telomere length and cognitive impairment in older adults].}, journal = {Revista espanola de geriatria y gerontologia}, volume = {57}, number = {6}, pages = {320-324}, doi = {10.1016/j.regg.2022.09.006}, pmid = {36319501}, issn = {1578-1747}, mesh = {Humans ; *Telomere Shortening ; Telomere ; *Cognitive Dysfunction/genetics ; Biomarkers ; }, abstract = {INTRODUCTION: Cognitive impairment is a transition stage between normal aging and dementia, the prevalence of last one increases with age; the damage of the functions and physical integrity, places the older adult in a greater susceptibility to get sick. Telomere length is a hallmark of aging to characterize this phenotype, as well as a biomarker that reflects the underlying state of the cell. In this work, the relative length of telomeres in older adults with cognitive impairment was correlated.<br><br>MATERIAL AND METHODS: Observational-analytical study, in samples of adult patients older than 65 years with and without cognitive impairment, in whom the relative length of telomeres was measured.<br><br>RESULTS: Ninety samples of older adults were included in the study and in the association analysis according to multivariate logistic models, cognitive impairment showed almost five times more risk for telomere shortening in relation to the presence of the diagnosis of cognitive impairment (Odds ratio 4.88, p=0.027).<br><br>CONCLUSIONS: When correlating the relative length of telomeres in older adults diagnosed with cognitive impairment, this association was confirmed for shorter.}, }
@article {pmid36311861, year = {2022}, author = {de Mendonça Filho, EJ and Frechette, A and Pokhvisneva, I and Arcego, DM and Barth, B and Tejada, CV and Sassi, R and Wazana, A and Atkinson, L and Meaney, MJ and Silveira, PP}, title = {Examining attachment, cortisol secretion, and cognitive neurodevelopment in preschoolers and its predictive value for telomere length at age seven.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {954977}, pmid = {36311861}, issn = {1662-5153}, abstract = {BACKGROUND: Secure attachment reflects caregiver-child relationship in which the caregiver is responsive when support and comforting are needed by the child. This pattern of bond has an important buffering role in the response to stress by the reduction of the negative experience and its associated physiological response. Disruption of the physiological stress system is thought to be a central mechanism by which early care impacts children. Early life stress causes cellular and molecular changes in brain regions associated with cognitive functions that are fundamental for early learning.<br><br>METHODS: The association between attachment, cortisol response before and after the Strange Situation Experiment, and neurodevelopment was examined in a sample of 107 preschoolers at age three. Also, the predictive effect of cortisol reactivity and attachment on telomere length at age seven was investigated in a followed-up sample of 77 children.<br><br>RESULTS: Children with insecure attachment had higher cortisol secretion and poorer neurodevelopmental skills at age three. A significant cortisol change was observed across the experiment with non-significant interaction with attachment. The attachment and neurodevelopment association was not mediated by cortisol secretion. Preschoolers' attachment and cortisol did not associate nor interacted to predict telomere length at age seven.<br><br>CONCLUSION: These findings add evidence to the detrimental effects of insecure attachment as an aggravator of the physiological response to stress and poorer neurodevelopment during the preschool period. Although attachment and cortisol were not predictive of telomere length, intervention policies that promote secure attachment are more likely to positively echo on several health domains.}, }
@article {pmid36311538, year = {2022}, author = {Carvalho, VS and Gomes, WR and Calado, RT}, title = {Recent advances in understanding telomere diseases.}, journal = {Faculty reviews}, volume = {11}, number = {}, pages = {31}, pmid = {36311538}, issn = {2732-432X}, abstract = {Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.}, }
@article {pmid36311389, year = {2022}, author = {Dobson, FS and Schull, Q and Criscuolo, F}, title = {Two aspects of longevity are associated with rates of loss of telomeres in birds.}, journal = {Ecology and evolution}, volume = {12}, number = {10}, pages = {e9364}, pmid = {36311389}, issn = {2045-7758}, abstract = {Telomeres, the terminal repetitive DNA sequences at the ends of linear chromosomes, have strong associations with longevity in some major taxa. Longevity has been linked to rate of decline in telomere length in birds and mammals, and absolute telomere length seems to be associated with body mass in mammals. Using a phylogenetic comparative method and 30 species of birds, we examined longevity (reflected by maximum lifespan), absolute telomere length, the rate of change in telomere length (TROC), and body mass (often strongly associated with longevity) to ascertain their degree of association. We divided lifespan into two life-history components, one reflected by body size (measured as body mass) and a component that was statistically independent of body mass. While both lifespan and body mass were strongly associated with a family tree of the species (viz., the phylogeny of the species), telomere measures were not. Telomere length was not significantly associated with longevity or body mass or our measure of mass-independent lifespan. TROC, however, was strongly associated with mass-independent lifespan, but only to a much lesser degree at best with body mass-predicted lifespan. Our results supported an association of TROC and longevity, in particular longevity that was independent of body size and part of the pace-of-life syndrome of life histories.}, }
@article {pmid36304436, year = {2022}, author = {Castro-Diehl, C and Smith, JA and Zhao, W and Wang, X and Mukherjee, B and Seeman, T and Needham, BL}, title = {Prediction of telomere length and telomere attrition using a genetic risk score: The multi-ethnic study of atherosclerosis (MESA).}, journal = {Frontiers in aging}, volume = {3}, number = {}, pages = {1021051}, pmid = {36304436}, issn = {2673-6217}, abstract = {Background: Short telomere length (TL) and telomere attrition (TA) have been associated with age-related diseases. Objective: We assessed whether a genetic risk score for short TL (GRS-TL) combining seven TL-associated genetic variants identified in a European-ancestry genome-wide association study (GWAS) was associated with TL and TA over 10 years. Methods: Relative TL (T/S ratio) was measured by the quantitative polymerase chain reaction method for a sample of white, African American, and Hispanic participants, who attended Exam 1 and/or 5 of the Multi-Ethnic Study of Atherosclerosis (MESA). Our final sample included 1,227 participants for the TL analysis and 1,138 for the TA analysis. Participants were 45-84 years at Exam 1. We used a linear mixed effects model and adjusted for age, sex, and population structure. Models were stratified by race/ethnicity. Results: In the TL analysis, higher GRS-TL significantly predicted shorter TL (estimates = -0.18 [S.E. = 0.08], p = 0.02 for white; -0.18 [0.07], p < 0.01 for African American; and -0.13 [0.05], p = 0.02 for Hispanic) in fully adjusted models. In the TA analysis, no association between GRS-TL and TA over 10 years was found. Conclusion: Although GRS-TL was developed in European-ancestry populations, it was significantly associated with TL (but not TA) in all three race/ethnic groups examined.}, }
@article {pmid36302456, year = {2022}, author = {Katz, R and Gay, EL and Kuipers, AL and Lee, JH and Honig, LS and Christensen, K and Feitosa, MF and Wojczynski, MK and Glynn, NW and , }, title = {Association of leukocyte telomere length with perceived physical fatigability.}, journal = {Experimental gerontology}, volume = {170}, number = {}, pages = {111988}, doi = {10.1016/j.exger.2022.111988}, pmid = {36302456}, issn = {1873-6815}, mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; Male ; Longitudinal Studies ; *Telomere/genetics ; *Leukocytes ; Fatigue/genetics ; Aging/genetics ; }, abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age.<br><br>METHODS: Two generations of participants (N&#xa0;=&#xa0;1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age&#xa0;=&#xa0;73.7&#xa0;&#xb1;&#xa0;10.4, range 60-108, 54.4&#xa0;% women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0&#xa0;&#xb1;&#xa0;1.1&#xa0;years later using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores&#xa0;=&#xa0;greater fatigability). Generalized estimating equations were generated to model the association between LTL and PFS Physical scores.<br><br>RESULTS: Prevalence of greater physical fatigability (PFS scores&#x2265;15) was 41.9&#xa0;%. Using generalized estimating equations, a one kilobase pair shorter LTL was associated with higher PFS Physical scores (&#x3b2;&#xa0;=&#xa0;1.8, p&#xa0;<&#xa0;.0001), accounting for family structure, and adjusting for field center, follow-up time, sex, and follow-up body mass index, physical activity, and chronic health conditions. When age was included as a covariate, the association was fully attenuated (&#x3b2;&#xa0;=&#xa0;0.1, p&#xa0;=&#xa0;.78).<br><br>CONCLUSION: LTL may provide an alternative method for estimating an individual's lifetime exposure to chronic stressors, but does not appear to provide additional information not captured by chronological age. Further research is needed to characterize the interaction between age, LTL, and perceived fatigability, and develop a method of identifying individuals at risk for deleterious aging.}, }
@article {pmid36296977, year = {2022}, author = {Cancello, R and Rey, F and Carelli, S and Cattaldo, S and Fontana, JM and Goitre, I and Ponzo, V and Merlo, FD and Zuccotti, G and Bertoli, S and Capodaglio, P and Bo, S and Brunani, A}, title = {Telomere Length and Mitochondrial DNA Copy Number Variations in Patients with Obesity: Effect of Diet-Induced Weight Loss-A Pilot Study.}, journal = {Nutrients}, volume = {14}, number = {20}, pages = {}, pmid = {36296977}, issn = {2072-6643}, mesh = {Humans ; *DNA Copy Number Variations ; Pilot Projects ; *Telomere/genetics ; Antioxidants ; Obesity/genetics ; DNA, Mitochondrial/genetics ; Weight Loss/genetics ; }, abstract = {BACKGROUND: Telomere length (TL) and mitochondrial DNA (mtDNA) copy number shifts are linked to metabolic abnormalities, and possible modifications by diet-induced weight loss are poorly explored. We investigated the variations before (T0) and after a 1-year (T12) lifestyle intervention (diet + physical activity) in a group of outpatients with obesity.<br><br>METHODS: Patients aged 25-70 years with BMI &#x2265; 30 kg/m[2] were enrolled. Clinical and biochemical assessments (including a blood sample for TL, mtDNA copy number and total antioxidant capacity, and TAC determinations) were performed at T0 and T12.<br><br>RESULTS: The change in TL and the mtDNA copy number was heterogeneous and not significantly different at T12. Patients were then divided by baseline TL values into lower than median TL (L-TL) and higher than median TL (H-TL) groups. The two groups did not differ at baseline for anthropometric, clinical, and laboratory characteristics. At T12, the L-TL group when compared to H-TL showed TL elongation (respectively, +0.57 &#xb1; 1.23 vs. -2.15 &#xb1; 1.13 kbp, p = 0.04), higher mtDNA copy number (+111.5 &#xb1; 478.5 vs. -2314.8 &#xb1; 724.2, respectively, p < 0.001), greater weight loss (-8.1 &#xb1; 2.7 vs. -6.1 &#xb1; 4.6 Kg, respectively, p = 0.03), fat mass reduction (-1.42 &#xb1; 1.3 vs. -1.22 &#xb1; 1.5%, respectively, p = 0.04), and increased fat-free mass (+57.8 &#xb1; 6.5 vs. +54.9 &#xb1; 5.3%, respectively, p = 0.04) and TAC levels (+58.5 &#xb1; 18.6 vs. +36.4 &#xb1; 24.1 &#xb5;M/L, respectively, p = 0.04).<br><br>CONCLUSIONS: TL and the mtDNA copy number significantly increased in patients with obesity and with lower baseline TL values after a 1-year lifestyle intervention. Larger longitudinal studies are needed to confirm the results of this pilot study.}, }
@article {pmid36294653, year = {2022}, author = {Xu, F and Li, X and Ren, H and Zeng, R and Wang, Z and Hu, H and Bao, J and Que, Y}, title = {The First Telomere-to-Telomere Chromosome-Level Genome Assembly of Stagonospora tainanensis Causing Sugarcane Leaf Blight.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {8}, number = {10}, pages = {}, pmid = {36294653}, issn = {2309-608X}, abstract = {The sexual morph Leptosphaeria taiwanensis Yen and Chi and its asexual morph Stagonospora tainanensis W. H. Hsieh is an important necrotrophic fungal phytopathogen, which causes sugarcane leaf blight, resulting in loss of cane tonnage and sucrose in susceptible sugarcane varieties. Decoding the genome and understanding of the basis of virulence is vitally important for devising effective disease control strategies. Here, we present a 38.25-Mb high-quality genome assembly of S. tainanensis strain StFZ01, denovo assembled with 10.19 Gb Nanopore sequencing long reads (~267×) and 3.82 Gb Illumina short reads (~100×). The genome assembly consists of 12 contigs with N50 of 2.86 Mb of which 5 belong to the telomere to telomere (T2T) chromosome. It contains 13.20% repeat sequences, 12,543 proteins, and 12,206 protein-coding genes with the BUSCO completeness 99.18% at fungi (n = 758) and 99.87% at ascomycota (n = 1706), indicating the high accuracy and completeness of our gene annotations. The virulence analysis in silico revealed the presence of 2379 PHIs, 599 CAZys, 248 membrane transport proteins, 191 cytochrome P450 enzymes, 609 putative secreted proteins, and 333 effectors in the StFZ01 genome. The genomic resources presented here will not only be helpful for development of specific molecular marker and diagnosis technique, population genetics, molecular taxonomy, and disease managements, it can also provide a significant precise genomic reference for investigating the ascomycetous genome, the necrotrophic lifestyle, and pathogenicity in the future.}, }
@article {pmid36292740, year = {2022}, author = {Dlouha, D and Vymetalova, J and Novakova, S and Huckova, P and Lanska, V and Hubacek, JA}, title = {Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients.}, journal = {Genes}, volume = {13}, number = {10}, pages = {}, pmid = {36292740}, issn = {2073-4425}, mesh = {Humans ; Adult ; Middle Aged ; *Telomere/genetics ; Leukocytes/metabolism ; *Heart Transplantation/adverse effects ; Genetic Loci ; DNA/metabolism ; }, abstract = {Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.}, }
@article {pmid36292646, year = {2022}, author = {M'Kacher, R and Miguet, M and Maillard, PY and Colicchio, B and Scheidecker, S and Najar, W and Arnoux, M and Oudrhiri, N and Borie, C and Biehler, M and Plesch, A and Heidingsfelder, L and Bennaceur-Griscelli, A and Dieterlen, A and Voisin, P and Junker, S and Carde, P and Jeandidier, E}, title = {A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy.}, journal = {Genes}, volume = {13}, number = {10}, pages = {}, pmid = {36292646}, issn = {2073-4425}, mesh = {Humans ; *Trisomy/genetics ; In Situ Hybridization, Fluorescence ; Chromosome Banding ; *Translocation, Genetic/genetics ; Chromosome Aberrations ; Telomere/genetics ; }, abstract = {Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.3q25 region identified by SNP array analysis. The size of the duplication is 26.7 Mb and contains 170 genes (OMIM). The duplication results in partial trisomy of the region in question with clinical consequences, including bilateral renal dysplasia, delayed development, and a heart defect. Moreover, the karyotype determined by R-banding and chromosome painting as well as by hybridization with specific sub-telomere probes revealed the presence of an unbalanced t(9;11)(p24;q22.3) translocation with a unique breakpoint involving the sub-telomere region of the short arm of chromosome 9. The karyotypes of the parents were normal. Telomere integrity in circulating lymphocytes from the child and from his parents was assessed using an automated high-throughput method based on fluorescence in situ hybridization (FISH) with telomere- and centromere-specific PNA probes followed by M-FISH multicolor karyotyping. Very short telomeres, as well as an increased frequency of telomere loss and formation of telomere doublets, were detected in the child's cells. Interestingly, similar telomere profiles were found in the circulating lymphocytes of the father. Moreover, an assessment of clonal telomere aberrations identified chromosomes 9 and 11 with particularly high frequencies of such aberrations. These findings strongly suggest that telomere dysfunction plays a central role in the formation of this specific unbalanced chromosome rearrangement via chromosome end-to-end fusion and breakage-fusion-bridge cycles.}, }
@article {pmid36290385, year = {2022}, author = {Dorador, AP and Dalikova, M and Cerbin, S and Stillman, CM and Zych, MG and Hawley, RS and Miller, DE and Ray, DA and Funikov, SY and Evgen'ev, MB and Blumenstiel, JP}, title = {Paramutation-like Epigenetic Conversion by piRNA at the Telomere of Drosophila virilis.}, journal = {Biology}, volume = {11}, number = {10}, pages = {}, pmid = {36290385}, issn = {2079-7737}, support = {P20 GM103418/GM/NIGMS NIH HHS/United States ; }, abstract = {First discovered in maize, paramutation is a phenomenon in which one allele can trigger an epigenetic conversion of an alternate allele. This conversion causes a genetically heterozygous individual to transmit alleles that are functionally the same, in apparent violation of Mendelian segregation. Studies over the past several decades have revealed a strong connection between mechanisms of genome defense against transposable elements by small RNA and the phenomenon of paramutation. For example, a system of paramutation in Drosophila melanogaster has been shown to be mediated by piRNAs, whose primary function is to silence transposable elements in the germline. In this paper, we characterize a second system of piRNA-mediated paramutation-like behavior at the telomere of Drosophila virilis. In Drosophila, telomeres are maintained by arrays of retrotransposons that are regulated by piRNAs. As a result, the telomere and sub-telomeric regions of the chromosome have unique regulatory and chromatin properties. Previous studies have shown that maternally deposited piRNAs derived from a sub-telomeric piRNA cluster can silence the sub-telomeric center divider gene of Drosophila virilis in trans. In this paper, we show that this silencing can also be maintained in the absence of the original silencing allele in a subsequent generation. The precise mechanism of this paramutation-like behavior may be explained by either the production of retrotransposon piRNAs that differ across strains or structural differences in the telomere. Altogether, these results show that the capacity for piRNAs to mediate paramutation in&amp;nbsp;trans may depend on the local chromatin environment and proximity to the uniquely structured telomere regulated by piRNAs. This system promises to provide significant insights into the mechanisms of paramutation.}, }
@article {pmid36289653, year = {2022}, author = {Rangel-Pozzo, A and Wechsler, J and Groult, J and Da Meda, L and Lebbe, C and Mai, S}, title = {Telomere-Associated Changes in Nuclear Architecture of Cancer-Associated Macrophage-like Cells in Liquid Biopsies from Melanoma Patients.}, journal = {Biomedicines}, volume = {10}, number = {10}, pages = {}, pmid = {36289653}, issn = {2227-9059}, abstract = {During phagocytosis, tumor-associated macrophages (TAMs) can incorporate genetic material from tumor cells. The incorporation of extra genetic material may be responsible for advanced malignant behavior observed in some TAMs, making TAMs potentially important players in cancer progression. More recently, similar cells were described in the blood as cancer-associated macrophage-like cells (CAMLs). CAMLs may be equivalent to TAMs cells in the blood, and they express macrophage markers. However, their origin is still unclear. In a previous study, we showed for the first time the distinct telomere 3D structure of circulating tumor cells (CTCs) in melanoma and other cancers. In the present pilot study, we investigated, comparatively, the 3D telomere structure of CAMLs, CTCs and leucocytes from nine melanoma patients with metastatic cutaneous melanoma stage IV. CTC capture was performed by size-based filtration followed by cytological and immunocytological evaluation. Three-dimensional Quantitative Fluorescent in situ Hybridization was performed to measure differences in five 3D telomere parameters. Telomere parameters, such as number, length, telomere aggregates, nuclear volume, and a/c ratio, were compared among different cellular types (CTCs, CAMLs, and normal leucocytes). Three telomere parameters were significantly different between CAMLs and leucocytes. The combination of two telomere parameters (telomere length against the number of telomeres) resulted in the identification of two CAMLs subpopulations with different levels of genomic instability. Those populations were classified as profile 1 and 2. Profile 2, characterized by a high number of short telomeres, was observed in four of the nine melanoma patients. To our knowledge, this is the first pilot study to investigate 3D telomere parameters as hallmarks of nuclear architecture in CAMLs' population in comparison to leucocytes from the same patient. Further studies involving a larger patient sample size are necessary to validate these findings and explore their potential prognostic value.}, }
@article {pmid36289597, year = {2022}, author = {Lupatov, AY and Yarygin, KN}, title = {Telomeres and Telomerase in the Control of Stem Cells.}, journal = {Biomedicines}, volume = {10}, number = {10}, pages = {}, pmid = {36289597}, issn = {2227-9059}, abstract = {Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the regenerative potential of high-turnover organs, causing or contributing to the onset of age-related diseases. In this review, stem cells are examined in the context of the current telomere-centric theory of cell aging, which assumes that telomere shortening depends not just on the number of cell doublings (mitotic clock) but also on the influence of various internal and external factors. The influence of the telomerase and telomere length on the functional activity of different stem cell types, as well as on their aging and prospects of use in cell therapy applications, is discussed.}, }
@article {pmid36285820, year = {2022}, author = {Iannarelli, NJ and Wade, TJ and Dempster, KS and Moore, J and MacNeil, AJ and O'Leary, DD}, title = {No Mediation Effect of Telomere Length or Mitochondrial DNA Copy Number on the Association Between Adverse Childhood Experiences (ACEs) and Central Arterial Stiffness.}, journal = {Journal of the American Heart Association}, volume = {11}, number = {21}, pages = {e026619}, pmid = {36285820}, issn = {2047-9980}, support = {363774//CIHR/Canada ; 399332//CIHR/Canada ; RFN 167014//CIHR/Canada ; }, mesh = {Young Adult ; Humans ; Female ; Adult ; DNA, Mitochondrial/genetics ; *Vascular Stiffness ; *Adverse Childhood Experiences ; DNA Copy Number Variations ; Pulse Wave Analysis ; Biomarkers/metabolism ; Telomere/genetics/metabolism ; *Cardiovascular Diseases/diagnosis/epidemiology/genetics ; }, abstract = {Background Adverse childhood experiences (ACEs) have been linked to increased cardiovascular disease (CVD) risk. Previous reports have suggested that accelerated biological aging-indexed by telomere length (TL) and mitochondrial DNA copy number (mtDNAcn)-may contribute to associations between ACEs and cardiovascular health outcomes. Here, we examine the potential mediating effects of TL and mtDNAcn on the association between ACEs and central arterial stiffness-an intermediate cardiovascular health outcome-as a novel pathway linking ACEs to CVD risk among young adults. Methods and Results One hundred and eighty-five (n=102 women; mean age, 22.5±1.5 years) individuals provided information on ACEs. TL (kb per diploid cell) and mtDNAcn (copies per diploid cell) were quantified using quantitative polymerase chain reaction techniques. Central arterial stiffness was measured as carotid-femoral pulse wave velocity (cfPWV; m/s). Multiple linear regression analyses were used to examine the associations between ACEs, TL, mtDNAcn, and cfPWV. ACEs were positively associated with cfPWV (β=0.147, P=0.035). TL (β=-0.170, P=0.011) and mtDNAcn (β=-0.159, P=0.019) were inversely associated with cfPWV. Neither TL (β=-0.027, P=0.726) nor mtDNAcn (β=0.038, P=0.620) was associated with ACEs. Neither marker mediated the association between ACEs and cfPWV. Conclusions An increasing number of ACEs were associated with a faster cfPWV and thus, a greater degree of central arterial stiffness. ACEs were not associated with either TL or mtDNAcn, suggesting that these markers do not represent a mediating pathway linking ACEs to central arterial stiffness.}, }
@article {pmid36283531, year = {2023}, author = {Li, X and Liu, H and Wan, H and Li, Y and Xu, S and Xiao, H and Xia, W}, title = {Sex-specific associations between legacy and novel per- and polyfluoroalkyl substances and telomere length in newborns in Wuhan, China: Mixture and single pollutant associations.}, journal = {The Science of the total environment}, volume = {857}, number = {Pt 3}, pages = {159676}, doi = {10.1016/j.scitotenv.2022.159676}, pmid = {36283531}, issn = {1879-1026}, mesh = {Pregnancy ; Female ; Male ; Infant, Newborn ; Humans ; *Fluorocarbons/analysis ; *Environmental Pollutants/analysis ; *Alkanesulfonic Acids/analysis ; China ; Telomere ; }, abstract = {Telomere length (TL) at birth predicts later life TL and is related to health. Prenatal exposure to environmental pollutants might affect TL, but the associations between intrauterine per- and polyfluoroalkyl substances (PFASs) exposure and neonatal TL remained inconclusive. This study aimed to explore the single pollutant and mixture associations between legacy and novel PFASs and TL in newborns. In 908 mother-newborn pairs from Wuhan, China, thirteen PFASs were measured in cord serum, and TL was determined in cord leukocytes. Weighted quantile sum (WQS) regression and generalized linear model (GLM) were utilized to analyze the associations between PFASs mixture and single PFASs and TL in newborns. Furthermore, stratified and interaction analyses were performed to evaluate if there were sex-specific associations. The concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) ranked the highest (geometric mean, 4.12, 1.61, and 0.77 ng/mL, respectively) among the 13 measured PFASs. Each unit increase in WQS index of PFASs mixture was associated with -5.19 % change (95% CI, -9.44, -0.73) of neonatal TL, and 8:2 Cl-PFESA contributed most (32.59 %) to the mixture association. In stratified analyses by neonatal sex, PFOS (-4.73 % change, 95% CI, -8.40, -0.93 for per doubling concentration) and 8:2 Cl-PFESA (-4.52 % change, 95% CI, -8.20, -0.70) were negatively associated with neonatal TL in male newborns, but no significant association appeared in females. In summary, intrauterine exposure to PFASs in mixture was associated with shorter neonatal TL, and the negative associations of 8:2 Cl-PFESA and PFOS with neonatal TL were observed only in boys. Future risk assessments are needed to pay more attention to the health effects of novel PFASs.}, }
@article {pmid36282763, year = {2022}, author = {Kertes, DA and Leri, J and Duan, K and Tarrence, J and Browning, C and Pickler, R and Ford, J}, title = {Demographic and health predictors of telomere length during adolescence.}, journal = {Developmental psychobiology}, volume = {64}, number = {7}, pages = {e22311}, pmid = {36282763}, issn = {1098-2302}, support = {R01 DA032371/DA/NIDA NIH HHS/United States ; P2C HD058484/HD/NICHD NIH HHS/United States ; R21 DA034960/DA/NIDA NIH HHS/United States ; R01 NR019008/NR/NINR NIH HHS/United States ; R01 MD011727/MD/NIMHD NIH HHS/United States ; }, mesh = {Adult ; Adolescent ; Humans ; *Telomere Shortening ; *Telomere ; Body Mass Index ; DNA ; Demography ; }, abstract = {Telomere length (TL) is proposed to play a mechanistic role in how the exposome affects health outcomes. Little is known about TL during adolescence, a developmental period during which precursors of adult-onset health problems often emerge. We examined health and demographic sources of variation in TL in 899 youth aged 11-17. Demographic and health information included age, sex, race, household income, caregiver age and marital status, youth tobacco exposure, body mass index, pubertal status, health problems, medication use, and season of data collection. Genomic DNA was extracted from saliva, and T/S ratios were computed following qPCR. Age, race, season of data collection, and household income were associated with the telomere to single copy (T/S) ratio. We found that T/S ratios were larger at younger ages, among Black youth, for saliva collected during autumn and winter, and among households with higher income. Analyses stratified by race revealed that the association between age and T/S ratio was present for Black youth, that season of collection was present across races, but that family demographic associations with T/S ratio varied by race. The results provide information for future telomere research and highlight adolescence as a potentially important developmental phase for racial disparities in telomere shortening and health.}, }
@article {pmid36276465, year = {2022}, author = {Mishra, R and Haldar, S and Biondi, S and Bhari, VK and Singh, G and Bhowmick, NA}, title = {TGF-β controls stromal telomere length through epigenetic modifications.}, journal = {3 Biotech}, volume = {12}, number = {11}, pages = {290}, pmid = {36276465}, issn = {2190-572X}, abstract = {UNLABELLED: Telomere length is primarily controlled by the enzyme telomerase, but being chromatin structures, telomeres undergo epigenetic regulation for their maintenance and function. Altered telomere length among cancer cells combined with shorter telomere length in cancer-associated stromal cells, strongly implicated with progression to prostate cancer metastasis and cancer death and providing a novel target for therapeutics. Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in stromal-epithelial interactions responsible for prostate androgen responsiveness, promoting tumorigenesis. However, the underlying mechanism remains unclear. We sought to establish a role for TGF-β in the regulation of telomere length in mouse and human prostate fibroblast. Polymerase chain reaction (PCR)-based telomere length measuring methods are widely used due to their repeatability and reproducibility. Using real-time RT-PCR-based telomere length measuring method, we identified that TGF-beta regulates telomere length via increased expression of histone methyltransferase, Suv39h1, which in turn affected histone methylation levels at the telomeric ends. Moreover, treatment of DAPT and non-steroidal antiandrogen bicalutamide demonstrated that notch and androgen signaling co-operated with TGF-ß in regulating stromal telomere length. Telomere variation in tumor cells and non-tumor cells within the tumor microenvironment greatly facilitates the clinical assessment of prostate cancer; therefore, understanding stromal telomere length regulation mechanism will hold significant prospects for cancer treatment, diagnosis, and prognosis.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03346-5.}, }
@article {pmid36270567, year = {2022}, author = {Tang, P and He, W and Shao, Y and Liu, B and Huang, H and Liang, J and Liao, Q and Tang, Y and Mo, M and Zhou, Y and Li, H and Huang, D and Liu, S and Zeng, X and Qiu, X}, title = {Associations between prenatal multiple plasma metal exposure and newborn telomere length: Effect modification by maternal age and infant sex.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {315}, number = {}, pages = {120451}, doi = {10.1016/j.envpol.2022.120451}, pmid = {36270567}, issn = {1873-6424}, mesh = {Infant ; Infant, Newborn ; Humans ; Pregnancy ; Female ; *Arsenic ; Lead ; Maternal Age ; Prospective Studies ; Telomere ; Bayes Theorem ; Barium ; Cohort Studies ; China ; Maternal Exposure ; }, abstract = {Exposure to metals during pregnancy may affect maternal and infant health. However, studies on the combined effects of metals on the telomere length (TL) of newborns are limited. A prospective cohort study was conducted among 1313 mother-newborn pairs in the Guangxi Zhuang Birth Cohort. The concentrations of metals in maternal plasma during the first trimester were measured using inductively coupled plasma-mass spectrometry. We explored the associations between nine plasma metals and newborn TL using generalized linear models (GLMs), principal component analysis (PCA), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). The GLMs revealed the inverse association between plasma arsenic (percent change, -5.56%; 95% CI: -7.69%, -3.38%) and barium concentrations (-9.84%; 95% CI: -13.81%, -5.68%) and newborn TL. Lead levels were related to significant decreases in newborn TL only in females. The PCA revealed a negative association between the PC3 and newborn TL (-4.52%; 95% CI: -6.34%, -2.68%). In the BKMR, the joint effect of metals was negatively associated with newborn TL. Qgcomp indicated that each one-tertile increase in metal mixture levels was associated with shorter newborn TL (-9.39%; 95% CI: -14.32%, -4.18%). The single and joint effects of multiple metals were more pronounced among pregnant women carrying female fetuses and among pregnant women <28 years of age. The finding suggests that prenatal exposure to arsenic, barium, antimony, and lead and mixed metals may shorten newborn TLs. The relationship between metal exposures and newborn TL may exhibit heterogeneities according to infant sex and maternal age.}, }
@article {pmid36267401, year = {2022}, author = {Wang, C and Alfano, R and Reimann, B and Hogervorst, J and Bustamante, M and De Vivo, I and Plusquin, M and Nawrot, TS and Martens, DS}, title = {Genetic regulation of newborn telomere length is mediated and modified by DNA methylation.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {934277}, pmid = {36267401}, issn = {1664-8021}, abstract = {Telomere length at birth determines later life telomere length and potentially predicts ageing-related diseases. However, the genetic and epigenetic settings of telomere length in newborns have not been analyzed. In addition, no study yet has reported how the interplay between genetic variants and genome-wide cytosine methylation explains the variation in early-life telomere length. In this study based on 281 mother-newborn pairs from the ENVIRONAGE birth cohort, telomere length and whole-genome DNA methylation were assessed in cord blood and 26 candidate single nucleotide polymorphism related to ageing or telomere length were genotyped. We identified three genetic variants associated with cord blood telomere length and 57 cis methylation quantitative trait loci (cis-mQTLs) of which 22 mQTLs confirmed previous findings and 35 were newly identified. Five SNPs were found to have significant indirect effects on cord blood telomere length via the mediating CpGs. The association between rs911874 (SOD2) and newborn telomere length was modified by nearby DNA methylation indicated by a significant statistical interaction. Our results suggest that DNA methylation in cis might have a mediation or modification effect on the genetic difference in newborn telomere length. This novel approach warrants future follow-up studies that are needed to further confirm and extend these findings.}, }
@article {pmid36266468, year = {2022}, author = {Asghar, M and Odeh, A and Fattahi, AJ and Henriksson, AE and Miglar, A and Khosousi, S and Svenningsson, P}, title = {Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson's disease and Lewy body dementia.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {17578}, pmid = {36266468}, issn = {2045-2322}, mesh = {Humans ; *Parkinson Disease/genetics/complications ; *Lewy Body Disease/genetics ; *Dementia/etiology ; Organelle Biogenesis ; Levodopa ; Cellular Senescence/genetics ; DNA, Mitochondrial/genetics ; Telomere/genetics ; }, abstract = {Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson's disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copies, but (7-9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1β) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings.}, }
@article {pmid36265486, year = {2022}, author = {Yadav, T and Zhang, JM and Ouyang, J and Leung, W and Simoneau, A and Zou, L}, title = {TERRA and RAD51AP1 promote alternative lengthening of telomeres through an R- to D-loop switch.}, journal = {Molecular cell}, volume = {82}, number = {21}, pages = {3985-4000.e4}, pmid = {36265486}, issn = {1097-4164}, support = {R01 CA218856/CA/NCI NIH HHS/United States ; R35 CA263934/CA/NCI NIH HHS/United States ; }, mesh = {Telomere Homeostasis ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; R-Loop Structures/genetics ; DNA Repair ; *RNA, Long Noncoding ; }, abstract = {Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR.}, }
@article {pmid36263045, year = {2022}, author = {Lai, TP and Verhulst, S and Dagnall, CL and Hutchinson, A and Spellman, SR and Howard, A and Katki, HA and Levine, JE and Saber, W and Aviv, A and Gadalla, SM}, title = {Decoupling blood telomere length from age in recipients of allogeneic hematopoietic cell transplant in the BMT-CTN 1202.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {966301}, pmid = {36263045}, issn = {1664-3224}, support = {U01 AG066529/AG/NIA NIH HHS/United States ; KL2 TR003018/TR/NCATS NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Humans ; *Hematopoietic Stem Cell Transplantation ; Telomere/genetics ; Tissue Donors ; *Transplants ; }, abstract = {The age of allogeneic hematopoietic cell transplant (HCT) donors and their hematopoietic cell telomere length (TL) might affect recipients' outcomes. Our goals were to examine the possible effect of these donors' factors on the recipients' hematopoietic cell TL and quantify hematopoietic cell TL shortening in the critical first three-month post-HCT. We measured hematopoietic cell TL parameters in 75 recipient-donor pairs, from the Blood and Marrow Transplant Clinical Trials Network (protocol#1202), by Southern blotting (SB), the Telomeres Shortest Length Assay (TeSLA), and quantitative PCR (qPCR). Recipients' hematopoietic cell TL parameters post-HCT correlated with donors' age (p<0.001 for all methods), but not recipients' own age, and with donors' pre-HCT hematopoietic cell TL (p<0.0001 for all). Multivariate analyses showed that donors' hematopoietic cell TL pre-HCT, independent of donors' age, explained most of the variability in recipients' hematopoietic cell TL post-HCT (81% for SB, 56% for TeSLA, and 65% for qPCR; p>0.0001 for all). SB and TeSLA detected hematopoietic cell TL shortening in all recipients post-HCT (mean=0.52kb and 0.47kb, respectively; >15-fold the annual TL shortening in adults; p<0.00001 for both), but qPCR detected shortening only in 57.5% of recipients. TeSLA detected a buildup of post-HCT of telomeres <3 kb in 96% of recipients (p<0.0001). In conclusion, HCT decouples hematopoietic cell TL in the recipients from their own age to reflect the donors' age. The potential donors' age effect on outcomes of HCT might be partially mediated by short hematopoietic cell TL in older donors. qPCR-based TL measurement is suboptimal for detecting telomere shortening post-HCT.}, }
@article {pmid36254044, year = {2022}, author = {Sung, MK and Koh, E and Kang, Y and Lee, JH and Park, JY and Kim, JY and Shin, SY and Kim, YH and Setou, N and Lee, US and Yang, HJ}, title = {Three months-longitudinal changes in relative telomere length, blood chemistries, and self-report questionnaires in meditation practitioners compared to novice individuals during midlife.}, journal = {Medicine}, volume = {101}, number = {41}, pages = {e30930}, pmid = {36254044}, issn = {1536-5964}, mesh = {Alanine Transaminase ; Aspartate Aminotransferases ; Glucose ; Humans ; Lipoproteins, HDL ; *Meditation/methods ; Self Report ; Surveys and Questionnaires ; Telomere ; Triglycerides ; }, abstract = {Aging accelerates during midlife. Researches have shown the health benefits of mind-body intervention (MBI). However, whether MBI is involved with aging process has not been well understood. In this study, we approach to examine the relations of MBI with this process by investigating an aging marker of the peripheral blood, blood chemistry, and self-report questionnaires. A quasi-experimental design was applied. Experienced MBI practitioners participated in a 3-month intensive meditation training, while the age, gender-matched MBI-naïve controls led a normal daily life. Measurements were taken at before and after the 3 months for relative telomere length (RTL), blood chemistry, and self-report questionnaires including items about sleep quality, somatic symptoms, depression, anxiety, stress, emotional intelligence (EI), and self-regulation. For RTL, the repeated measures analysis of variance showed a significant group*time interaction (P = .013) with a significant post hoc result (P = .030) within the control group: RTL was significantly reduced in the control while it was maintained in the meditation group. In repeated measures analysis of variance for blood chemistries, there were significant group differences between the groups in glucose and total protein. In the post hoc comparison analysis, at post measurements, the meditation group exhibited significantly lower values than the control group in both glucose and total protein. There were significant group-wise differences in the correlations of RTL with triglyceride (TG), high-density lipoprotein (HDL), glutamic oxaloacetic transaminase and glutamic pyruvic transaminase. Any of self-report results did not show significant changes in group*time interaction. However, there were group differences with significant (P < .05) or a tendency (.05 < P < .1) level. There were significant improvements in depression, stress and EI as well as tendencies of improvement in sleep quality and anxiety, in the meditation group compared to the control group. Our results suggest that meditation practice may have a potential to modify aging process in molecular cellular level combined with changes in psychological dimension.}, }
@article {pmid36253798, year = {2022}, author = {Squassina, A and Meloni, A and Congiu, D and Bosganas, P and Patrinos, GP and Lin, R and Turecki, G and Severino, G and Ardau, R and Chillotti, C and Pisanu, C}, title = {Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment.}, journal = {Human genomics}, volume = {16}, number = {1}, pages = {45}, pmid = {36253798}, issn = {1479-7364}, mesh = {*Bipolar Disorder/diagnosis/drug therapy/genetics ; Cell Line ; Humans ; Lithium/pharmacology/therapeutic use ; Lithium Chloride/pharmacology/therapeutic use ; Lithium Compounds/pharmacology/therapeutic use ; *Neural Stem Cells/metabolism ; Telomere/genetics ; }, abstract = {BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15).<br><br>RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors.<br><br>CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.}, }
@article {pmid36253342, year = {2023}, author = {Hassani, MA and Murid, J and Yan, J}, title = {Regulator of telomere elongation helicase 1 gene and its association with malignancy.}, journal = {Cancer reports (Hoboken, N.J.)}, volume = {6}, number = {1}, pages = {e1735}, pmid = {36253342}, issn = {2573-8348}, mesh = {Humans ; DNA ; *Neoplasms/genetics ; *Telomere/genetics ; Tumor Microenvironment ; *DNA Helicases/genetics ; }, abstract = {BACKGROUND: With the progression of next-generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression.<br><br>RECENT FINDINGS: A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine-rich quadruplex DNA (G4-DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome-wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune-deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1, thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over-expression was directed toward G4-unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre-malignant cellular compartments.<br><br>CONCLUSIONS: Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.}, }
@article {pmid36249518, year = {2021}, author = {Albosale, AH and Mashkina, EV}, title = {Association of Relative Telomere Length and Risk of High Human Papillomavirus Load in Cervical Epithelial Cells.}, journal = {Balkan journal of medical genetics : BJMG}, volume = {24}, number = {2}, pages = {65-70}, pmid = {36249518}, issn = {1311-0160}, abstract = {Importunate high-risk HPV (HR-HPV) infection is the most common trigger for the cervical carcinogenesis process. In this respect, the presence of cancer can be imputed to telomere lengthening or shortening. This paper explores the possible correlation between relative telomere length and viral load in two groups of women, namely: those with high-risk HPV infection and those who do not have this infection. Thus, samples comprising of 50 women in each group were evaluated for this research. The Amplisens HPV HCR screen-titre-FRT PCR kite was employed for quantitative analysis. Relative telomere length was quantified by real-time PCR. In each of the two HPV load groups, there was no correlation between age and telomere length. Telomere shortening was found in the cervical cell samples of women with high HPV loads, compared with women in the control group. Telomere shortening is associated with elevated HPV loads.}, }
@article {pmid36248806, year = {2022}, author = {Ye, M and Wang, Y and Zhan, Y}, title = {Genetic association of leukocyte telomere length with Graves' disease in Biobank Japan: A two-sample Mendelian randomization study.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {998102}, pmid = {36248806}, issn = {1664-3224}, mesh = {Biological Specimen Banks ; Genome-Wide Association Study ; *Graves Disease/genetics ; Humans ; Japan/epidemiology ; Leukocytes ; *Mendelian Randomization Analysis ; Telomere ; }, abstract = {BACKGROUND: Telomere length (TL) has been recognized to be fundamental to the risk of autoimmune disorders. However, the role of leukocyte TL in Graves' disease has not yet been fully elucidated. In the study, we exploited the two-sample Mendelian randomization (MR) design to evaluate the causal effect of leukocyte TL on the risk of Graves' disease.<br><br>METHODS: Genome-wide association study (GWAS) data of leukocyte TL from the Singapore Chinese Health Study (SCHS) cohort and Graves' disease from Biobank Japan (BBJ, 2176 cases and 210,277 controls) were analyzed. Nine single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for TL. We used the inverse variance weighted (IVW) approach as the main estimator and MR-Egger regression, weighted median, simple mode, and weighed mode methods as complementary estimators. Horizontal pleiotropy was assessed using the intercept from MR-Egger.<br><br>RESULTS: The analysis demonstrated that genetically predicted longer leukocyte TL was causally associated with a lower risk of Graves' disease using the IVW method (odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.23-2.17, P=2.27e-04, and other complementary MR approaches&#xa0;achieved similar results. The intercept from the MR-Egger analysis provided no noticeable evidence of horizontal pleiotropy (&#x3b2;=0.02, P=0.641).&#xa0;MR-PRESSO method reported no outliers (P=0.266).<br><br>CONCLUSIONS: Our results provided evidence to support a genetic predisposition to shorter leukocyte TL with an increased risk of Graves' disease. Further studies are warranted to explore the mechanism underlying the association.}, }
@article {pmid36235538, year = {2022}, author = {Valera-Gran, D and Prieto-Botella, D and Hurtado-Pomares, M and Baladia, E and Petermann-Rocha, F and Sánchez-Pérez, A and Navarrete-Muñoz, EM}, title = {The Impact of Foods, Nutrients, or Dietary Patterns on Telomere Length in Childhood and Adolescence: A Systematic Review.}, journal = {Nutrients}, volume = {14}, number = {19}, pages = {}, pmid = {36235538}, issn = {2072-6643}, mesh = {Animals ; *Antioxidants ; *Diet ; Feeding Behavior ; Monosaccharides ; Nutrients ; Telomere ; Vegetables ; }, abstract = {Environmental factors such as diet can affect telomere length (TL) dynamics. However, the role that children's and adolescents' diets play in maintaining TL is not well understood. Thus, we conducted a systematic review to examine the association between the intake of nutrients, foods, food groups, and/or dietary patterns and TL in childhood and adolescence. Following the PRISMA guidelines, we searched MEDLINE via PubMed, Embase, and Cochrane databases and additional registers and methods. The five selected studies were cross-sectional and conducted in children and adolescents aged 2 to 18 years. The main results suggest that a higher consumption of fish, nuts and seeds, fruits and vegetables, green leafy and cruciferous vegetables, olives, legumes, polyunsaturated fatty acids, and an antioxidant-rich diet might positively affect TL. On the contrary, a higher intake of dairy products, simple sugar, sugar-sweetened beverages, cereals, especially white bread, and a diet high in glycaemic load were factors associated with TL shortening. To our knowledge, this is the first systematic review examining the impact of dietary intake factors on TL in childhood and adolescence. Although limited, these results are consistent with previous studies in different adult populations. Further research is needed to ascertain potential nutritional determinants of TL in childhood and adolescence.}, }
@article {pmid36233645, year = {2022}, author = {Zia, S and Khan, N and Tehreem, K and Rehman, N and Sami, R and Baty, RS and Tayeb, FJ and Almashjary, MN and Alsubhi, NH and Alrefaei, GI and Shahid, R}, title = {Transcriptomic Analysis of Conserved Telomere Maintenance Component 1 (CTC1) and Its Association with Leukemia.}, journal = {Journal of clinical medicine}, volume = {11}, number = {19}, pages = {}, pmid = {36233645}, issn = {2077-0383}, abstract = {Telomere length (TEL) regulation is important for genome stability and is governed by the coordinated role of shelterin proteins, telomerase (TERT), and CST (CTC1/OBFC1/TEN1) complex. Previous studies have shown the association of telomerase expression with the risk of acute lymphoblastic leukemia (ALL). However, no data are available for CST association with the ALL. The current pilot study was designed to evaluate the CST expression levels in ALL. In total, 350 subjects were recruited, including 250 ALL cases and 100 controls. The subjects were stratified by age and categorized into pediatrics (1-18 years) and adults (19-54 years). TEL and expression patterns of CTC1, OBFC1, and TERT genes were determined by qPCR. The univariable logistic regression analysis was performed to determine the association of gene expression with ALL, and the results were adjusted for age and sex in multivariable analyses. Pediatric and adult cases did not reflect any change in telomere lengths relative to controls. However, expression of CTC1, OBFC1, and TERT genes were induced among ALL cases. Multivariable logistic regression analyses showed association of CTC1 with ALL in pediatric [β estimate (standard error (SE)= -0.013 (0.007), p = 0.049, and adults [0.053 (0.023), p = 0.025]. The association of CTC1 remained significant when taken together with OBFC1 and TERT in a multivariable model. Furthermore, CTC1 showed significant association with B-cell ALL [-0.057(0.017), p = 0.002) and T-cell ALL [-0.050 (0.018), p = 0.008] in pediatric group while no such association was noted in adults. Together, our findings demonstrated that telomere modulating genes, particularly CTC1, are strongly associated with ALL. Therefore, CTC1 can potentially be used as a risk biomarker for the identification of ALL in both pediatrics and adults.}, }
@article {pmid36231453, year = {2022}, author = {Chen, XY and Lo, CKM and Chan, KL and Leung, WC and Ip, P}, title = {Association between Childhood Exposure to Family Violence and Telomere Length: A Meta-Analysis.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {19}, pages = {}, pmid = {36231453}, issn = {1660-4601}, mesh = {Child ; *Domestic Violence ; Humans ; *Intimate Partner Violence ; Telomere ; }, abstract = {The aims of this meta-analysis were to examine the association between childhood exposure to family violence and telomere length and the moderating variables that influence this association. Relevant works published on or before 1st September 2022 were identified through a search in five major databases in English and 19 articles (N = 18,977) finally met the inclusion criteria. A meta-analysis was conducted to compute the pooled effect size (correlation; r), and moderator analyses were performed using a random effects meta-analytic model. The studies yielded a significant inverse association between childhood exposure to family violence and telomere length, with a small effect size (r = -0.038, 95% CI [-0.070, -0.005], p = 0.025). Furthermore, the strength of this association was stronger in studies examining the co-occurrence of multiple types of violence than in those examining just one type (Q = 8.143, p = 0.004). These findings suggested that victims' telomere length may be negatively influenced by childhood exposure to family violence and that such impairment appears to be stronger for those who are exposed to multiple types of violence. Future studies are necessary to examine the moderating and mediating factors underlying the association between childhood exposure to family violence and telomere length.}, }
@article {pmid36230999, year = {2022}, author = {Shokr, H and Lush, V and Dias, IH and Ekárt, A and De Moraes, G and Gherghel, D}, title = {The Use of Retinal Microvascular Function and Telomere Length in Age and Blood Pressure Prediction in Individuals with Low Cardiovascular Risk.}, journal = {Cells}, volume = {11}, number = {19}, pages = {}, pmid = {36230999}, issn = {2073-4409}, mesh = {Adult ; Aged ; Biomarkers ; Blood Pressure/physiology ; *Cardiovascular Diseases ; Heart Disease Risk Factors ; Humans ; Middle Aged ; Risk Factors ; Telomere ; }, abstract = {Ageing represents a major risk factor for many pathologies that limit human lifespan, including cardiovascular diseases. Biological ageing is a good biomarker to assess early individual risk for CVD. However, finding good measurements of biological ageing is an ongoing quest. This study aims to assess the use retinal microvascular function, separate or in combination with telomere length, as a predictor for age and systemic blood pressure in individuals with low cardiovascular risk. In all, 123 healthy participants with low cardiovascular risk were recruited and divided into three groups: group 1 (less than 30 years old), group 2 (31-50 years old) and group 3 (over 50 years old). Relative telomere length (RTL), parameters of retinal microvascular function, CVD circulatory markers and blood pressure (BP) were measured in all individuals. Symbolic regression- analysis was used to infer chronological age and systemic BP measurements using either RTL or a combination of RTL and parameters for retinal microvascular function. RTL decreased significantly with age (p = 0.010). There were also age-related differences between the study groups in retinal arterial time to maximum dilation (p = 0.005), maximum constriction (p = 0.007) and maximum constriction percentage (p = 0.010). In the youngest participants, the error between predicted versus actual values for the chronological age were smallest in the case of using both retinal vascular functions only (p = 0.039) or the combination of this parameter with RTL (p = 0.0045). Systolic BP was better predicted by RTL also only in younger individuals (p = 0.043). The assessment of retinal arterial vascular function is a better predictor than RTL for non-modifiable variables such as age, and only in younger individuals. In the same age group, RTL is better than microvascular function when inferring modifiable risk factors for CVDs. In older individuals, the accumulation of physiological and structural biological changes makes such predictions unreliable.}, }
@article {pmid36229075, year = {2022}, author = {Yang, Z and Sharma, K and de Lange, T}, title = {TRF1 uses a noncanonical function of TFIIH to promote telomere replication.}, journal = {Genes &amp; development}, volume = {36}, number = {17-18}, pages = {956-969}, pmid = {36229075}, issn = {1549-5477}, support = {R01 AG016642/AG/NIA NIH HHS/United States ; R35 CA210036/CA/NCI NIH HHS/United States ; }, mesh = {*Telomeric Repeat Binding Protein 1 ; *Telomere/genetics/metabolism ; DNA Replication/genetics ; DNA Helicases/genetics/metabolism ; DNA/metabolism ; }, abstract = {Telomeric DNA challenges the replisome and requires TRF1 for efficient duplication. TRF1 recruits the BLM helicase, but BLM loss does not explain the extensive telomere fragility, ATR signaling, and sister telomere associations (STAs) induced by TRF1 deletion. Here, we document that Helix2 of the TRFH domain and Helix1 of the Myb domain of TRF1 are required for efficient telomere replication. Mutation of both helices generated a TRF1 separation-of-function mutant (TRF1-E83K/LW-TI) that induced severe telomere replication defects but no ATR signaling or STAs. We identified the transcription and nucleotide excision repair (NER) factor TFIIH as a critical effector of TRF1. Loss of TFIIH subunits, but no other NER factors, caused the same telomere replication phenotypes as the TRF1-E83K/LW-TI mutant independent of the effects on TRF1 expression. TFIIH subunits coimmunoprecipitated with wild-type TRF1 but not with TRF1-E83K/LW-TI. These results establish that the major mechanism by which TRF1 ensures telomere replication involves a noncanonical function of TFIIH.}, }
@article {pmid36222081, year = {2022}, author = {Sheikh-Wu, SF and Liang, Z and Downs, CA}, title = {The Relationship Between Telomeres, Cognition, Mood, and Physical Function: A Systematic Review.}, journal = {Biological research for nursing}, volume = {}, number = {}, pages = {10998004221132287}, doi = {10.1177/10998004221132287}, pmid = {36222081}, issn = {1552-4175}, abstract = {Background and Purpose: Cognitive, affective, and physical symptoms and alterations in their function are seen across chronic illnesses. Data suggest that environmental, psychological, and physiological factors contribute to symptom experience, potentially through loss of telomeres (telomere attrition), structures at the ends of chromosomes. Telomere length is affected by many factors including environmental (e.g., exercise, diet, smoking) and physiological (e.g., response to stress), as well as from oxidative damage and inflammation that occurs in many disease processes. Moreover, telomere attrition is associated with chronic disease (cancer, cardiovascular disease, Alzheimer's disease) and predicts higher morbidity and mortality rates. However, findings are inconsistent among telomere roles and relationships with health outcomes. This article aims to synthesize the current state-of-the-science of telomeres and their relationship with cognitive, affective, and physical function and symptoms. Method: A comprehensive literature search was performed in two databases: CINAHL and PUBMED. A total of 33 articles published between 2000 and 2022 were included in the final analysis. Results: Telomere attrition is associated with various changes in cognitive, affective, and physical function and symptoms. However, findings are inconsistent. Interventional studies (e.g., meditation and exercise) may affect telomere attrition, potentially impacting health outcomes. Conclusion: Nursing research and practice are at the forefront of furthering the understanding of telomeres and their relationships with cognitive, affective, and physical function and symptoms. Future interventions targeting modifiable risk factors may be developed to improve health outcomes across populations.}, }
@article {pmid36221106, year = {2022}, author = {Sanchez, M and Kannengiesser, C and Hoang, S and Potier, L and Fumeron, F and Venteclef, N and Scheen, A and Gautier, JF and Hadjadj, S and Marre, M and Roussel, R and Mohammedi, K and Velho, G}, title = {Leukocyte telomere length, allelic variations in related genes and risk of coronary heart disease in people with long-standing type 1 diabetes.}, journal = {Cardiovascular diabetology}, volume = {21}, number = {1}, pages = {206}, pmid = {36221106}, issn = {1475-2840}, mesh = {Adaptor Proteins, Signal Transducing/genetics ; Adult ; *Coronary Disease/diagnosis/epidemiology/genetics ; Cytoskeletal Proteins/genetics ; *Diabetes Mellitus, Type 1/diagnosis/epidemiology/genetics ; Humans ; Leukocytes ; *Myocardial Infarction/complications ; Prospective Studies ; Telomere/genetics ; }, abstract = {BACKGROUND: Type 1 diabetes is associated with accelerated vascular aging and advanced atherosclerosis resulting in increased rates of cardiovascular disease and premature death. We evaluated associations between Leukocyte telomere length (LTL), allelic variations (SNPs) in LTL-related genes and the incidence of coronary heart disease (CHD) in adults with long-standing type 1 diabetes.<br><br>METHODS: We assessed associations of LTL, measured at baseline by RT-PCR, and of SNPs in 11 LTL-related genes with the risk of coronary heart disease (CHD: myocardial infarction or coronary revascularization) and all-cause death during follow-up in two multicenter French-Belgian prospective cohorts of people with long-standing type 1 diabetes.<br><br>RESULTS: In logistic and Cox analyses, the lowest tertile of LTL distribution (short telomeres) at baseline was associated with the prevalence of myocardial infarction at baseline and with increased risk of CHD (Hazard ratio 3.14 (1.39-7.70), p&#x2009;=&#x2009;0.005, for shorter vs longer tertile of LTL) and all-cause death (Hazard ratio 1.63 (95% CI 1.04-2.55), p&#x2009;=&#x2009;0.03, for shorter vs combined intermediate and longer tertiles of LTL) during follow-up. Allelic variations in six genes related to telomere biology (TERC, NAF1, TERT, TNKS, MEN1 and BICD1) were also associated with the incidence of CHD during follow-up. The associations were independent of sex, age, duration of diabetes, and a range of relevant confounding factors at baseline.<br><br>CONCLUSIONS: Our results suggest that short LTL is an independent risk factor for CHD in people with type 1 diabetes.}, }
@article {pmid36219936, year = {2022}, author = {Hatse, S and Serena, M and Vulsteke, C and Punie, K and Neven, P and Smeets, A and Laenen, A and Wildiers, H}, title = {Impact of baseline telomere length on survival and chemotherapy related toxicity in breast cancer patients receiving (neo)adjuvant anthracycline containing chemotherapy.}, journal = {Translational oncology}, volume = {26}, number = {}, pages = {101551}, pmid = {36219936}, issn = {1936-5233}, abstract = {PURPOSE: The aim of this study is to assess baseline mean leukocyte telomere length (TL) as a potential predictive factor for chemotherapy toxicity and a prognostic marker for long-term outcome in early breast cancer (BC) patients.<br><br>METHODS: 445 BC patients were selected, diagnosed between 2007 and 2010 with early BC and treated with (neo)adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) or with FEC and Docetaxel (FEC-D). RT-qPCR was performed on germline DNA samples collected at diagnosis before any treatment, to measure mean leukocyte TL. Uni- and multivariable logistic regression or Cox proportional hazard regression analyses were carried out to assess correlation between baseline TL and toxicity parameters (derived from the medical chart) or longer-term outcome.<br><br>RESULTS: Baseline TL correlated with age as expected (p&#xa0;=&#xa0;0.005), but not with febrile neutropenia (n&#xa0;=&#xa0;97), left ventricular ejection fraction >10% decrease (n&#xa0;=&#xa0;17) nor other toxicity endpoints measured (all p&#xa0;>&#xa0;0.05). TL was neither associated with overall survival, breast cancer specific survival or distant disease-free survival (all p&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: Baseline TL is not associated with chemotherapy-related toxicity nor long-term outcome in BC patients.}, }
@article {pmid36218957, year = {2023}, author = {Vaquero-Sedas, MI and Vega-Palas, MA}, title = {Epigenetic nature of Arabidopsis thaliana telomeres.}, journal = {Plant physiology}, volume = {191}, number = {1}, pages = {47-55}, pmid = {36218957}, issn = {1532-2548}, mesh = {*Arabidopsis/genetics ; Epigenesis, Genetic ; Telomere/genetics ; Heterochromatin/genetics ; }, abstract = {The epigenetic features of defined chromosomal domains condition their biochemical and functional properties. Therefore, there is considerable interest in studying the epigenetic marks present at relevant chromosomal loci. Telomeric regions, which include telomeres and subtelomeres, have been traditionally considered heterochromatic. However, whereas the heterochromatic nature of subtelomeres has been widely accepted, the epigenetic status of telomeres remains controversial. Here, we studied the epigenetic features of Arabidopsis (Arabidopsis thaliana) telomeres by analyzing multiple genome-wide ChIP-seq experiments. Our analyses revealed that Arabidopsis telomeres are not significantly enriched either in euchromatic marks like H3K4me2, H3K9ac, and H3K27me3 or in heterochromatic marks such as H3K27me1 and H3K9me2. Thus, telomeric regions in Arabidopsis have a bimodal chromatin organization with telomeres lacking significant levels of canonical euchromatic and heterochromatic marks followed by heterochromatic subtelomeres. Since heterochromatin is known to influence telomere function, the heterochromatic modifications present at Arabidopsis subtelomeres could play a relevant role in telomere biology.}, }
@article {pmid36216345, year = {2022}, author = {Baser, E and Inandiklioglu, N and Aydogan Kırmızı, D and Ercan, F and Caniklioğlu, A and Kara, M and Onat, T and Yalvac, ES}, title = {Placental and Umbilical Cord Blood Oxidative Stress Level and Telomere Homeostasis in Early Onset Severe Preeclampsia.}, journal = {Zeitschrift fur Geburtshilfe und Neonatologie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-1938-0010}, pmid = {36216345}, issn = {1439-1651}, abstract = {OBJECTIVE: Although the etiopathogenesis of preeclampsia (PE) is unknown, evidence suggests that it may be associated with increased oxidative stress. Studies have shown that oxidative stress can affect DNA fragments called telomeres. However, the interactions of PE, oxidative stress, and telomere length are not clearly known. This study aims to evaluate the oxidative/anti-oxidative stress balance in the placenta and umbilical cord and examine the effect of oxidative stress on telomeres.<br><br>MATERIALS-METHOD: Cord blood and placental samples were collected from 27 pregnant women with severe PE (28[0/7]-33[6/7] gestational weeks) and 53 healthy pregnant women. Telomere length (TL) was measured by real-time PCR in the cord blood and placenta tissue. Total antioxidant status (TAS) and total oxidant status (TOS) levels were measured in the cord blood and placenta tissue using a colorimetric method.<br><br>RESULTS: No significant differences were found between groups regarding age, BMI, gravida, parity, and newborn gender (p>0.05). Cord blood and placental TL of PE patients were significantly shorter than the control group, while cord blood and placental TAS and TOS levels were higher (p<0.05). The results of a multivariate logistic regression analysis showed that the level of placental TOS in PE patients (OR=1.212, 95% CI=1.068-1.375) was an independent risk factor affecting PE.<br><br>CONCLUSION: This study found that oxidative stress is an independent risk factor in the development of PE and shortens TL in both placental and umbilical cord blood. Future research on telomere homeostasis may offer a new perspective for the treatment of PE.}, }
@article {pmid36214766, year = {2022}, author = {Liang, Z and Saugar, EE and Alamian, A and Ferreira, T and Downs, CA}, title = {Changes in Telomere Length and Indicators of Oxidative Stress in Critically Ill Mechanically Ventilated Adults - A Pilot Study.}, journal = {Biological research for nursing}, volume = {}, number = {}, pages = {10998004221133395}, doi = {10.1177/10998004221133395}, pmid = {36214766}, issn = {1552-4175}, abstract = {BACKGROUND: Telomeres are structures at the end of chromosomes that shorten with each cell division. The purpose of this pilot project is to report changes in telomere length (T/S ratio), indicators of oxidative stress (serum protein carbonyl, vitamin C, GSH:GSSG, and total antioxidant capacity) from Intensive Care Unit (ICU) admission to ICU discharge, and to explore their association with ICU-related morbidities among critically ill mechanically ventilated adults.<br><br>METHODS: Blood was collected from mechanically ventilated patients (n = 25) at enrollment and within 48 hours of ICU discharge. Telomere length from peripheral blood mononuclear cells (PBMCs) was determined using RTqPCR. ELISAs were used to measure indicators of oxidative stress. Descriptive analysis, paired t-tests, and Pearson's correlations were performed.<br><br>RESULTS: Mean age was 62.0 &#xb1; 12.3&#xa0;years, 28.6% were male, and 76.2% were White with disease severity using APACHE III (74.6 &#xb1; 24.6) and SOFA (7.6 &#xb1; 3.2). Mean T/S ratios shortened (ICU: 0.712, post-ICU: 0.683, p < 0.001, n = 19) and serum protein carbonyl increased (ICU: 7437&#xa0;nmol/mg &#xb1; 3328, post-ICU: 10,254&#xa0;nmol/mg &#xb1; 3962, p < 0.005) as did the oxidative stress index (protein carbonyl/GSH:GSSG, ICU: 1049.972 &#xb1; 420.923, post-ICU: 1348.971 &#xb1; 417.175, p = 0.0104). T/S ratio was positively associated with APACHE III scores (ICU: r = 0.474, post-ICU: r = 0.628, p < 0.05).<br><br>CONCLUSIONS: Pilot findings suggest that critical illness significantly correlates with telomere attrition, perhaps due to increased oxidative stress. Future larger and longitudinal studies investigating mechanisms of telomere attrition and associations with clinical outcomes are needed to identify potential modifiable factors for subsequent intervention to improve outcomes for critically ill patients.}, }
@article {pmid36214364, year = {2023}, author = {Hope, SF and Angelier, F and Ribout, C and Groffen, J and Kennamer, RA and Hopkins, WA}, title = {Warmer incubation temperatures and later lay-orders lead to shorter telomere lengths in wood duck (Aix sponsa) ducklings.}, journal = {Journal of experimental zoology. Part A, Ecological and integrative physiology}, volume = {339}, number = {1}, pages = {101-111}, doi = {10.1002/jez.2659}, pmid = {36214364}, issn = {2471-5646}, mesh = {Animals ; *Ducks/genetics ; Temperature ; *Embryonic Development/physiology ; Hot Temperature ; Telomere ; }, abstract = {The environment that animals experience during development shapes phenotypic expression. In birds, two important aspects of the early-developmental environment are lay-order sequence and incubation. Later-laid eggs tend to produce weaker offspring, sometimes with compensatory mechanisms to accelerate their growth rate to catch-up to their siblings. Further, small decreases in incubation temperature slow down embryonic growth rates and lead to wide-ranging negative effects on many posthatch traits. Recently, telomeres, noncoding DNA sequences at the end of chromosomes, have been recognized as a potential proxy for fitness because longer telomeres are positively related to lifespan and individual quality in many animals, including birds. Although telomeres appear to be mechanistically linked to growth rate, little is known about how incubation temperature and lay-order may influence telomere length. We incubated wood duck (Aix sponsa) eggs at two ecologically-relevant temperatures (34.9°C and 36.2°C) and measured telomere length at hatch and 1 week after. We found that ducklings incubated at the lower temperature had longer telomeres than those incubated at the higher temperature both at hatch and 1 week later. Further, we found that later-laid eggs produced ducklings with shorter telomeres than those laid early in the lay-sequence, although lay-order was not related to embryonic developmental rate. This study contributes to our broader understanding of how parental effects can affect telomere length early in life. More work is needed to determine if these effects on telomere length persist until adulthood, and if they are associated with effects on fitness in this precocial species.}, }
@article {pmid36213488, year = {2022}, author = {Bürgin, D and Clemens, V and Varghese, N and Eckert, A and Huber, M and Bruttin, E and Boonmann, C and Unternährer, E and O'Donovan, A and Schmid, M}, title = {Adverse and traumatic exposures, posttraumatic stress disorder, telomere length, and hair cortisol - Exploring associations in a high-risk sample of young adult residential care leavers.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {26}, number = {}, pages = {100524}, pmid = {36213488}, issn = {2666-3546}, abstract = {BACKGROUND: Childhood adversities (CAs), potentially traumatic exposures (PTEs), and posttraumatic stress disorder (PTSD) are known to increase the risk for poor health outcomes, including diseases of aging and early mortality. Telomere length (TL) and hair cortisol concentrations (HCC) are biomarkers known to be associated with CA and PTEs, and PTSD, but there is considerable heterogeneity in findings.<br><br>OBJECTIVES: This study aims to investigate the association of CAs, PTEs, and PTSD with TL and HCC in a high-risk sample of young adults who were previously placed in youth residential care institutions throughout Switzerland.<br><br>METHOD: Our sample includes 130 participants (30.8% women, M Age&#xa0;=&#xa0;26.5&#xa0;&#xb1;&#xa0;3.7 years) with previous youth residential care placements (MPlacements=&#xa0;3.9). CAs and PTEs, as well as PTSD, were assessed with self-reported questionnaires and semi-structured clinical interviews. Immune cell TL was measured with quantitative polymerase chain reaction (qPCR) in whole blood. Hair samples were collected for HCC measurement and assayed with high-sensitivity ELISA. Multivariate regression models were fitted to describe the associations between CAs, PTEs, and PTSD with TL and HCC, adjusting for covariates.<br><br>RESULTS: In our high-risk sample, a higher burden of CAs, PTEs, Criterion A trauma, and PTSD was associated with longer TL. PTEs, Criterion A trauma, and PTSD were associated with lower HCC, however no significant associations between CAs and HCC were found. The magnitude of these effects varied depending on the dimensional or categorical nature of the stress-phenotype and the specific measure used.<br><br>CONCLUSIONS: Our findings are in contrast with many, but not all, previous studies of associations between adversity and both TL and HCC. For instance, our findings are in line with other studies that find a state of hypocortisolism in PTSD. Better measurement of adversities and trauma, multisystem biomarker approaches, and more research in larger high-risk samples at the upper end of the adversity-continuum is warranted.}, }
@article {pmid36210421, year = {2022}, author = {Xu, L and Qiu, Z and Cong, YS}, title = {Comparison of Telomere Length between Buccal Cells and Blood Cells.}, journal = {Bulletin of experimental biology and medicine}, volume = {173}, number = {5}, pages = {677-679}, pmid = {36210421}, issn = {1573-8221}, mesh = {*Blood Cells ; DNA/genetics ; Humans ; *Mouth Mucosa ; Reproducibility of Results ; Telomere/genetics ; Telomere Homeostasis ; }, abstract = {Telomere length (TL) in blood cells is commonly used as a proxy for TL in other tissue types. The source of DNA of adequate quality and quantity is important for TL analysis. Compared to blood cells, buccal cells easy for genomic DNA preparation would facilitate the rapid and reliable TL analysis. However, the feasibility of buccal cells for TL analysis remains yet unestablished. We characterized TL of buccal cells and blood cells collected from 52 individuals using buccal cell swabs and fingertip sticks. Relative TL (RTL) determined by quantitative PCR showed that there is a strong correlation between buccal RTL and blood RTL (r=0.877, p<0.001), suggesting that buccal cells are adequate sources of DNA for TL analysis. The validity of sampling using buccal cell swabs provides simple operation and good reproducibility for TL analysis, that overcomes the discomfort and risk of infection caused by blood sampling.}, }
@article {pmid36208022, year = {2022}, author = {Olsson, M and Bererhi, B and Miller, E and Schwartz, T and Rollings, N and Lindsay, W and Wapstra, E}, title = {Inbreeding effects on telomeres in hatchling sand lizards (Lacerta agilis): An optimal family affair?.}, journal = {Molecular ecology}, volume = {31}, number = {24}, pages = {6605-6616}, doi = {10.1111/mec.16723}, pmid = {36208022}, issn = {1365-294X}, mesh = {Pregnancy ; Animals ; Female ; Humans ; *Inbreeding ; *Lizards/genetics ; Telomere/genetics ; Telomere Shortening ; Genotype ; }, abstract = {Telomeres are nucleotide-protein caps, predominantly at the ends of Metazoan linear chromosomes, showing complex dynamics with regard to their lengthening and shortening through life. Their complexity has entertained the idea that net telomere length and attrition could be valuable biomarkers of phenotypic and genetic quality of their bearer. Intuitively, those individuals could be more heterozygous and, hence, less inbred. However, some inbred taxa have longer, not shorter, telomeres. To understand the role of inbreeding in this complex scenario we need large samples across a range of genotypes with known maternity and paternity in telomere-screened organisms under natural conditions. We assessed the effects of parental and hatchling inbreeding on telomere length in >1300 offspring from >500 sires and dams in a population of sand lizards (Lacerta agilis). Maternal and paternal ID and their interactions predict hatchling telomere length at substantial effect sizes (R[2] > .50). Deviation from mean maternal heterozygosity statistically predicts shorter offspring telomeres but this only when sibship is controlled for by paternal ID, and then is still limited (R[2] = .06). Raw maternal heterozygosity scores, ignoring absolute deviation from the mean, explained 0.07% of the variance in hatchling telomere length. In conclusion, inbreeding is not a driver of telomere dynamics in the sand lizard (Lacerta agilis) study system.}, }
@article {pmid36206470, year = {2022}, author = {Miki, A and Matsuda, Y and Aida, J and Watanabe, J and Sanada, Y and Sakuma, Y and Lefor, AK and Fukushima, N and Sata, N and Arai, T and Takubo, K and Ishiwata, T}, title = {Telomere Attrition in Intraductal Papillary Mucinous Neoplasms of the Pancreas Associated With Carcinogenesis and Aging.}, journal = {Pancreas}, volume = {51}, number = {6}, pages = {678-683}, doi = {10.1097/MPA.0000000000002081}, pmid = {36206470}, issn = {1536-4828}, mesh = {*Adenocarcinoma, Mucinous/pathology ; Aging ; Carcinogenesis ; *Carcinoma, Pancreatic Ductal/pathology ; *Carcinoma, Papillary/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Pancreas/pathology ; *Pancreatic Intraductal Neoplasms/pathology ; *Pancreatic Neoplasms/pathology ; Telomere/genetics ; }, abstract = {OBJECTIVES: It is challenging to preoperatively distinguish malignant and benign forms of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The aims of this study were to investigate whether telomere length is associated with pathological grade of IPMNs and age and to clarify the utility of telomere length as a marker to identify malignant IPMNs.<br><br>METHODS: Pancreas tissue was obtained from 28 patients after resection. We measured the telomere lengths of tumor cells in IPMNs and normal duct cells by quantitative fluorescence in situ hybridization. The association of normalized telomere-centromere ratio (NTCR) to pathological grade of IPMNs and age were determined.<br><br>RESULTS: The NTCR showed a gradual decrease with increasing pathological grade of IPMNs. The NTCR in intermediate- and high-grade dysplasia and adenocarcinoma lesions was significantly shorter than in normal pancreatic ducts (P < 0.05). In multivariate analysis, telomere length was most associated with carcinogenesis. When the cutoff value of NTCR was set to 0.74, the sensitivity for detection of high-grade dysplasia and adenocarcinoma was 82.8%, with a specificity of 87.5%.<br><br>CONCLUSIONS: Telomere shortening occurs with carcinogenesis and aging. A significant reduction of telomere length in IPMNs may be useful for surgical decision making.}, }
@article {pmid36205590, year = {2022}, author = {Madsen, T and Klaassen, M and Raven, N and Dujon, AM and Jennings, G and Thomas, F and Hamede, R and Ujvari, B}, title = {Transmissible cancer and longitudinal telomere dynamics in Tasmanian devils (Sarcophilus harrisii).}, journal = {Molecular ecology}, volume = {31}, number = {24}, pages = {6531-6540}, doi = {10.1111/mec.16721}, pmid = {36205590}, issn = {1365-294X}, mesh = {Animals ; Animals, Wild/genetics ; *Facial Neoplasms/epidemiology/genetics/pathology ; *Marsupialia/genetics ; Telomere/genetics ; }, abstract = {A plethora of intrinsic and environmental factors have been shown to influence the length of telomeres, the protector of chromosome ends. Despite the growing interest in infection-telomere interactions, there is very limited knowledge on how transmissible cancers influence telomere maintenance. An emblematic example of transmissible cancer occurs in the Tasmanian devil (Sarcophilus harrisii), whose populations have been dramatically reduced by infectious cancer cells. To investigate associations between telomere dynamics and the transmissible cancer, we used longitudinal data from a Tasmanian devil population that has been exposed to the disease for over 15 years. We detected substantial temporal variation in individual telomere length (TL), and a positive significant association between TL and age, as well as a marginally significant trend for devils with devil facial tumour disease (DFTD) having longer telomeres. A proportional hazard analysis yielded no significant effect of TL on the development of DFTD. Like previous studies, we show the complexity that TL dynamics may exhibit across the lifetime of organisms. Our work highlights the importance of long-term longitudinal sampling for understanding the effects of wildlife diseases on TL.}, }
@article {pmid36203452, year = {2022}, author = {Tomasova, K and Kroupa, M and Zinkova, A and Korabecna, M and Vymetalkova, V and Skrobanek, P and Sojka, L and Levy, M and Hemminki, K and Liska, V and Hosek, P and Kumar, R and Vodickova, L and Vodicka, P}, title = {Monitoring of telomere dynamics in peripheral blood leukocytes in relation to colorectal cancer patients' outcomes.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {962929}, pmid = {36203452}, issn = {2234-943X}, abstract = {We investigated the possible associations between leukocyte telomere length, therapy outcomes, and clinicopathological features in patients with colorectal cancer. Additionally, telomerase reverse transcriptase (TERT) expression was evaluated. Telomere length was measured using singleplex qPCR in 478 consecutive leukocyte DNA samples from 198 patients. Blood was drawn at diagnosis prior to any therapy and then at 6-month intervals for 18 months. Following diagnosis, the telomeres gradually shortened during the course of the treatment regardless of the patient's age. The most pronounced decrease was observed 12 months after the diagnosis (p < 0.0001). Based on tumor localization, the decrease in telomere length one year after the diagnosis followed different trajectories (p = 0.03). In patients treated with adjuvant therapy, telomere length correlated with the time elapsed after completion of therapy (p = 0.03). TERT expression did not correlate with the telomere length; however, it was higher in women than men (1.35-fold, 95% CI 1.11-1.65, p = 0.003) and in smokers than non-smokers (1.27-fold, 95% CI 1.01-1.61, p = 0.04). Leukocyte telomere length declines naturally during aging, but the accelerated shortening observed in our patients was age-independent. Telomere length manifestly reflected chemotherapy impact and could be linked to therapy toxicity.}, }
@article {pmid36202783, year = {2022}, author = {Piñeiro-Hermida, S and Martínez, P and Bosso, G and Flores, JM and Saraswati, S and Connor, J and Lemaire, R and Blasco, MA}, title = {Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {5656}, pmid = {36202783}, issn = {2041-1723}, mesh = {Animals ; Bleomycin/toxicity ; Female ; Fibroblasts/metabolism ; Male ; Mice ; *Pulmonary Fibrosis/chemically induced/genetics/pathology ; Telomere/metabolism ; *Telomeric Repeat Binding Protein 1/genetics ; }, abstract = {TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis.}, }
@article {pmid36202131, year = {2022}, author = {Aviv, A}, title = {The bullwhip effect, T-cell telomeres, and SARS-CoV-2.}, journal = {The lancet. Healthy longevity}, volume = {3}, number = {10}, pages = {e715-e721}, pmid = {36202131}, issn = {2666-7568}, support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; R56 AG073226/AG/NIA NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; }, mesh = {Adaptive Immunity ; Aged ; *COVID-19 ; Humans ; *SARS-CoV-2/genetics ; T-Lymphocytes ; Telomere/genetics ; }, abstract = {Both myeloid cells, which contribute to innate immunity, and lymphoid cells, which dominate adaptive immunity, partake in defending against SARS-CoV-2. In response to the virus, the otherwise slow haematopoietic production supply chain quickly unleashes its preconfigured myeloid element, which largely resists a bullwhip-like effect. By contrast, the lymphoid element risks a bullwhip-like effect when it produces T cells and B cells that are specifically designed to clear the virus. As T-cell production is telomere-length dependent and telomeres shorten with age, older adults are at higher risk of a T-cell shortfall when contracting SARS-CoV-2 than are younger adults. A poorly calibrated adaptive immune response, stemming from a bullwhip-like effect, compounded by a T-cell deficit, might thus contribute to the propensity of people with inherently short T-cell telomeres to develop severe COVID-19. The immune systems of these individuals might also generate an inadequate T-cell response to anti-SARS-CoV-2 vaccination.}, }
@article {pmid36196242, year = {2022}, author = {Wilson, C and Murnane, JP}, title = {High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells.}, journal = {NAR cancer}, volume = {4}, number = {4}, pages = {zcac029}, pmid = {36196242}, issn = {2632-8674}, abstract = {Chromosome instability (CIN) is an early step in carcinogenesis that promotes tumor cell progression and resistance to therapy. Using plasmids integrated adjacent to telomeres, we have previously demonstrated that the sensitivity of subtelomeric regions to DNA double-strand breaks (DSBs) contributes to telomere loss and CIN in cancer. A high-throughput screen was created to identify compounds that affect telomere loss due to subtelomeric DSBs introduced by I-SceI endonuclease, as detected by cells expressing green fluorescent protein (GFP). A screen of a library of 1832 biologically-active compounds identified a variety of compounds that increase or decrease the number of GFP-positive cells following activation of I-SceI. A curated screen done in triplicate at various concentrations found that inhibition of classical nonhomologous end joining (C-NHEJ) increased DSB-induced telomere loss, demonstrating that C-NHEJ is functional in subtelomeric regions. Compounds that decreased DSB-induced telomere loss included inhibitors of mTOR, p38 and tankyrase, consistent with our earlier hypothesis that the sensitivity of subtelomeric regions to DSBs is a result of inappropriate resection during repair. Although this assay was also designed to identify compounds that selectively target cells experiencing telomere loss and/or chromosome instability, no compounds of this type were identified in the current screen.}, }
@article {pmid36193690, year = {2022}, author = {Spano, L and Etain, B and Laplanche, JL and Leboyer, M and Gard, S and Bellivier, F and Marie-Claire, C}, title = {Telomere length and mitochondrial DNA copy number in bipolar disorder: A sibling study.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/15622975.2022.2131907}, pmid = {36193690}, issn = {1814-1412}, abstract = {OBJECTIVES: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences.<br><br>METHODS: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA.<br><br>RESULTS: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors.<br><br>CONCLUSIONS: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.}, }
@article {pmid36189312, year = {2022}, author = {Li, SC and Jia, ZK and Yang, JJ and Ning, XH}, title = {Telomere-related gene risk model for prognosis and drug treatment efficiency prediction in kidney cancer.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {975057}, pmid = {36189312}, issn = {1664-3224}, mesh = {*Carcinoma, Renal Cell/drug therapy/genetics/pathology ; Humans ; Immune Checkpoint Inhibitors ; *Kidney Neoplasms/drug therapy/genetics/pathology ; NIMA-Related Kinases/genetics ; Prognosis ; Protein Kinase C-theta/genetics ; Proteomics ; RNA ; Risk Factors ; Telomere/genetics ; }, abstract = {Kidney cancer is one of the most common urological cancers worldwide, and kidney renal clear cell cancer (KIRC) is the major histologic subtype. Our previous study found that von-Hippel Lindau (VHL) gene mutation, the dominant reason for sporadic KIRC and hereditary kidney cancer-VHL syndrome, could affect VHL disease-related cancers development by inducing telomere shortening. However, the prognosis role of telomere-related genes in kidney cancer has not been well discussed. In this study, we obtained the telomere-related genes (TRGs) from TelNet. We obtained the clinical information and TRGs expression status of kidney cancer patients in The Cancer Genome Atlas (TCGA) database, The International Cancer Genome Consortium (ICGC) database, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Totally 353 TRGs were differential between tumor and normal tissues in the TCGA-KIRC dataset. The total TCGA cohort was divided into discovery and validation TCGA cohorts and then using univariate cox regression, lasso regression, and multivariate cox regression method to conduct data analysis sequentially, ten TRGs (ISG15, RFC2, TRIM15, NEK6, PRKCQ, ATP1A1, ELOVL3, TUBB2B, PLCL1, NR1H3) risk model had been constructed finally. The kidney patients in the high TRGs risk group represented a worse outcome in the discovery TCGA cohort (p<0.001), and the result was validated by these four cohorts (validation TCGA cohort, total TCGA cohort, ICGC cohort, and CPTAC cohort). In addition, the TRGs risk score is an independent risk factor for kidney cancer in all these five cohorts. And the high TRGs risk group correlated with worse immune subtypes and higher tumor mutation burden in cancer tissues. In addition, the high TRGs risk group might benefit from receiving immune checkpoint inhibitors and targeted therapy agents. Moreover, the proteins NEK6, RF2, and ISG15 were upregulated in tumors both at the RNA and protein levels, while PLCL1 and PRKCQ were downregulated. The other five genes may display the contrary expression status at the RNA and protein levels. In conclusion, we have constructed a telomere-related genes risk model for predicting the outcomes of kidney cancer patients, and the model may be helpful in selecting treatment agents for kidney cancer patients.}, }
@article {pmid36186140, year = {2022}, author = {Liu, Y and Huang, Y and Liu, C and Liu, Q}, title = {Longer Leukocyte Telomere Length Increases the Risk of Atrial Fibrillation: A Mendelian Randomization Study.}, journal = {Aging and disease}, volume = {13}, number = {5}, pages = {1311-1313}, pmid = {36186140}, issn = {2152-5250}, }
@article {pmid36184605, year = {2022}, author = {Guh, CY and Shen, HJ and Chen, LW and Chiu, PC and Liao, IH and Lo, CC and Chen, Y and Hsieh, YH and Chang, TC and Yen, CP and Chen, YY and Chen, TW and Chen, LY and Wu, CS and Egly, JM and Chu, HC}, title = {XPF activates break-induced telomere synthesis.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {5781}, pmid = {36184605}, issn = {2041-1723}, mesh = {DNA ; Endonucleases/metabolism ; RNA ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; Telomere Homeostasis ; }, abstract = {Alternative Lengthening of Telomeres (ALT) utilizes a recombination mechanism and break-induced DNA synthesis to maintain telomere length without telomerase, but it is unclear how cells initiate ALT. TERRA, telomeric repeat-containing RNA, forms RNA:DNA hybrids (R-loops) at ALT telomeres. We show that depleting TERRA using an RNA-targeting Cas9 system reduces ALT-associated PML bodies, telomere clustering, and telomere lengthening. TERRA interactome reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells. One of TERRA interacting proteins, the endonuclease XPF, is highly enriched at ALT telomeres and recruited by telomeric R-loops to induce DNA damage response (DDR) independent of CSB and SLX4, and thus triggers break-induced telomere synthesis and lengthening. The attraction of BRCA1 and RAD51 at telomeres requires XPF in FANCM-deficient cells that accumulate telomeric R-loops. Our results suggest that telomeric R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.}, }
@article {pmid36182724, year = {2022}, author = {He, D and Meng, P and Li, C and Jia, Y and Wen, Y and Pan, C and Zhang, Z and Zhang, J and Zhang, H and Chen, Y and Zhao, Y and Qin, X and Cai, Q and Wei, W and Shi, S and Chu, X and Zhang, N and Zhang, F}, title = {Association between telomere length and insomnia: A mendelian randomization and colocalization study.}, journal = {Sleep medicine}, volume = {100}, number = {}, pages = {304-310}, doi = {10.1016/j.sleep.2022.09.002}, pmid = {36182724}, issn = {1878-5506}, mesh = {Female ; Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study/methods ; *Sleep Initiation and Maintenance Disorders/genetics ; Polymorphism, Single Nucleotide/genetics ; Telomere/genetics ; }, abstract = {BACKGROUND: Previous studies have suggested a potential association between sleep and telomere length (TL), but its genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between TL and insomnia.<br><br>METHODS: The genome-wide association study (GWAS) datasets of TL and insomnia-related traits were used, including insomnia, snoring, daytime dozing and napping. Based on the polygenic risk scores (PRS) of TL, linear regression and linkage disequilibrium score (LDSC) regression were used to preliminarily explore the association between TL and insomnia parameters in the UK Biobank cohort. Then, we investigated the causal association between TL and insomnia by mendelian randomization (MR) analysis and colocalization analysis.<br><br>RESULTS: In the UK Biobank cohort, the association between TL and insomnia was observed in the female samples (t&#xa0;=&#xa0;2.968, P&#xa0;=&#xa0;3.00&#xa0;&#xd7;&#xa0;10[-3]). LDSC detected a genetic correlation between short TL and insomnia (Rg&#xa0;=&#xa0;-9.27&#xa0;&#xd7;&#xa0;10[-2], P&#xa0;=&#xa0;8.00&#xa0;&#xd7;&#xa0;10[-4]). We found no evidence supporting significant causal association between insomnia and TL in IVW method (b&#xa0;=&#xa0;-5.95&#xa0;&#xd7;&#xa0;10[-3], P&#xa0;=&#xa0;0.57), with horizontal pleiotropy and heterogeneity tests indicating the validity of our MR study. Finally, rs12638862 was classified as colocalized by COLOC (PP4&#xa0;=&#xa0;0.99), and TERC may be involved in regulating the association between insomnia and TL.<br><br>CONCLUSIONS: Our study found no evidence for causal association between insomnia and TL in individuals of European ancestry. We detected a candidate gene associated with both insomnia and TL, providing novel clues for understanding the roles of this association.}, }
@article {pmid36182046, year = {2022}, author = {Hanis, F and Chung, ELT and Kamalludin, MH and Idrus, Z}, title = {Blood Profile, Hormones, and Telomere Responses: Potential Biomarkers in Horses Exhibiting Abnormal Oral Behavior.}, journal = {Journal of equine veterinary science}, volume = {118}, number = {}, pages = {104130}, doi = {10.1016/j.jevs.2022.104130}, pmid = {36182046}, issn = {0737-0806}, mesh = {Animals ; *Leptin ; *Ghrelin ; Hydrocortisone ; Creatine Kinase ; Biomarkers ; Telomere/genetics ; }, abstract = {The high prevalence of abnormal oral behavior (AOB) in working horses has been linked to management issues and the pathophysiology of this behavior remains unclear. Therefore, this study aims to elucidate the blood profile, hormones, and telomere length responses between low and high levels of AOB among different horse working groups. A total of 207 healthy horses from various breeds were initially selected from four working groups (leisure riding, equestrian, endurance, and patrolling) and observed for the time spent on AOB. Then, six horses each with higher and lower AOB than the population means were randomly selected from each of the working groups and categorized as high and low AOB horses, respectively. Blood samples were collected for hematology, biochemistry, cortisol, ghrelin, leptin, and relative telomere length analyzes. High AOB horses notably had higher values of glucose, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatine kinase (CK) compared to low AOB horses. High AOB horses also recorded higher plasma cortisol and ghrelin, but lower leptin concentrations. Among working groups, both endurance and patrolling horses presented the highest values in sodium, potassium, chloride, phosphate, ALT, and CK. While patrolling horses had the lowest levels of urea, ALP, and albumin levels, equestrian and leisure horses recorded the highest and lowest plasma cortisol and leptin concentrations, respectively. Finally, the telomere length of endurance and patrolling horses were significantly greater than leisure and equestrian horses. The present findings suggest that AOB horses had distinctive physiological characteristics that could be linked to improper diet and a demanding workload, while ghrelin and leptin hormones could be potential biomarkers for this behavior.}, }
@article {pmid36181470, year = {2023}, author = {Raftopoulou, C and Abawi, O and Sommer, G and Binou, M and Paltoglou, G and Flück, CE and van den Akker, ELT and Charmandari, E}, title = {Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {108}, number = {2}, pages = {443-452}, doi = {10.1210/clinem/dgac560}, pmid = {36181470}, issn = {1945-7197}, mesh = {Female ; Humans ; Child ; Adolescent ; Male ; *Adrenal Hyperplasia, Congenital/drug therapy/genetics/complications ; Hydrocortisone/therapeutic use ; Glucocorticoids/pharmacology/therapeutic use ; Prospective Studies ; Prednisolone/therapeutic use ; Telomere/genetics ; }, abstract = {CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids.<br><br>OBJECTIVE: To investigate LTL in children with CAH.<br><br>METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 &#xb1; 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z.<br><br>RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05).<br><br>CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.}, }
@article {pmid36177720, year = {2022}, author = {Akinnibosun, OA and Maier, MC and Eales, J and Tomaszewski, M and Charchar, FJ}, title = {Telomere therapy for chronic kidney disease.}, journal = {Epigenomics}, volume = {14}, number = {17}, pages = {1039-1054}, doi = {10.2217/epi-2022-0073}, pmid = {36177720}, issn = {1750-192X}, mesh = {Animals ; Fibrosis ; Longitudinal Studies ; Nucleoproteins/genetics ; *Renal Insufficiency, Chronic/genetics/therapy ; *Telomere/genetics ; }, abstract = {Chronic kidney disease (CKD) is estimated to affect almost 10% of individuals worldwide and is one of the leading causes of morbidity and mortality. Renal fibrosis, a central pathway in CKD progression (irrespective of etiology), is associated with shortened or dysfunctional telomeres in animal studies. Telomeres are specialized nucleoprotein structures located at the chromosome end that maintain genomic integrity. The mechanisms of associations between telomere length and CKD have not yet been fully elucidated, however, CKD patients with shorter telomere length may have decreased renal function and a higher mortality rate. A plethora of ongoing research has focused on possible therapeutic applications of telomeres with the overall goal to preserve telomere length as a therapy to treat CKD.}, }
@article {pmid36175852, year = {2022}, author = {de Oliveira, FM and Jamur, VR and Merfort, LW and Pozzo, AR and Mai, S}, title = {Three-dimensional nuclear telomere architecture and differential expression of aurora kinase genes in chronic myeloid leukemia to measure cell transformation.}, journal = {BMC cancer}, volume = {22}, number = {1}, pages = {1024}, pmid = {36175852}, issn = {1471-2407}, mesh = {Aurora Kinase A/genetics ; Blast Crisis ; Chromosome Aberrations ; *Graft vs Host Disease ; Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; *Leukemia, Myeloid ; RNA, Messenger ; Telomere/genetics ; }, abstract = {BACKGROUND: Telomere dysfunction results in aneuploidy, and ongoing chromosomal abnormalities. The three-dimensional (3D) nuclear organization of telomeres allows for a distinction between normal and tumor cells. On the other hand, aurora kinase genes (AURKA and AURKB) play an important role regulating the cell cycle. A correlation between overexpression of aurora kinase genes and clinical aggressiveness has been demonstrated in different types of neoplasias. To better understand cellular and molecular mechanisms of CML evolution, it was examined telomere dysfunction (alterations in the 3D nuclear telomere architecture), and the expression levels of AURKA and AURKB genes in two clinical distinct subgroups of CML samples, from the same patient.<br><br>METHODS: Eighteen CML patients, in total, 36 bone marrow samples (18 patients, chronic vs. accelerated/blast phase) were eligible for 3D telomeric investigations. Quantitative 3D imaging, cytologic diagnosis and cytogenetic determination of additional chromosomal abnormalities were assessed according to standard protocols.<br><br>RESULTS: Using TeloView software, two CML subgroups were defined based on their 3D telomeric profiles, reflecting the different stages of the disease (chronic vs. accelerated/blast phase). Statistical analyses showed significant differences between the CML subgroups (p&#x2009;<&#x2009;0.001). We also found that AURKA and AURKB mRNA were expressed at significantly higher levels in both CML subgroups, when compared with healthy donors. Our findings suggest that the evolution of CML progresses from a low to a high level of telomere dysfunction, that is, from an early stage to a more aggressive stage, followed by disease transformation, as demonstrated by telomere, additional chromosomal abnormalities, and gene expression profile dynamics.<br><br>CONCLUSIONS: Thus, we demonstrated that 3D telomere organization, in accordance with the genomic instability observed in CML samples were able to distinguish subgroup CML patients. Classifying CML patients based on these characteristics might represent an important strategy to define better therapeutic strategies.}, }
@article {pmid36175503, year = {2022}, author = {Bird, L}, title = {Gift of life: APC to T cell telomere transfer.}, journal = {Nature reviews. Immunology}, volume = {22}, number = {11}, pages = {653}, pmid = {36175503}, issn = {1474-1741}, mesh = {Humans ; *T-Lymphocytes ; *Telomere/genetics ; }, }
@article {pmid36175493, year = {2022}, author = {Porrazzo, A and Cipressa, F and De Gregorio, A and De Pittà, C and Sales, G and Ciapponi, L and Morciano, P and Esposito, G and Tabocchini, MA and Cenci, G}, title = {Author Correction: Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.}, journal = {Communications biology}, volume = {5}, number = {1}, pages = {1033}, doi = {10.1038/s42003-022-03984-8}, pmid = {36175493}, issn = {2399-3642}, }
@article {pmid36174712, year = {2022}, author = {Zhu, X and Fu, H and Sun, J and Di, Q and Xu, Q}, title = {N6-methyladenosine modification on Hmbox1 is related to telomere dysfunction in DEHP-induced male reproductive injury.}, journal = {Life sciences}, volume = {309}, number = {}, pages = {121005}, doi = {10.1016/j.lfs.2022.121005}, pmid = {36174712}, issn = {1879-0631}, mesh = {Animals ; Male ; Mice ; *Diethylhexyl Phthalate/toxicity ; *Telomerase/metabolism ; Telomere/genetics ; Adenosine ; Homeodomain Proteins/metabolism ; }, abstract = {AIMS: Di (2-ethylhexyl) phthalate (DEHP), as an environmental endocrine-disrupting chemical (EDC), can induce male reproductive injury. N6-methyladenosine (m6A) plays a vital role in environmental exposure-induced diseases by regulating gene expression. Therefore, we aim to investigate the role of m6A in DEHP-induced reproductive injury.<br><br>MAIN METHODS: We established an in vivo model of mice exposed to DEHP to explore the effect of DEHP on reproductive injury and m6A. To further explore the molecular mechanism of DEHP toxicity, we built a model of GC-2 cells exposed to mono-(2-ethylhexyl) phthalate (MEHP) in vitro and further silenced Mettl3 in GC-2cells. Besides, we also conducted MeRIP-qPCR and RIP assays to identify the target genes for m6A modification.<br><br>KEY FINDINGS: DEHP induced testicular injury and senescence. And telomeres shortening, reduced levels of telomere repeat-binding factor 1 (TRF1), TRF2, protection of telomeres 1 (POT1), and telomerase reverse transcriptase (TERT) can be observed in DEHP-treated testes. MEHP also induced GC-2 cellular senescence and telomere dysfunction. Besides, increased m6A mediated by METTL3 stabilized homeobox containing 1 (Hmbox1) in an m6A-dependent manner in MEHP-exposed GC-2 cells. Mettl3 knockdown led to lower m6A modification and reduced Hmbox1 stability, resulting in further shortening of telomere length.<br><br>SIGNIFICANCE: our work uncovered that DEHP led to male reproductive injury by telomere dysfunction and m6A modified Hmbox1 contributed to maintaining telomere homeostasis in this process, suggesting that accurate regulation of m6A modification level by drugs has potential value in the treatment of DEHP-induced male reproductive injury.}, }
@article {pmid36172207, year = {2022}, author = {Xia, F and Li, Q and Luo, X and Wu, J}, title = {Association between urinary metals and leukocyte telomere length involving an artificial neural network prediction: Findings based on NHANES 1999-2002.}, journal = {Frontiers in public health}, volume = {10}, number = {}, pages = {963138}, pmid = {36172207}, issn = {2296-2565}, mesh = {Adult ; Aged ; *Cadmium ; Humans ; Leukocytes/physiology ; Molybdenum ; Neural Networks, Computer ; Nutrition Surveys ; *Telomere ; }, abstract = {OBJECTIVE: Leukocytes telomere length (LTL) was reported to be associated with cellular aging and aging related disease. Urine metal also might accelerate the development of aging related disease. We aimed to analyze the association between LTL and urinary metals.<br><br>METHODS: In this research, we screened all cycles of National Health and Nutrition Examination Survey (NHANES) dataset, and download the eligible dataset in NHANES 1999-2002 containing demographic, disease history, eight urine metal, and LTL. The analysis in this research had three steps including baseline difference comparison, multiple linear regression (MLR) for hazardous urine metals, and artificial neural network (ANN, based on Tensorflow framework) to make LTL prediction.<br><br>RESULTS: The MLR results showed that urinary cadmium (Cd) was negatively correlated with LTL in the USA population [third quantile: -9.36, 95% confidential interval (CI) = (-19.7, -2.32)], and in the elderly urinary molybdenum (Mo) was positively associated with LTL [third quantile: 24.37, 95%CI = (5.42, 63.55)]. An ANN model was constructed, which had 24 neurons, 0.375 exit rate in the first layer, 15 neurons with 0.53 exit rate in the second layer, and 7 neurons with 0.86 exit rate in the third layer. The squared error loss (LOSS) and mean absolute error (MAE) in the ANN model were 0.054 and 0.181, respectively, which showed a low error rate.<br><br>CONCLUSION: In conclusion, in adults especially the elderly, the relationships between urinary Cd and Mo might be worthy of further research. An accurate prediction model based on ANN could be further analyzed.}, }
@article {pmid36169361, year = {2022}, author = {Maximov, VN and Orlov, PS and Gurazeva, AA and Melnikova, ES and Gafarov, VV and Chervova, OA and Voevoda, MI and Malyutina, SK}, title = {[The relationship between the relative length of leukocyte telomeres and mtDNA copy number and acute coronary syndrome in a 15-year follow-up.].}, journal = {Advances in gerontology = Uspekhi gerontologii}, volume = {35}, number = {3}, pages = {351-360}, pmid = {36169361}, issn = {1561-9125}, mesh = {*Acute Coronary Syndrome/diagnosis/genetics ; Aged ; Biomarkers ; DNA Copy Number Variations ; DNA, Mitochondrial/genetics ; Female ; Follow-Up Studies ; Humans ; Leukocytes ; Male ; Middle Aged ; *Myocardial Infarction ; Telomere/genetics ; }, abstract = {We studied the relationship between the leucocyte telomere length (LTL) and the copy number of mitochondrial DNA (CNmtDNA) and the development of acute coronary syndrome during 15 years of follow-up. A random population sample was examined at baseline in 2003-2005 (n=9 360, men and women 45-69 years old, Novosibirsk, the HAPIEE project) and followed-up for 15 years. In the frame of nested case-control design, we selected cases - incident myocardial infarction/acute coronary syndrome (MI/ACS) among those free from baseline CVD (n=256) and sex- and age-stratified control among those free from baseline CVD and cancer and alive by the end of follow-up (n=799). The relative LTL and CNmtDNA were assessed using quantitative real-time PCR. Results. The carriers of shorter telomeres had increased 15-year risk of MI/ACS with adjusted OR=1,87 (95% CI 1,70-2,06) per 1 LTL decile independent of other factors. Fewer CNmtDNA was associated with increased risk of MI/ACS with adjusted OR=1,19 (95% CI 1,12-1,26) per 1 CNmtDNA decile. The identified associations were confirmed in tertile analysis and in stepwise analysis with continuous variables of both biomarkers. All associations persisted after adjusting for gender, age, and traditional CVD risk factors. Conclusion. The LTL and CNmtDNA were independent predictors of the 15-year risk of MI/ACS in the middle- and elderly Siberian (Caucasoid) population cohort. These findings highlight the need for further research to elucidate the mechanisms by which LTL and mtDNA copy number may affect human health.}, }
@article {pmid36168042, year = {2022}, author = {Carey, A and Niedernhofer, L and Camell, C}, title = {Telomeres are a life-extending gift.}, journal = {Nature cell biology}, volume = {24}, number = {10}, pages = {1449-1450}, pmid = {36168042}, issn = {1476-4679}, mesh = {*Telomere/genetics ; Cellular Senescence ; }, }
@article {pmid36160016, year = {2022}, author = {Kahrizi, MS and Patra, I and Jalil, AT and Achmad, H and Alesaeidi, S and Al-Gazally, ME and Alesaeidi, S}, title = {Leukocyte telomere length and obesity in children and adolescents: A systematic review and meta-analysis.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {861101}, pmid = {36160016}, issn = {1664-8021}, abstract = {Background: Several studies have revealed the negative effects of adiposity on telomere length shortening. However, the results of the studies assessing the negative relationship between obesity and leukocyte telomere length (LTL) are not consistent. This systematic review and meta-analysis are aimed to pool the results of articles assessing the relationship between obesity and LTL among children and adolescents. Methods: To retrieve the related studies, four online databases including PubMed, Embase, ProQuest, and Scopus were searched until May 2022. Observational studies evaluating the relationship between obesity and LTL among apparently healthy children and adolescents (aged ≤18 years) were included in the study. We considered the studies that had reported a mean ± standard deviation of LTL. The random-effects model was used to assess the pooled weighted mean difference (WMD) and a 95% confidence interval (CI). Results: The search yielded seven studies from an initial 3,403 records identified. According to the results of seven articles with 4,546 participants, obesity was associated with LTL shortening among children and adolescents (WMD = -0.081; 95% CI: -0.137 to -0.026; p = 0.004; I[2] = 99.9%). Also, no publication bias was observed. According to the results of subgrouping, significant results were only attributed to the studies conducted in Europe, with high quality scores, among overweight and obese adolescents, with a baseline LTL lower than 1, and performed in community-based school settings. Also, according to the subgrouping and meta-regression results, the obesity definition criteria and baseline LTL were the possible sources of between-study heterogeneity. Conclusion: We observed shorter LTL among overweight and obese children and adolescents. To obtain more reliable results, further longitudinal prospective studies with large sample sizes and more consistent and accurate definitions of obesity are required.}, }
@article {pmid36159052, year = {2022}, author = {Krishna, M and Shetty, A and Manjappa, AB and Shetty, V and Hegde, MN and Kumar, BM}, title = {Comparative characterization and analysis of telomere length in stem cells derived from deciduous and permanent teeth.}, journal = {Dental research journal}, volume = {19}, number = {}, pages = {64}, pmid = {36159052}, issn = {1735-3327}, abstract = {BACKGROUND: Understanding the influence of age on growth kinetics and telomere length in dental stem cells is essential for the successful development of cell therapies. Hence, the present study compared the basic cellular and phenotypical characteristics of stem cells from human exfoliated deciduous teeth (SHEDs) and dental pulp stem cells (DPSCs) of permanent teeth and their telomere lengths using quantitative real-time polymerase chain reaction.<br><br>MATERIALS AND METHODS: The study is an in vitro original research article. Primary cultures of SHED and DPSCs (n = 6 each) were successfully established in vitro, and the parameters analyzed were the morphology, viability, proliferation rate, population doubling time (PDT), phenotypic markers expression, and the relative telomere lengths. Data were analyzed by analysis of variance and P < 0.05 was considered statistically significant.<br><br>RESULTS: SHED and DPSCs exhibited a small spindle-shaped fibroblast-like morphology with >90% viability. The proliferation assay showed that the cells had a typical growth pattern. The PDT values of SHED and DPSCs were 29.03 &#xb1; 9.71 h and 32.05 &#xb1; 9.76 h, respectively. Both cells were positive for surface markers CD29, CD44, and CD90. However, they were negative for CD45 and human leukocyte antigen DR. Although the differences in relative telomere lengths between the individual cell lines of SHED and DPSCs were observed, no significant (P > 0.05) variations were found for the mean T/S ratios of both the cells.<br><br>CONCLUSION: SHED and DPSCs displayed similar morphology, proliferation rates, and phenotypic features. The relative telomere lengths were slightly shorter in DPSCs than SHED, but the values were not significantly different. Thus, SHED and DPSCs can be considered as recognized sources for regenerative applications in dentistry.}, }
@article {pmid36153564, year = {2022}, author = {Meeser, A and Bartenhagen, C and Werr, L and Hellmann, AM and Kahlert, Y and Hemstedt, N and Nürnberg, P and Altmüller, J and Ackermann, S and Hero, B and Simon, T and Peifer, M and Fischer, M and Rosswog, C}, title = {Reliable assessment of telomere maintenance mechanisms in neuroblastoma.}, journal = {Cell &amp; bioscience}, volume = {12}, number = {1}, pages = {160}, pmid = {36153564}, issn = {2045-3701}, abstract = {BACKGROUND: Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved.<br><br>METHODS: Whole genome sequencing (WGS) data of 68 primary neuroblastoma samples were analyzed. Telomere length was calculated from WGS data or by telomere restriction fragment analysis (n&#x2009;=&#x2009;39). ALT was assessed by C-circle assay (CCA, n&#x2009;=&#x2009;67) and detection of ALT-associated PML nuclear bodies (APB) by combined fluorescence in situ hybridization and immunofluorescence staining (n&#x2009;=&#x2009;68). RNA sequencing was performed (n&#x2009;=&#x2009;64) to determine expression of TERT and telomeric long non-coding RNA (TERRA). Telomerase activity was examined by telomerase repeat amplification protocol (TRAP, n&#x2009;=&#x2009;15).<br><br>RESULTS: Tumors were considered as telomerase-positive if they harbored a TERT rearrangement, MYCN amplification or high TERT expression (45.6%, 31/68), and ALT-positive if they were positive for APB and CCA (19.1%, 13/68). If all these markers were absent, tumors were considered TMM-negative (25.0%, 17/68). According to these criteria, the majority of samples were classified unambiguously (89.7%, 61/68). Assessment of additional ALT-associated parameters clarified the TMM status of the remaining seven cases with high likelihood: ALT-positive tumors had higher TERRA expression, longer telomeres, more telomere insertions, a characteristic pattern of telomere variant repeats, and were associated with ATRX mutations.<br><br>CONCLUSIONS: We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.}, }
@article {pmid36151328, year = {2023}, author = {Revy, P and Kannengiesser, C and Bertuch, AA}, title = {Genetics of human telomere biology disorders.}, journal = {Nature reviews. Genetics}, volume = {24}, number = {2}, pages = {86-108}, pmid = {36151328}, issn = {1471-0064}, support = {R01 HL131744/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Telomere/genetics/metabolism ; Aging/genetics ; Telomere Homeostasis ; Genomic Instability ; Biology ; *Telomerase/genetics ; }, abstract = {Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.}, }
@article {pmid36146670, year = {2022}, author = {Wight, DJ and Aimola, G and Beythien, G and Flamand, L and Kaufer, BB}, title = {Impact of Host Telomere Length on HHV-6 Integration.}, journal = {Viruses}, volume = {14}, number = {9}, pages = {}, pmid = {36146670}, issn = {1999-4915}, support = {Stg 677673/ERC_/European Research Council/International ; }, mesh = {Child ; HeLa Cells ; *Herpesvirus 6, Human/genetics ; Humans ; In Situ Hybridization, Fluorescence ; *Roseolovirus Infections/genetics ; Telomere ; Virus Integration ; }, abstract = {Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration.}, }
@article {pmid36145097, year = {2022}, author = {Ogłuszka, M and Lipiński, P and Starzyński, RR}, title = {Effect of Omega-3 Fatty Acids on Telomeres-Are They the Elixir of Youth?.}, journal = {Nutrients}, volume = {14}, number = {18}, pages = {}, pmid = {36145097}, issn = {2072-6643}, mesh = {Animals ; Cellular Senescence ; Cross-Sectional Studies ; *Fatty Acids, Omega-3/pharmacology ; Humans ; Inflammation ; Rats ; *Telomere ; Telomere Shortening ; }, abstract = {Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres-the food compound's ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length.}, }
@article {pmid36143917, year = {2022}, author = {Liutkeviciene, R and Mikalauskaite, R and Gedvilaite, G and Glebauskiene, B and Kriauciuniene, L and Žemaitienė, R}, title = {Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {58}, number = {9}, pages = {}, pmid = {36143917}, issn = {1648-9144}, mesh = {Adult ; Aged ; Case-Control Studies ; DNA, Mitochondrial/genetics ; Female ; Humans ; Leukocytes ; Male ; *Optic Atrophy, Hereditary, Leber/diagnosis/genetics/therapy ; *Telomerase/genetics ; Telomere/genetics ; }, abstract = {Background and Objectives: To evaluate the association of relative leukocyte telomere length (RLTL) and telomerase complex regulatory markers with Leber's hereditary optic neuropathy (LHON). Material and Methods: A case-control study was performed in patients with LHON (≥18 years) and healthy subjects. The diagnosis of LHON was based on a genetic blood test (next-generation sequencing with Illumina MiSeq, computer analysis: BWA2.1 Illumina BaseSpace, Alamut, and mtDNA Variant analyzer 1000 were performed) and diagnostic criteria approved by the LHON disease protocol. Statistical analysis was performed using the standard statistical software package, IBM SPSS Statistics 27. Statistically significant results were considered when p < 0.05. Results: Significantly longer RLTL was observed in LHON patients than in healthy controls (p < 0.001). RLTL was significantly longer in women and men with LOHN than in healthy women and men in the control group (p < 0.001 and p = 0.003, respectively). In the elderly group (>32 years), RLTL was statistically significantly longer in LHON patients compared with healthy subjects (p < 0.001). The GG genotype of the TERC rs12696304 polymorphism was found to be statistically significantly higher in the LHON group (p = 0.041), and the C allele in the TERC rs12696304 polymorphism was found to be statistically significantly less common in the LHON group (p < 0.001). The RLTL of LHON patients was found to be statistically significantly longer in the TERC rs12696304 polymorphism in all tested genotypes (CC, p = 0.005; CG, p = 0.008; GG, p = 0.025), TEP1 rs1760904 polymorphism in the GA genotype (p < 0.001), and TEP1 gene rs1713418 in the AA and AG genotypes (p = 0.011 and p < 0.001, respectively). Conclusions: The RLTL in LHON patients was found to be longer than in healthy subjects regardless of treatment with idebenone. The TERC rs12696304 polymorphism, of all studied polymorphisms, was the most significantly associated with changes in LHON and telomere length.}, }
@article {pmid36140830, year = {2022}, author = {Jenner, LP and Peska, V and Fulnečková, J and Sýkorová, E}, title = {Telomeres and Their Neighbors.}, journal = {Genes}, volume = {13}, number = {9}, pages = {}, pmid = {36140830}, issn = {2073-4425}, mesh = {Base Sequence ; DNA ; *DNA, Satellite ; Humans ; Repetitive Sequences, Nucleic Acid ; *Telomere/genetics ; }, abstract = {Telomeres are essential structures formed from satellite DNA repeats at the ends of chromosomes in most eukaryotes. Satellite DNA repeat sequences are useful markers for karyotyping, but have a more enigmatic role in the eukaryotic cell. Much work has been done to investigate the structure and arrangement of repetitive DNA elements in classical models with implications for species evolution. Still more is needed until there is a complete picture of the biological function of DNA satellite sequences, particularly when considering non-model organisms. Celebrating Gregor Mendel's anniversary by going to the roots, this review is designed to inspire and aid new research into telomeres and satellites with a particular focus on non-model organisms and accessible experimental and in silico methods that do not require specialized equipment or expensive materials. We describe how to identify telomere (and satellite) repeats giving many examples of published (and some unpublished) data from these techniques to illustrate the principles behind the experiments. We also present advice on how to perform and analyse such experiments, including details of common pitfalls. Our examples are a selection of recent developments and underexplored areas of research from the past. As a nod to Mendel's early work, we use many examples from plants and insects, especially as much recent work has expanded beyond the human and yeast models traditional in telomere research. We give a general introduction to the accepted knowledge of telomere and satellite systems and include references to specialized reviews for the interested reader.}, }
@article {pmid36139914, year = {2022}, author = {Konstantinidou, F and Budani, MC and Marconi, GD and Gonnella, F and Sarra, A and Trubiani, O and Stuppia, L and Tiboni, GM and Gatta, V}, title = {The Aftermath of Long-Term Cigarette Smoking on Telomere Length and Mitochondrial DNA Copy Number in Human Cumulus Cells Prior to In Vitro Fertilization-A Pilot Study.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {36139914}, issn = {2076-3921}, abstract = {Cigarette smoking among women of reproductive age is known to take a toll on systemic health and fertility potential by severely impacting ovarian tissues and cells, such as granulosa and cumulus cells (CCs). The purpose of this study was to determine the potential damage caused by tobacco smoke at a molecular level in the CCs of females who had undergone in vitro fertilization. The level of intracellular damage was determined by estimating the average telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN), as well as the expression profile of telomere maintenance genes TERF1, TERF2, POT1 and microRNAs miR-155, miR-23a and miR-185. Western blotting analysis was performed to detect consequent protein levels of TERF1, TERF2 and POT1. Our results evidenced significantly lower relative TL and mtDNA-CN and a down-regulation pattern for all three described genes and corresponding proteins in the CCs of smokers compared with controls (p < 0.05). No significant differences were found in the miRNAs' modulation. Combined, our data add another piece to the puzzle of the complex regulatory molecular networks controlling the general effects of tobacco smoke in CCs. This pilot study extends the until now modest number of studies simultaneously investigating the mtDNA-CN and TL pathways in the human CCs of smoking women.}, }
@article {pmid36138138, year = {2022}, author = {Chandyo, RK and Schwinger, C and Kvestad, I and Ulak, M and Ranjitkar, S and Shrestha, M and Nguyen, LV and Corona-Perez, D and DeVivo, I and Shrestha, L and Strand, TA}, title = {The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.}, journal = {Journal of exposure science &amp; environmental epidemiology}, volume = {}, number = {}, pages = {}, pmid = {36138138}, issn = {1559-064X}, abstract = {BACKGROUND: Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults.<br><br>OBJECTIVES: To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18-23 months of age among 497 children from Bhaktapur, Nepal.<br><br>METHODS: In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models.<br><br>RESULTS: Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with &#x2264;2 rooms and without separate kitchen.<br><br>SIGNIFICANCE: Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings.<br><br>IMPACT STATEMENTS: Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a "biological marker" of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking.<br><br>CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014).}, }
@article {pmid36137363, year = {2022}, author = {Verma, AK and Singh, P and Al-Saeed, FA and Ahmed, AE and Kumar, S and Kumar, A and Dev, K and Dohare, R}, title = {Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors.}, journal = {Tissue &amp; cell}, volume = {79}, number = {}, pages = {101925}, doi = {10.1016/j.tice.2022.101925}, pmid = {36137363}, issn = {1532-3072}, mesh = {Humans ; Telomere Shortening/genetics ; Telomere/genetics/metabolism ; *Telomerase/genetics/metabolism ; Aging/genetics ; *Neoplasms ; Life Style ; *Diabetes Mellitus ; RNA, Messenger ; }, abstract = {Telomeres are often considered as the 'ageing clock' that determines the lifespan at the cellular level, forming the ends of a chromosome, which shorten each time the cell divides itself to the point where they become so short the cell is unable to divide itself further. Telomere length alteration is often linked with lifestyle factors such as age, obesity, exposure to pesticides and pollution, depression, unhealthy diet, lack of exercise, and stress. The current review discusses the mechanism of telomere shortening in relation to ageing and lifestyle factors in general and its association with chronic diseases like diabetes which may influence the health and lifespan of an individual by increasing telomere shortening. Accelerated or excessive telomere shortening is also associated with the early onset of age-related disorders globally and, hence, reduced lifespan of individuals. Upregulated Telomerase activity and reactivation of telomeres is observed in > 70 % of cancer patients by TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, making it a useful marker in diagnosis and prognosis of various cancers. The study presents a systematic review of the unregulated Telomere activity with progression of various cancer and extrapolation of suitable pathways and prognostic information correlated with mRNA levels of TERT, which are critical among thymic epithelial tumors (TETs). In most cancers, unlimited proliferation is due to the reactivation of reverse transcriptase gene TERT. All these observations are comprehensively presented in the paper and might be useful for researchers working in the field of telomere dynamics and finding the correlation of age shortening with mRNA expression profiling.}, }
@article {pmid36136831, year = {2022}, author = {Chico-Sordo, L and Polonio, AM and Córdova-Oriz, I and Medrano, M and Herraiz, S and Bronet, F and García-Velasco, JA and Varela, E}, title = {Telomeres and oocyte maturation rate are not reduced by COVID-19 except in severe cases.}, journal = {Reproduction (Cambridge, England)}, volume = {164}, number = {5}, pages = {259-267}, doi = {10.1530/REP-22-0243}, pmid = {36136831}, issn = {1741-7899}, mesh = {*COVID-19 ; Female ; Humans ; Leukocytes, Mononuclear ; Male ; Oocytes ; Prospective Studies ; SARS-CoV-2 ; Telomere ; }, abstract = {IN BRIEF: COVID-19 does not affect the telomeres or fertility outcomes in mild cases. However, in women with severe symptoms, telomeres of granulosa cells are shorter, and the oocyte maturation rate is decreased.<br><br>ABSTRACT: The coronavirus SARS-CoV-2 causes COVID-19 disease and affects primarily the lungs and also other organs, causing accelerated cell aging. One of the main pathways involved in aging is telomere attrition, which ultimately leads to defective tissue regeneration and organ dysfunction. Indeed, short telomeres in aged people aggravate the COVID-19 symptoms, and COVID-19 survivors showed shorter telomeres in blood cells. The SARS-CoV-2 has been detected in testis, but the ovaries, which express the viral entry factors, have not been fully explored. Our objective was to analyze telomeres and reproductive outcomes in women who had COVID-19 and controls. In this prospective cohort study, granulosa cells (GCs) and blood were collected from 65 women. Telomere length (TL) was measured by high-throughput in situ hybridization. Mean TL of GCs and peripheral blood mononuclear cells (PBMCs) was alike in control and mild cases. However, mean TL of GCs was lower in severe cases compared to controls (P = 0.017). Control and COVID groups had similar ovarian reserve and number of total oocytes after puncture. However, the oocyte maturation rate was lower in severe cases (P = 0.018). Interestingly, a positive correlation between the oocyte maturation rate and TL of GCs was found in the control group (P = 0.024). Our findings point to a potential impact of the coronavirus infection on telomeres and reproductive outcomes in severe cases. This might be considered upon possible new SARS-CoV threats, to favor treatments that enhance oocyte maturation in women severely affected by coronavirus undergoing ART.}, }
@article {pmid36130485, year = {2022}, author = {McKinney, AM and Mathur, R and Stevers, NO and Molinaro, AM and Chang, SM and Phillips, JJ and Costello, JF}, title = {GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.}, journal = {Cell reports}, volume = {40}, number = {12}, pages = {111344}, pmid = {36130485}, issn = {2211-1247}, support = {F31 CA243187/CA/NCI NIH HHS/United States ; P01 CA118816/CA/NCI NIH HHS/United States ; P50 CA097257/CA/NCI NIH HHS/United States ; R01 CA244838/CA/NCI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/metabolism ; Adenosine Monophosphate ; ErbB Receptors/genetics/metabolism ; GA-Binding Protein Transcription Factor/metabolism ; *Glioblastoma/genetics ; Humans ; Mutation/genetics ; Oncogenes ; RNA, Messenger ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; }, abstract = {Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling.}, }
@article {pmid36130216, year = {2022}, author = {Seo, B and Yang, K and Kahe, K and Qureshi, AA and Chan, AT and De Vivo, I and Cho, E and Giovannucci, EL and Nan, H}, title = {Association of omega-3 and omega-6 fatty acid intake with leukocyte telomere length in US males.}, journal = {The American journal of clinical nutrition}, volume = {116}, number = {6}, pages = {1759-1766}, pmid = {36130216}, issn = {1938-3207}, support = {U01 CA167552/GF/NIH HHS/United States ; }, mesh = {Male ; Humans ; Cross-Sectional Studies ; *Telomere ; Case-Control Studies ; Follow-Up Studies ; Leukocytes ; *Fatty Acids, Omega-3/pharmacology ; Fatty Acids, Omega-6 ; Fatty Acids ; }, abstract = {BACKGROUND: Omega-3 (n-3) and omega-6 (n-6) fatty acids may contribute to oxidative stress and inflammation, which are related to telomere shortening. Evidence supporting an association between intake of n-3 or n-6 fatty acids and leukocyte telomere length (LTL) in males has been limited.<br><br>OBJECTIVES: We conducted a cross-sectional study to examine the associations of total or individual n-3 or total n-6 fatty acid intake with LTL in US males.<br><br>METHODS: We included 2,494 US males with LTL measurement from 4 nested case-control studies within the Health Professionals Follow-Up Study. Individuals with previous histories of cancers, diabetes, and cardiovascular diseases at or before blood collection were excluded. Blood collection was performed between 1993 and 1995, and relevant information including n-3 and n-6 intake was collected in 1994 by questionnaire. The LTL was log-transformed and Z scores of the LTL were calculated for statistical analyses by standardizing the LTL in comparison with the mean within each selected nested case-control study.<br><br>RESULTS: We found that consumption of DHA (22:6n-3) was positively associated with LTL. In the multivariable-adjusted model, compared with individuals who had the lowest intake of DHA (i.e., first quartile group), the percentage differences (95% CIs) of LTL were -3.7 (-13.7, 7.5), 7.0 (-4.3, 19.7), and 8.2 (-3.5, 21.3) for individuals in the second, third, and fourth quartiles of consumption, respectively (P-trend&#xa0;=&#xa0;0.0498). We did not find significant associations between total n-3 or total n-6 fatty acid intakes and LTL. In addition, we found that males who consumed canned tuna had longer LTL than those who did not; in the multivariable-adjusted model, the percentage difference of LTL was 10.5 (95% CI: 1.3, 20.4) (P&#xa0;=&#xa0;0.02).<br><br>CONCLUSIONS: Our results suggest that higher intakes of DHA and canned tuna consumption are associated with longer LTL.}, }
@article {pmid36126117, year = {2022}, author = {Foley, JF}, title = {Telomeres to go.}, journal = {Science signaling}, volume = {15}, number = {752}, pages = {eade9136}, doi = {10.1126/scisignal.ade9136}, pmid = {36126117}, issn = {1937-9145}, mesh = {*Cellular Senescence/genetics ; *Telomere/genetics ; }, abstract = {By acquiring telomeres from antigen-presenting cells, some T cells are protected from senescence.}, }
@article {pmid36125668, year = {2023}, author = {Tian, C and Heng, D and Zhao, N and Liu, L and Sheng, X and Chen, J and Liu, L}, title = {Short telomeres impede germ cell specification by upregulating MAPK and TGFβ signaling.}, journal = {Science China. Life sciences}, volume = {66}, number = {2}, pages = {324-339}, pmid = {36125668}, issn = {1869-1889}, abstract = {Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably, elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Re-elongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.}, }
@article {pmid36125233, year = {2022}, author = {Park, HS and Son, BR and Kwon, J}, title = {Usefulness of Genetic Aberration and Shorter Telomere Length in Myelodysplastic Syndrome: A Pilot Study.}, journal = {Laboratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/labmed/lmac100}, pmid = {36125233}, issn = {1943-7730}, abstract = {OBJECTIVE: We aimed to evaluate the clinical usefulness of genetic aberration and shorter telomere length (TL) in individuals with myelodysplastic syndrome (MDS).<br><br>METHODS: A targeted sequencing panel with 49 genes and TL measurement by quantitative real-time polymerase chain reaction were performed for 46 subjects.<br><br>RESULTS: According to the revised International Prognostic Scoring System (IPSS-R) subtypes, the mutation frequency was 33.3%, 57.9%, and 100% in the very low/low, intermediate, and very high/high risk groups, respectively. A shorter telomere was detected in 43.5%. We defined group 1 as IPSS-R-high or -very high risk, group 2 as having 1 or more genetic aberrations, group 3 as having a shorter TL, and group 4 as having a longer TL than the age-matched reference. Group 1 and group 2 showed an adverse prognosis. The TL was not strongly correlated with MDS prognosis. However, it may be related to a poor long-term prognosis.<br><br>CONCLUSION: Genetic variation and shorter TL may be helpful in reclassifying non-high-risk groups.}, }
@article {pmid36122232, year = {2022}, author = {Silva, B and Arora, R and Azzalin, CM}, title = {The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {39}, pages = {e2208669119}, pmid = {36122232}, issn = {1091-6490}, mesh = {DNA ; Endonucleases/metabolism ; Humans ; *RNA, Long Noncoding ; *Telomerase/genetics ; Telomere/genetics/metabolism ; }, abstract = {A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.}, }
@article {pmid36121249, year = {2022}, author = {Sharqawi, M and Hantisteanu, S and Bilgory, A and Aslih, N and Shibli Abu Raya, Y and Atzmon, Y and Estrada, D and Limonad, O and Meisel-Sharon, S and Shalom-Paz, E}, title = {The Impact of Lifestyle on Sperm Function, Telomere Length, and IVF Outcomes.}, journal = {American journal of men's health}, volume = {16}, number = {5}, pages = {15579883221119931}, pmid = {36121249}, issn = {1557-9891}, mesh = {Female ; Fertilization in Vitro ; Humans ; Life Style ; Male ; Pregnancy ; *Semen ; *Sperm Motility ; Spermatozoa ; Telomere ; }, abstract = {Many risk factors can potentially influence sperm quality. Telomeres confer stability on the chromosome and their dysfunction has been implicated in conditions such as cancer, aging, and lifestyle. The impact of lifestyle on sperm cell telomeres is unclear. The objectives of this study were to evaluate the impact of lifestyle behaviors on telomere length in sperm and to follow the correlation with pregnancy outcomes in patients undergoing in vitro fertilization (IVF). In this prospective observational study, sperm was analyzed for telomere length (TL). Men were asked to report lifestyle behaviors including occupation (physical or sedentary), smoking duration and amount, physical activity, dietary habits, and where they keep their cellular phone (bag, pants, or shirt pocket). Correlations among semen analysis, TL, men's habits, and embryo quality and pregnancy outcomes were evaluated. Among 34 patients recruited, 12 had longer TL and 13 shorter TL. Sperm motility was negatively correlated with TL (Pearson correlation = -.588, p = .002). Smoking adversely affected native sperm motility (53% motility in nonsmokers vs. 37% in smokers; p = .006). However, there was no significant impact on TL. The group with longer telomeres demonstrated significant association with healthy diet (10/12 vs. 6/13; p = .05) and a trend toward more sports activity, weekly (16/84 vs. 7/91; p = .04) compared with the shorter telomeres group. This study suggests that lifestyle, healthy diet, and sports activity are associated with long telomeres in sperm. Sperm quality is also influenced by patients' habits. The study strongly recommends maintaining a healthy lifestyle to preserve general health and fertility.}, }
@article {pmid36119151, year = {2022}, author = {Kazantseva, AV and Davydova, YD and Enikeeva, RF and Mustafin, RN and Lobaskova, MM and Malykh, SB and Khusnutdinova, EK}, title = {Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency.}, journal = {Russian journal of genetics}, volume = {58}, number = {9}, pages = {1135-1144}, pmid = {36119151}, issn = {1022-7954}, abstract = {The changes in the telomere length caused by the terminal underreplication in the existing literature are related to depressive disorders. However, the use of the telomere length as a biomarker of depressive states is ambiguous, which is due to the effect of various environmental factors on both the psychoemotional state and cellular aging of an organism. In order to identify the possible use of the relative telomere length (RTL) measured in peripheral blood leukocytes as a biomarker of enhanced liability to depression prior to the clinical symptoms, as well as to determine the link between telomere length, sociodemographic factors, allelic variants of the genes involved in the regulation of telomere elongation, and depression level, the association analysis of reverse transcriptase (TERT rs7726159), telomerase RNA component (TERC rs1317082), and the CST complex encoding protein (OBFC1 rs2487999) gene polymorphisms was performed with RTL and depression level in mentally healthy individuals (N = 1065) aged 18-25 years. Together with genetic variants, the examined regression models included various sociodemographic parameters as predictors. As a result of statistical analysis, we failed to observe the association between RTL and individual differences in depression level in the studied sample. Nevertheless, multiple regression analysis allowed us to construct a statistically significant model of individual variance in RTL (P = 4.3е-4; r [2] = 0.018), which included rs7726159 in the TERT gene (P = 0.020; β = 0.078) and such environmental predictors as age (P = 0.001; β = -0.027) and place of residence in childhood (urban/rural area) (P = 0.048; β = 0.063). The data obtained confirm the involvement of TERT gene variants and age in telomere length in mentally healthy individuals aged 18-25 years and indicate a negative effect of urban residency on telomere length shortening, which reflects the cellular aging of an organism.}, }
@article {pmid36116241, year = {2022}, author = {Saini, D and Jain, V and Das, B}, title = {Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India.}, journal = {Mutation research}, volume = {825}, number = {}, pages = {111797}, doi = {10.1016/j.mrfmmm.2022.111797}, pmid = {36116241}, issn = {1873-135X}, mesh = {Humans ; Male ; Shelterin Complex ; Leukocytes, Mononuclear/radiation effects ; Background Radiation ; Telomere/genetics/metabolism ; *Radiation Exposure/adverse effects ; X-ray Repair Cross Complementing Protein 1/metabolism ; Cell Cycle Proteins/metabolism ; *DNA Glycosylases/metabolism ; }, abstract = {The high level natural radiation areas (HLNRA) of Kerala coast provide unique opportunity to study the biological effect of chronic low dose ionizing radiation (LDIR) on human population below 100 mSv. The radiation level in this area varies from < 1.0-45 mGy /year due to patchy distribution of monazite in the sand, which contains [232]Th (8-10%), [238]U (0.3%), and their decay products. Telomere length attrition has been correlated to DNA damage due to genotoxic agents. The objective of the present study is to evaluate the effect of natural chronic LDIR exposure on telomere length and transcriptional response of telomere specific and DNA damage repair genes in peripheral blood mononuclear cells (PBMCs) of individuals from normal level natural radiation areas (NLNRA) and HLNRA of Kerala coast, southwest India. Blood samples were collected from 71 random male donors (24-80 years) from NLNRA (≤1.50 mGy/year; N = 19) and two HLNRA dose groups [1.51-10 mGy/year (N = 17); > 10 mGy/year, (N = 35)]. Genomic DNA was isolated from PBMCs and relative telomere length (RTL) was determined using real time q-PCR. Radio-adaptive response (RAR) study was carried out in PBMCs of 40 random males from NLNRA (N = 20) and HLNRA (>10 mGy/year; N = 20), where PBMCs were given a challenged dose of 2.0 Gy gamma radiation at 4 h. Transcriptional profile of telomere specific (TRF1, TRF2, POT1, TIN2, TPP1, RAP1), DNA damage response (RAD17, ATM, CHEK1) and base excision repair pathway (BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH, MBD4) genes were analysed at basal level and after a challenge dose of 2.0 Gy at 4 h. Our results did not show any significant effect of chronic LDR on RTL among the individuals from NLNRA and two HLNRA groups (p = 0.195). However, influence of age on RTL was clearly evident among NLNRA and HLNRA individuals. At basal level, TRF1, TRF2, TIN2, MBD4, NEIL1 and RAD17 showed significant up-regulation, whereas XRCC1 was significantly down regulated in HLNRA individuals. After a challenge dose of 2.0 Gy, significant transcriptional up-regulation was observed at telomere specific (TRF2, POT1) and BER (MBD4, NEIL1) genes in HLNRA individuals as compared to NLNRA suggesting their role in RAR. In conclusion, elevated level of natural chronic LDR exposure did not have any adverse effect on telomere length in Kerala coast. Significant transcriptional response at TRF2, MBD4 and NEIL1 at basal level and with a challenge dose of 2.0 Gy suggested their active involvement in efficient repair and telomere maintenance in individuals from HLNRA of Kerala coast.}, }
@article {pmid36110146, year = {2022}, author = {Panelli, DM and Diwan, M and Cruz, GI and Leonard, SA and Chueh, J and Gotlib, IH and Bianco, K}, title = {An exploratory analysis of leukocyte telomere length among pregnant and non-pregnant people.}, journal = {Brain, behavior, &amp; immunity - health}, volume = {25}, number = {}, pages = {100506}, pmid = {36110146}, issn = {2666-3546}, abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a biomarker that is affected by older age, psychosocial stress, and medical comorbidities. Despite the relevance of these factors to obstetric practice, little is known about LTL in pregnancy. Our study explored longitudinal LTL dynamics in pregnant and non-pregnant people.<br><br>OBJECTIVE: This pilot study compares changes in LTL between pregnant and non-pregnant people over time, explores potential correlations between LTL and mental health measures, and investigates associations between short first-trimester LTL and adverse pregnancy outcomes.<br><br>STUDY DESIGN: This was a prospective pilot cohort study of nulliparous pregnant and non-pregnant people between ages 18 and 50 who presented for care at a single institution from January to November 2020. Pregnant people were enrolled between 10 and 14 weeks gestation. Participants had two blood samples drawn for LTL; the first on the day of enrollment and the second on postpartum day 1 (pregnant cohort) or 7 months later (non-pregnant cohort). LTL was measured using quantitative PCR. The primary outcome was the difference between pregnant and non-pregnant people in LTL change between the two timepoints (basepair difference per 30-day period). Secondary outcomes included differences in responses to the Patient Health Questionnaire-9 (PHQ-9) and a survey about stress related to COVID-19. Differences in LTL were tested using t-tests and linear regression models, both crude and adjusted for age. A subgroup analysis was conducted within the pregnant cohort to examine whether shorter first-trimester LTL was associated with adverse pregnancy outcomes. We conducted t-tests to compare LTL between people with and without each categorical outcome and computed Pearson correlation coefficients between LTL and continuous outcomes such as gestational age at delivery.<br><br>RESULTS: 46 pregnant and 30 non-pregnant people were enrolled; 44 pregnant and 18 non-pregnant people completed all LTL assessments. There were no between-group differences in LTL change (-4.2&#xa0;&#xb1;&#xa0;22.2 bp per 30 days pregnant versus -6.4&#xa0;&#xb1;&#xa0;11.2 bp per 30 days non-pregnant, adjusted beta 2.1, 95% CI -9.0-13.2, p&#xa0;=&#xa0;0.60). The prevalence of depression and pandemic-related stress were both low overall. The two groups did not differ in PHQ-9 scores, and no correlations were significant between LTL and PHQ-9 scores. Among the 44 pregnant people, shorter first-trimester LTL was significantly correlated with earlier gestational age at delivery (r&#xa0;=&#xa0;0.35, p&#xa0;=&#xa0;0.02).<br><br>CONCLUSION: In this exploratory pilot cohort of reproductive-aged people with low levels of psychological stress, we described baseline changes in LTL over time in pregnant and non-pregnant participants. We found a correlation between shorter first-trimester LTL and earlier gestational age at delivery, which warrants further investigation in a larger cohort.}, }
@article {pmid36109671, year = {2022}, author = {Lanna, A and Vaz, B and D'Ambra, C and Valvo, S and Vuotto, C and Chiurchiù, V and Devine, O and Sanchez, M and Borsellino, G and Akbar, AN and De Bardi, M and Gilroy, DW and Dustin, ML and Blumer, B and Karin, M}, title = {An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.}, journal = {Nature cell biology}, volume = {24}, number = {10}, pages = {1461-1474}, pmid = {36109671}, issn = {1476-4679}, support = {110229/WT_/Wellcome Trust/United Kingdom ; MR/M003833/1/MRC_/Medical Research Council/United Kingdom ; 100262Z/12/Z/WT_/Wellcome Trust/United Kingdom ; MR/P00184X/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Telomerase/genetics/metabolism ; Immunologic Memory ; T-Lymphocytes/metabolism ; Telomere/genetics/metabolism ; Cellular Senescence/genetics ; }, abstract = {The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.}, }
@article {pmid36104328, year = {2022}, author = {Bowyer, P and Currin, A and Delneri, D and Fraczek, MG}, title = {Telomere-to-telomere genome sequence of the model mould pathogen Aspergillus fumigatus.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {5394}, pmid = {36104328}, issn = {2041-1723}, support = {208396/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {*Aspergillus fumigatus/genetics ; DNA Transposable Elements/genetics ; *Fungi ; Humans ; Sequence Analysis, DNA ; Telomere/genetics ; }, abstract = {The pathogenic fungus Aspergillus fumigatus is a major etiological agent of fungal invasive and chronic diseases affecting tens of millions of individuals worldwide. Draft genome sequences of two clinical isolates (Af293 and A1163) are commonly used as reference genomes for analyses of clinical and environmental strains. However, the reference sequences lack coverage of centromeres, an accurate sequence for ribosomal repeats, and a comprehensive annotation of chromosomal rearrangements such as translocations and inversions. Here, we used PacBio Single Molecule Real-Time (SMRT), Oxford Nanopore and Illumina HiSeq sequencing for de novo genome assembly and polishing of two laboratory reference strains of A. fumigatus, CEA10 (parental isolate of A1163) and its descendant A1160. We generated full length chromosome assemblies and a comprehensive telomere-to-telomere coverage for CEA10 and near complete assembly of A1160 including ribosomal repeats and the sequences of centromeres, which we discovered to be composed of long transposon elements. We envision these high-quality reference genomes will become fundamental resources to study A. fumigatus biology, pathogenicity and virulence, and to discover more effective treatments against diseases caused by this fungus.}, }
@article {pmid36103374, year = {2022}, author = {Barbosa, ARC and Nunes, DP and Lima, DB and Colombo, FA and Nunes, JB and Santos Orlandi, AAD and Rocha, GDS and Pereira, DS and Corona, LP and Brito, TRP}, title = {Association of Social Support Network with Telomere Length: A Cross-Sectional Study with Community-Dwelling Older Adults.}, journal = {Rejuvenation research}, volume = {25}, number = {6}, pages = {253-259}, doi = {10.1089/rej.2022.0037}, pmid = {36103374}, issn = {1557-8577}, mesh = {Humans ; Aged ; *Independent Living ; Cross-Sectional Studies ; *Activities of Daily Living ; Social Support ; Telomere ; }, abstract = {Considering that telomere length can be determined not only by issues related to cell biology but also by aspects related to social factors and environmental exposures, studies on the relationship between social aspects and telomere length can help to better understand the still scarcely known aspects of the human aging process. Thus, this research seeks to verify whether social support networks are associated with telomere length in older adults. This is a cross-sectional study conducted with 448 individuals aged at least 60 years living in the urban area of an inland Brazilian municipality. Relative quantification of telomere length was obtained through real-time qPCR. Social support was assessed through the Medical Outcomes Study Social Support Scale. Descriptive statistics and multiple logistic regression were used in data analysis. The evaluated social support networks for older adults consist in a mean of 16.4 people, and the percentage of older adults who reported up to five members in their network was 27.75%. Shorter telomere length was identified in 25% of the participants, and the older adults who reported having up to five members in their support network were more likely to have a shorter telomere length than those who reported more numerous networks (odds ratio: 1.89, p = 0.011) regardless of gender, age, household arrangement, cognitive decline, and dependence for basic and instrumental activities of daily living, which suggests that measures that stimulate the creation and maintenance of social support networks should be implemented to improve older adults' health.}, }
@article {pmid36098743, year = {2022}, author = {Liu, Z and Wei, X and Gao, Y and Gao, X and Li, X and Zhong, Y and Wang, X and Liu, C and Shi, T and Lv, J and Liu, T}, title = {Zbtb34 promotes embryonic stem cell proliferation by elongating telomere length.}, journal = {Aging}, volume = {14}, number = {17}, pages = {7126-7136}, pmid = {36098743}, issn = {1945-4589}, mesh = {Alanine/genetics ; Animals ; Cell Proliferation ; DNA ; DNA, Complementary ; *DNA, Single-Stranded ; DNA-Binding Proteins/genetics ; Embryonic Stem Cells/metabolism ; Mice ; Repressor Proteins/*metabolism ; Shelterin Complex ; Telomere/genetics/metabolism ; *Telomere-Binding Proteins/genetics/metabolism ; }, abstract = {Zbtb34 is a novel zinc finger protein, which is revealed by biological software analysis to have 3 zinc fingers, but its functions remain unknown. In this study, mouse Zbtb34 cDNA was amplified by PCR and inserted into the plasmid pEGFP-N1 to generate Zbtb34-EGFP fusion protein. The upregulation of Zbtb34 in mouse embryonic stem cells promoted telomere elongation and increased cell proliferation. In order to understand the above phenomena, the telomere co-immunoprecipitation technique was employed to investigate the relationship between Zbtb34 and telomeres. The results indicated that Zbtb34 could bind to the DNA sequences of the telomeres. Alanine substitution of the third zinc finger abolished such binding. Since Pot1 is the only protein binding to the single-stranded DNA at the end of the telomeres, we further investigated the relationship between Zbtb34 and Pot1. The results revealed that the upregulation of Zbtb34 decreased the binding of Pot1b to the telomeres. Through the upregulation of Pot1b, the binding of Zbtb34 to the telomeres was also reduced. In conclusion, we showed that the main biological function of Zbtb34 was to bind telomere DNA via its third ZnF, competing with Pot1b for the binding sites, resulting in telomere elongation and cell proliferation.}, }
@article {pmid36091172, year = {2022}, author = {Fiesco-Roa, M&#xd3; and García-de Teresa, B and Leal-Anaya, P and van 't Hek, R and Wegman-Ostrosky, T and Frías, S and Rodríguez, A}, title = {Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {949435}, pmid = {36091172}, issn = {2234-943X}, abstract = {Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.}, }
@article {pmid36087937, year = {2022}, author = {Svyryd, Y and Pascual-Ramos, V and Contreras-Yañez, I and Muñoz-Tellez, LA and Luna-Muñoz, L and López-Hernández, MA and Aguayo-Gómez, A and Mutchinick, OM}, title = {Telomeres Length Variations in a Rheumatoid Arthritis Patients Cohort at Early Disease Onset and after Follow-Up.}, journal = {Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion}, volume = {74}, number = {4}, pages = {202-211}, doi = {10.24875/RIC.22000048}, pmid = {36087937}, issn = {0034-8376}, mesh = {Humans ; *Arthritis, Rheumatoid/genetics ; Follow-Up Studies ; Telomere/genetics ; Telomere Shortening ; }, abstract = {BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial joint inflammation, progressive disability, premature immune aging, and telomere length (TL) shortening.<br><br>OBJECTIVES: The objective of the study was to study TL changes in patients at early disease onset and after follow-up.<br><br>METHODS: Relative leukocyte TL (rLTL) was measured by quantitative polymerase chain reaction (qPCR) in 88 at-admission patients (AAP) with < 1 year of symptoms onset, self-compared after follow-up, and a reference group of sex- and age-matched healthy individuals. Correlations between rLTL percentage change after variable disease exposure time (DET) and clinical laboratory disease activity markers and treatments were assessed. Non-parametrical statistics were applied, considering < 0.05 p-value significant.<br><br>RESULTS: The median (p25, p75) rLTL was lower in patients after DET (0.61, 0.49-0.70) than in AAP (0.64, 0.50-0.77), p = 0.017. Furthermore, telomeres at early stages of RA were shorter than in the reference group (0.77, 0.59-0.92; p = 0.003). HLA-DRB1*04 allele carrier status did not significantly affect rLTL at an early stage and after follow-up. The patients' rLTL shortening was mainly associated with longer at-admission telomeres (OR 16.2, 95%CI: 3.5-74.4; p < 0.0001).<br><br>CONCLUSIONS: At follow-up, RA patients showed significantly shorter rLTL than AAP, particularly in those AAP with longer telomeres, disregarding disease activity and treatments, denoting an rLTL shortening effect influenced by age, DET, and native rLTL.}, }
@article {pmid36085441, year = {2023}, author = {Qureshi, F and Aris, IM and Rifas-Shiman, SL and Perng, W and Oken, E and Rich-Edwards, J and Cardenas, A and Baccarelli, AA and Enlow, MB and Belfort, MB and Tiemeier, H}, title = {Associations of cord blood leukocyte telomere length with adiposity growth from infancy to adolescence.}, journal = {Pediatric obesity}, volume = {18}, number = {1}, pages = {e12977}, pmid = {36085441}, issn = {2047-6310}, support = {UH3 OD023286/OD/NIH HHS/United States ; T32 CA009001/CA/NCI NIH HHS/United States ; R01 HD034568/HD/NICHD NIH HHS/United States ; R03 AG067064/AG/NIA NIH HHS/United States ; R01 HD082078/HD/NICHD NIH HHS/United States ; R01 ES031259/ES/NIEHS NIH HHS/United States ; }, mesh = {Child ; Infant, Newborn ; Male ; Infant ; Adolescent ; Female ; Humans ; *Adiposity ; *Fetal Blood ; Obesity ; Body Mass Index ; Leukocytes ; Telomere ; Biomarkers ; }, abstract = {OBJECTIVE: Leukocyte telomere length (LTL) may be a biomarker for chronic disease susceptibility, but no work has tested this hypothesis directly. Our study investigated associations of LTL at birth with markers of adiposity growth that are linked with cardiometabolic health later in life.<br><br>METHODS: Participants were 375 children in Project Viva (48% female, 71% White). Body mass index (BMI) trajectories from birth to 18&#x2009;years were tracked using repeated measures of BMI collected in physical examinations and via medical records, then used to predict age (months) and magnitude (kg/m[2]) of BMI peak and rebound. LTL was measured from cord blood via duplex quantitative PCR. A binary variable indicating LTL shorter than the reference population average was the primary exposure.<br><br>RESULTS: LTL was unrelated to BMI at peak or rebound, but associations were apparent with the timing of BMI growth milestones. Short LTL was related to a later age of peak for females (&#x3b2;&#xa0;=&#xa0;0.99, 95% CI&#xa0;=&#xa0;0.16, 1.82; psex interaction &#xa0;=&#xa0;0.015) and an earlier age of rebound for both males and females (&#x3b2;combined &#xa0;=&#xa0;-5.26, 95% CI&#xa0;=&#xa0;-9.44, -1.08).<br><br>CONCLUSION: LTL at birth may be an early biomarker of altered adiposity growth. Newborn telomere biology may shed new insight into the developmental origins of health and disease.}, }
@article {pmid36078786, year = {2022}, author = {Montiel Ishino, FA and Rowan, CE and Villalobos, K and Rajbhandari-Thapa, J and Williams, F}, title = {A Time-Varying Effect Model (TVEM) of the Complex Association of Tobacco Use and Smoke Exposure on Mean Telomere Length: Differences between Racial and Ethnic Groups Assessed in the National Health and Nutrition Examination Survey.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {17}, pages = {}, pmid = {36078786}, issn = {1660-4601}, mesh = {Adult ; Aged ; *Cotinine ; Ethnicity ; Humans ; Middle Aged ; Nutrition Surveys ; Telomere ; *Tobacco Smoke Pollution ; Tobacco Use ; }, abstract = {Telomere length is affected by lifestyle and environmental factors and varies between racial and ethnic groups; however, studies are limited, with mixed findings. This study examined the effects of tobacco use and smoke exposure on mean telomere length to identify critical age periods by race/ethnicity. We used time-varying effect modeling on the National Health and Nutrition Examination Survey for continuous years 1999-2002 to observe the effects of active tobacco use and environmental tobacco smoke-measured through serum cotinine-and mean telomere length for adults 19 to 85 and older (N = 7826). Models were run for Mexican American, other Hispanic, non-Hispanic White, non-Hispanic Black, and other/multi-race categories to allow for time-varying group differences, and controlled for biological sex, socioeconomic status, education, and ever-smoker status. Serum cotinine was found to have an increasing effect on telomere length from age 37 to approximately age 74 among Mexican Americans. Among other/multi-race individuals serum cotinine was found to have a decreasing effect at approximately age 42, and among Blacks, it had an overall decreasing effect from age 61 to 78. Findings reveal a further need to focus additional support and resources to intervene regarding disparate health effects from tobacco use and environmental smoke exposure for already vulnerable groups at particular ages.}, }
@article {pmid36077523, year = {2022}, author = {Jitjumnong, M and Chalermkitpanit, P and Suantawee, T and Dechsupa, S and Vajarintarangoon, L and Honsawek, S}, title = {Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36077523}, issn = {1422-0067}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Antioxidants ; Case-Control Studies ; Humans ; *Intervertebral Disc Degeneration/genetics ; Oxidative Stress/genetics ; Telomere/genetics ; *Telomere Shortening ; }, abstract = {Lumbar disc degeneration (LDD) contributes to low back pain. This study aimed to determine relative telomere length (RTL), oxidative stress status, and antioxidant levels and examine the relationships between RTL, oxidative stress, and the severity in LDD patients. A total of 100 subjects, 50 LDD patients and 50 healthy controls, were enrolled in the case-control study. Blood leukocyte RTL was analyzed using quantitative real-time polymerase chain reaction. Lipid peroxidation was determined by malondialdehyde (MDA) assay. Plasma 8-hydroxy 2'-deoxyguanosine (8-OHdG) values were determined using enzyme-linked immunosorbent assay. Total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP) in plasma were also measured. The LDD patients had significantly shorter telomeres than the healthy controls (p = 0.04). Blood leukocyte RTL was inversely correlated with the LDD severity (r = -0.41, p = 0.005). Additionally, plasma MDA and 8-OHdG levels were markedly greater in LDD patients than in the controls (p = 0.01 and p = 0.002, respectively). Furthermore, the plasma MDA level showed a positive correlation with the radiographic severity (r = 0.49, p = 0.001). There was a positive correlation between plasma 8-OHdG and the severity (r = 0.60, p < 0.001). Moreover, plasma TAC and FRAP levels were significantly lower in LDD patients than in the controls (p = 0.04). No significant differences in plasma TAC and FRAP were observed among the three groups of LDD severity. We found that RTL was negatively correlated with the severity while plasma MDA and 8-OHdG levels were positively correlated with the severity. These findings suggest that blood leukocyte RTL, plasma MDA, and 8-OHdG may have potential as noninvasive biomarkers for the assessment of severity in LDD.}, }
@article {pmid36074986, year = {2022}, author = {Andrés, V and Díez, J}, title = {Failing Hypertensive Heart: a Question of Altered Telomere Biology?.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {79}, number = {10}, pages = {2185-2187}, doi = {10.1161/HYPERTENSIONAHA.122.19937}, pmid = {36074986}, issn = {1524-4563}, mesh = {Biology ; Heart ; *Heart Failure/genetics ; Humans ; *Hypertension/genetics ; Telomere/genetics ; }, }
@article {pmid36074951, year = {2022}, author = {Pölönen, J and Pinola, P and Ronkainen, J and Blakemore, AI and Buxton, JL and Tapanainen, JS and Franks, S and Piltonen, TT and Sebert, S and Morin-Papunen, L}, title = {Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes.}, journal = {European journal of endocrinology}, volume = {187}, number = {5}, pages = {651-661}, pmid = {36074951}, issn = {1479-683X}, mesh = {Adult ; Biomarkers ; Cohort Studies ; Cross-Sectional Studies ; DNA ; Female ; Humans ; Leukocytes ; Longitudinal Studies ; Middle Aged ; *Polycystic Ovary Syndrome/epidemiology/genetics ; Telomere ; }, abstract = {OBJECTIVE: Telomeres are DNA-protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population.<br><br>DESIGN: This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL.<br><br>METHODS: The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age.<br><br>RESULTS: Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96).<br><br>CONCLUSIONS: This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.}, }
@article {pmid36070080, year = {2022}, author = {Faingelernt, Y and Nassar, R and Ling, G and Kodman, Y and Feuerstein, T and Yerushalmi, B}, title = {Early-life liver cirrhosis and variable clinical presentation in telomere disease.}, journal = {Acta paediatrica (Oslo, Norway : 1992)}, volume = {111}, number = {12}, pages = {2416-2421}, doi = {10.1111/apa.16539}, pmid = {36070080}, issn = {1651-2227}, mesh = {Child, Preschool ; Humans ; *Telomerase/genetics/metabolism ; Telomere/genetics ; Liver Cirrhosis/genetics ; Mutation ; Phenotype ; }, abstract = {AIM: Telomeres are DNA sequences of tandem TTAGGG repeats that protect chromosome ends from degradation and instability. Constitutional loss-of-function telomerase mutations result in rapid telomere shortening, premature senescence and cell death. Liver cirrhosis is rare and has only been reported in adults. We present five family members of Bedouin-Muslim origin, all of which carry the same mutation, and yet demonstrate an extremely variable phenotypical presentation, including liver cirrhosis during early childhood.<br><br>METHODS: A multidisciplinary long-term follow-up of two healthy and three affected patients was analysed. The mutation (r.95G>C) was identified in all patients using Sanger sequencing. Telomere length samples were obtained and analysed.<br><br>RESULTS: Clinical phenotypes were extremely variable, including age at first symptoms, organ involvement, disease severity and patient prognosis. The most prominent clinical phenotype is liver involvement, including end-stage liver disease early in life, which affects three members of the family. Affected patients had markedly shorter telomeres.<br><br>CONCLUSION: We describe an unusual presentation of early liver failure in telomere disease patients. Little, if any, is known about the association between the genotype and phenotype among children with telomere disease and whether the mutation we have described (r.95G>C) is predisposed to early severe hepatic involvement.}, }
@article {pmid36069016, year = {2022}, author = {Young, RC and Westneat, DF and Vangorder-Braid, J and Sirman, AE and Siller, SJ and Kittilson, J and Ghimire, A and Heidinger, BJ}, title = {Stressors interact across generations to influence offspring telomeres and survival.}, journal = {Proceedings. Biological sciences}, volume = {289}, number = {1982}, pages = {20220868}, pmid = {36069016}, issn = {1471-2954}, mesh = {Animals ; Longevity ; *Sparrows/physiology ; Telomere ; }, abstract = {Parental stress often has long-term consequences for offspring. However, the mechanisms underlying these effects and how they are shaped by conditions offspring subsequently experience are poorly understood. Telomeres, which often shorten in response to stress and predict longevity, may contribute to, and/or reflect these cross-generational effects. Traditionally, parental stress is expected to have negative effects on offspring telomeres, but experimental studies in captive animals suggest that these effects may depend on the subsequent conditions that offspring experience. Yet, the degree to which parental stress influences and interacts with stress experienced by offspring to affect offspring telomeres and survival in free-living organisms is unknown. To assess this, we experimentally manipulated the stress exposure of free-living parent and offspring house sparrows (Passer domesticus). We found a weak, initial, negative effect of parental stress on offspring telomeres, but this effect was no longer evident at the end of post-natal development. Instead, the effects of parental stress depended on the natural sources of stress that offspring experienced during post-natal development whereby some outcomes were improved under more stressful rearing conditions. Thus, the effects of parental stress on offspring telomeres and survival are context-dependent and may involve compensatory mechanisms of potential benefit under some circumstances.}, }
@article {pmid36067971, year = {2022}, author = {Assavanopakun, P and Sapbamrer, R and Kumfu, S and Chattipakorn, N and Chattipakorn, SC}, title = {Effects of air pollution on telomere length: Evidence from in vitro to clinical studies.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {312}, number = {}, pages = {120096}, doi = {10.1016/j.envpol.2022.120096}, pmid = {36067971}, issn = {1873-6424}, mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/adverse effects/analysis ; Cellular Senescence ; Environmental Exposure/adverse effects/analysis ; Humans ; *Occupational Exposure ; Particulate Matter/analysis ; Telomere ; }, abstract = {Air pollution remains the major environmental problem globally. There is extensive evidence showing that the variety of air pollutants from environmental and occupational exposures cause adverse effects to our health. The clinical symptoms of those effects may present at a late stage, so surveillance is difficult to manage. Several biomarkers have been used for the early detection of health issues following exposure to air pollution, including the use of telomere length which indicates cellular senescence in response to oxidative stress. Oxidative stress is one of the most plausible mechanisms associated with exposure to air pollutants. Some specific contexts including age groups, gender, ethnicity, occupations, and health conditions, showed significant alterations in telomere length after exposure to air pollutants. Several reports demonstrated both negative and positive associations between telomere length and air pollution, the studies using different concentrations and exposure times to air pollution on the study of telomere lengths. Surprisingly, some studies reported that low levels of exposure to air pollutants (lower than regulated levels) caused the alterations in telomere length. Those findings suggest that telomere length could be one of most practical biomarkers in air pollution surveillance. Therefore, this review aimed to summarize and discuss the relationship between telomere length and exposure to air pollution. The knowledge from this review will be beneficial for the planning of public health to reduce health problems in the general population, particularly in vulnerable people, who still live in areas with high air pollution.}, }
@article {pmid36066716, year = {2023}, author = {Kato, TA}, title = {Nontraditional Method for Telomere Staining by PNA Probes.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2519}, number = {}, pages = {111-116}, pmid = {36066716}, issn = {1940-6029}, mesh = {DNA Probes/genetics ; In Situ Hybridization, Fluorescence/methods ; *Peptide Nucleic Acids/chemistry ; Telomere/genetics ; }, abstract = {The standard FISH uses DNA probes to hybridize to the designated complementary strands. This is DNA-DNA interaction, and it usually takes much longer time to obtain detectable signals compared to other reactions such as immunochemical reactions and simple chemical reactions. Certain proteins bind to specific DNA sequences and regulate the biological function of DNA. These DNA-binding proteins have specific domains to interact with single- or double-stranded DNA. Some of telomere proteins apparently bind to telomere sequence and form nucleoprotein complex to protect chromosome ends. Using telomere PNA probes, probes can be accumulated at the telomere sites in a non-hybridization manner. This chapter introduces nontraditional PNA telomere staining protocol without DNA-DNA hybridization to visualize telomere locations on metaphase chromosomes.}, }
@article {pmid36066715, year = {2023}, author = {Kato, TA}, title = {Telomere Aberration Detection by PNA FISH Probe.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2519}, number = {}, pages = {105-110}, pmid = {36066715}, issn = {1940-6029}, mesh = {DNA Probes ; In Situ Hybridization, Fluorescence/methods ; *Repetitive Sequences, Nucleic Acid ; *Telomere/genetics ; }, abstract = {Telomere is a structure of the end cap of chromosomes. Telomere gets shorter as cell aging and progressing cell division. Shorter telomere may cause telomere fusion, thus inducing genomic instability. Telomere dysfunction can be visualized by PNA FISH probe against telomere repeat sequence (TTAGGG)n. PNA probes have higher hybridization affinity than DNA probes. The traditional FISH or modified FISH protocol can stain telomere relatively easier than whole-chromosome painting probes. This chapter introduces PNA telomere FISH protocol to visualize telomere signals on metaphase chromosomes.}, }
@article {pmid36060975, year = {2022}, author = {Ghoussaini, R and Tamim, H and Elbejjani, M and Makki, M and Nasreddine, L and Ismaeel, H and Nasrallah, MP and Zgheib, NK}, title = {C-peptide is a predictor of telomere shortening: A five-year longitudinal study.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {978747}, pmid = {36060975}, issn = {1664-2392}, mesh = {C-Peptide ; Humans ; Longitudinal Studies ; Risk Factors ; *Telomere/genetics ; *Telomere Shortening ; }, abstract = {AIM: Relative telomere length (RTL) predicts the development of many age-related diseases. Yet, few studies have evaluated their longitudinal effect on RTL. We investigated longitudinally the association between cardiometabolic risk factors and RTL.<br><br>METHODS: This was a longitudinal study with a 5-year follow-up period, based on data collected in 2014 and 2019. Of 478 participants in 2014, 198 consented to be followed-up in 2019. The associations between RTL and risk factors were analyzed using t-test, ANOVA or simple linear regression as applicable.<br><br>RESULTS: RTL was significantly shortened after 5 years (P<0.001). Older age (P=0.018) and gender (P=0.05) were significantly associated with shorter RTL at follow-up. Higher baseline C-peptide correlated with shorter RTL (P=0.04) and shortening of RTL (P=0.03) after 5 years. Multivariate linear regression including both age and gender revealed a significant trend for C-peptide and change in RTL after 5 years (P=0.04). Interestingly, there was a trend of shorter RTL at follow-up with diabetes, though the findings were not statistically significant.<br><br>CONCLUSIONS: Higher C-peptide level contributes to telomere shortening over time, suggesting that metabolic dysregulation may play a role in early aging. Further understanding of this relationship and addressing high C-peptide levels can be important to prevent premature aging.}, }
@article {pmid36059259, year = {2022}, author = {Pan, L and Tormey, D and Bobon, N and Baumann, P}, title = {Rap1 prevents fusions between long telomeres in fission yeast.}, journal = {The EMBO journal}, volume = {41}, number = {20}, pages = {e110458}, pmid = {36059259}, issn = {1460-2075}, mesh = {Amino Acids/metabolism ; *Schizosaccharomyces/genetics/metabolism ; *Schizosaccharomyces pombe Proteins/genetics/metabolism ; Shelterin Complex ; Telomere/genetics/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/genetics/metabolism ; }, abstract = {The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length regulation. Previous studies have addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a mutagenesis screen in combination with high-throughput sequencing to identify several amino acid positions in Rap1 that have key roles in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner, whereby longer telomeres are prone to undergoing end fusions, while telomeres within the normal length range are sufficiently protected. The protection of long telomeres is in part dependent on their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrate that long telomeres represent a challenge for the maintenance of genome integrity, thereby providing an explanation for species-specific upper limits on telomere length.}, }
@article {pmid36057868, year = {2022}, author = {Schellnegger, M and Lin, AC and Hammer, N and Kamolz, LP}, title = {Physical Activity on Telomere Length as a Biomarker for Aging: A Systematic Review.}, journal = {Sports medicine - open}, volume = {8}, number = {1}, pages = {111}, pmid = {36057868}, issn = {2199-1170}, abstract = {BACKGROUND: Overall life expectancy continues to rise, approaching 80 years of age in several developed countries. However, healthy life expectancy lags far behind, which has, in turn, contributed to increasing costs in healthcare. One way to improve health and attenuate the socio-economic impact of an aging population is to increase overall fitness through physical activity. Telomere attrition or shortening is a well-known molecular marker in aging. As such, several studies have focused on whether exercise influences health and aging through telomere biology. This systematic review examines the recent literature on the effect of physical activity on telomere length (TL) and/or telomerase activity as molecular markers of aging.<br><br>METHODS: A focused search was performed in the databases PubMed and Web of Science for retrieving relevant articles over the past ten years. The search contained the following keywords: exercise, sport, physical activity, fitness, sedentary, physical inactivity, telomere, telomere length, t/s ratio, and telomerase. PRISMA guidelines for systematic reviews were observed.<br><br>RESULTS: A total of 43 articles were identified and categorized into randomized controlled trials (RCT), observational or interventional studies. RCTs (n&#x2009;=&#x2009;8) showed inconsistent findings of increased TL length with physical activity in, e.g. obese, post-menopausal women. In comparison with a predominantly sedentary lifestyle, observational studies (n&#x2009;=&#x2009;27) showed significantly longer TL with exercise of moderate to vigorous intensity; however, there was no consensus on the duration and type of physical activity and training modality. Interventional studies (n&#x2009;=&#x2009;8) also showed similar findings of significantly longer TL prior to exercise intervention; however, these studies had smaller numbers of enrolled participants (mostly of high-performance athletes), and the physical activities covered a range of exercise intensities and duration. Amongst the selected studies, aerobic training of moderate to vigorous intensity is most prevalent. For telomere biology analysis, TL was determined mainly from leukocytes using qPCR. In some cases, especially in RCT and interventional studies, different sample types such as saliva, sperm, and muscle biopsies were analyzed; different leukocyte cell types and potential genetic markers in regulating telomere biology were also investigated.<br><br>CONCLUSIONS: Taken together, physical activity with regular aerobic training of moderate to vigorous intensity appears to help preserve TL. However, the optimal intensity, duration of physical activity, as well as type of exercise still need to be further elucidated. Along with TL or telomerase activity, participants' fitness level, the type of physical activity, and training modality should be assessed at different time points in future studies, with the plan for long-term follow-up. Reducing the amount of sedentary behavior may have a positive effect of preserving and increasing TL. Further molecular characterization of telomere biology in different cell types and tissues is required in order to draw definitive causal conclusions on how physical activity affects TL and aging.}, }
@article {pmid36057690, year = {2022}, author = {Porrazzo, A and Cipressa, F and De Gregorio, A and De Pittà, C and Sales, G and Ciapponi, L and Morciano, P and Esposito, G and Tabocchini, MA and Cenci, G}, title = {Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.}, journal = {Communications biology}, volume = {5}, number = {1}, pages = {905}, pmid = {36057690}, issn = {2399-3642}, mesh = {Animals ; Dose-Response Relationship, Radiation ; *Drosophila melanogaster/genetics/radiation effects ; Gamma Rays ; Humans ; RNA ; *Telomere/genetics ; }, abstract = {It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is considerably reduced when flies are previously exposed to a protracted dose of 0.4 Gy delivered at a dose rate of 2.5 mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TFs frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and in the epigenetic routes involved in radioresistance.}, }
@article {pmid36057525, year = {2022}, author = {Batista, LFZ and Dokal, I and Parker, R}, title = {Telomere biology disorders: time for moving towards the clinic?.}, journal = {Trends in molecular medicine}, volume = {28}, number = {10}, pages = {882-891}, pmid = {36057525}, issn = {1471-499X}, support = {MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; R01 CA258386/CA/NCI NIH HHS/United States ; R01 HL137793/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Biology ; Cell Cycle Proteins/genetics/metabolism ; *Dyskeratosis Congenita/genetics/metabolism ; Humans ; Mutation ; Nuclear Proteins/genetics ; RNA/metabolism ; RNA-Binding Proteins/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics ; }, abstract = {Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients.}, }
@article {pmid36055854, year = {2022}, author = {Seibt, KD and Ghaffari, MH and Scheu, T and Koch, C and Sauerwein, H}, title = {Effects of different feeding levels during a 14-week preweaning phase in dairy heifer calves on telomere length and mitochondrial DNA copy number in blood.}, journal = {Journal of dairy science}, volume = {105}, number = {10}, pages = {8509-8522}, doi = {10.3168/jds.2022-21891}, pmid = {36055854}, issn = {1525-3198}, mesh = {*Animal Feed/analysis ; Animals ; Cattle ; DNA Copy Number Variations ; DNA, Mitochondrial ; *Diet/veterinary ; Female ; Milk/metabolism ; Mitochondria ; Reactive Oxygen Species/metabolism ; Telomere ; Weaning ; }, abstract = {Telomeres cap the ends of eukaryotic chromosomes, and the telomere length (TL) is related to cellular age. The mitochondrial DNA copy number (mtDNAcn) reflects the abundance of mitochondria in a cell. In addition to generating energy, mitochondria are also the main producers of reactive oxygen species, which in turn can accelerate TL attrition and impair mitochondrial function. Nutrition in early life could influence mtDNAcn and TL in later life. In the present study, we investigated the effects of feeding different levels of milk replacer (MR) on TL shortening and energetic status by examining mtDNAcn of heifers during their first year of life. In this study, whole blood samples were obtained from German Holstein heifer calves 36 to 48 h after birth (wk 1) and at wk 12 and wk 16 of life (n = 37), as well as from 31 calves when reaching 1 yr of age. Calves were fed either a high level of MR (14% solids) at 10 L/d (1.4 kg of MR/d; n = 18) or a restrictive low level at 5.7 L/d (0.8 kg of MR/d; n = 19) until linear weaning in wk 13 to 14 of life. Additional whole blood samples were taken from their respective dams 36 to 48 h after calving. Relative TL (qT) and mtDNAcn in cells from whole blood were measured by multiplex quantitative PCR. The greatest qT values were observed in neonates (36-48 h after birth), with decreasing qT values thereafter. Delta qT values were calculated as ΔqT = qT (first year of life) - initial qT (36-48 h after birth). We found no effect of the feeding regimen on qT values, but qT decreased with age. The mtDNAcn was lowest in neonates, increased until wk 12 of life, and then remained at a constant level until after weaning (wk 16). After the first year of life, mtDNAcn was decreased and returned to levels comparable to those of the neonatal stage. No differences in mtDNAcn were detectable between feeding groups within each time point. When comparing the values of qT and mtDNAcn between the calves and their dams after calving (36-48 h after birth and after calving), greater values were observed in calves than in dams. Delta qT values were negative in all but 2 calves (on the restricted diet), indicating that the change in TL with age was not uniform among individual animals, whereas no difference in mean ΔqT values occurred between the feeding groups. Additional analyses of the correlation between qT, mtDNAcn, and various indicators of oxidative status from birth until wk 16 of life did not indicate major interactions between oxidative status, qT and mtDNAcn. The results of this study support an age-dependent decrease of TL in calves independent of the MR feeding level and show the dynamic changes of mtDNAcn in early life.}, }
@article {pmid36054116, year = {2022}, author = {Chen, L and Dickerhoff, J and Sakai, S and Yang, D}, title = {DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting.}, journal = {Accounts of chemical research}, volume = {55}, number = {18}, pages = {2628-2646}, doi = {10.1021/acs.accounts.2c00337}, pmid = {36054116}, issn = {1520-4898}, support = {K01 CA083886/CA/NCI NIH HHS/United States ; U01 CA240346/CA/NCI NIH HHS/United States ; R01 GM083117/GM/NIGMS NIH HHS/United States ; R01 CA122952/CA/NCI NIH HHS/United States ; R01 CA177585/CA/NCI NIH HHS/United States ; S10 RR016649/RR/NCRR NIH HHS/United States ; R01 CA153821/CA/NCI NIH HHS/United States ; P30 CA023168/CA/NCI NIH HHS/United States ; }, mesh = {Chromatin ; DNA/chemistry ; *G-Quadruplexes ; Guanine/chemistry ; Humans ; Ligands ; Oncogenes ; Proto-Oncogene Proteins c-bcl-2/genetics ; Receptors, Drug/genetics ; Telomere/genetics ; Vascular Endothelial Growth Factor A ; }, abstract = {DNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important and have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular structures are stabilized by K[+] or Na[+] and form readily under physiological solution conditions. Moreover, G-quadruplexes are epigenetic features and can alter chromatin structure and function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand the structures and functions of DNA G-quadruplexes formed in key oncogene promoters and human telomeres and their interactions with small molecules. Using high-field NMR spectroscopy, we determined the high-resolution structures of physiologically relevant telomeric G-quadruplexes in K[+] solution with a major form (hybrid-2) and a minor form (hybrid-1), as well as a two-tetrad intermediate. The intrinsic structural polymorphism of telomeric DNA may be important for the biology of human telomeres, and we proposed a model for the interconversion. More recently, we have worked on G-quadruplexes of MYC, BCL2, PDGFR-β, VEGF, and k-RAS oncogene promoters. We determined the structure of the major G-quadruplex formed in the MYC promoter, a prototype for parallel G-quadruplexes. It is the first example of the parallel-stranded G3NG3 structure motif with a 1-nt loop, which is prevalent in promoter sequences and likely evolutionarily selected to initiate folding. Remarkably, the parallel MYC promoter G-quadruplexes are highly stable. Additionally, we determined the molecular structures of G-quadruplexes formed in human BCL2, VEGF, and PDGFR-β promoters, each adopting a unique structure. For example, the BCL2 promoter contains distinct interchangeable G-quadruplexes in two adjacent regions, suggesting precise regulation by different proteins. The PDGFR-β promoter adopts unique "broken-strand" and vacancy G-quadruplexes, which can be recognized by cellular guanine metabolites for a potential regulatory role.Structural information on G-quadruplexes in complex with small-molecules is critical for understanding specific recognition and structure-based rational drug design. Our studies show that many G-quadruplexes contain unique structural features such as capping and loop structures, allowing specific recognition by drugs and protein. This represents a paradigm shift in understanding DNA as a drug target: Rather than a uniform, nonselective binding site in duplex DNA, the G-quadruplex is being pursued as a new class of selectively targetable drug receptors. We focus on targeting the biologically relevant MYC promoter G-quadruplex (MycG4) with small molecules and have determined its first and additional drug complex structures. Very recently, we have discovered clinically tested indenoisoquinolines as strong MycG4 binders and potent MYC inhibitors. We have also discovered drugs targeting the unique dGMP-bound-vG4 formed in the PDGFR-β promoter. Moreover, we determined the complex structures of the first small molecules that specifically recognize the physiologically relevant human telomeric G-quadruplexes. Unlike the previously recognized dogma that the optimal G-quadruplex ligands are large aromatic or cyclic compounds, our results suggest that smaller asymmetric compounds with appropriate functional groups are better choices to specifically bind G-quadruplexes. This body of work lays a strong foundation for future work aimed at understanding the cellular functions of G-quadruplexes and G-quadruplex-targeted drug design.}, }
@article {pmid36051868, year = {2022}, author = {Rodríguez-Fernández, B and Gispert, JD and Guigo, R and Navarro, A and Vilor-Tejedor, N and Crous-Bou, M}, title = {Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy.}, journal = {Computational and structural biotechnology journal}, volume = {20}, number = {}, pages = {4251-4256}, pmid = {36051868}, issn = {2001-0370}, abstract = {Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer's disease (AD), Parkinson's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (βIVW = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results.}, }
@article {pmid36047552, year = {2022}, author = {Coukos, A and Daccord, C and Lazor, R and Blum, S and Naveiras, O and Unger, S and Vionnet, J and Gaide, O and Koutsokera, A and Moschouri, E and Sempoux, C and Good, JM and Moradpour, D and Baerlocher, GM and Fraga, M}, title = {[Short telomere syndrome in adults: a rare entity that should be evoked].}, journal = {Revue medicale suisse}, volume = {18}, number = {793}, pages = {1606-1613}, doi = {10.53738/REVMED.2022.18.793.1606}, pmid = {36047552}, issn = {1660-9379}, mesh = {Adult ; *Bone Marrow Diseases/genetics/pathology ; Child ; Growth Disorders ; Humans ; Hypercalcemia ; Metabolic Diseases ; *Nephrocalcinosis ; Syndrome ; Telomere/genetics/pathology ; }, abstract = {Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.}, }
@article {pmid36041576, year = {2022}, author = {Dey, A and Pandav, K and Nath, M and Barthwal, R and Prasad, R}, title = {Molecular rec§ognition of telomere DNA sequence by 2, 6 anthraquinone derivatives leads to thermal stabilization and induces apoptosis in cancer cells.}, journal = {International journal of biological macromolecules}, volume = {221}, number = {}, pages = {355-370}, doi = {10.1016/j.ijbiomac.2022.08.156}, pmid = {36041576}, issn = {1879-0003}, mesh = {Base Sequence ; Telomere/genetics/metabolism ; *G-Quadruplexes ; Anthraquinones/pharmacology ; *Telomerase/genetics ; DNA/chemistry ; Apoptosis ; Anthracenes ; *Neoplasms/drug therapy/genetics ; }, abstract = {According to current research, anti-cancer anthraquinones impact telomere disruption and may interact with G-quadruplex DNA that triggers signaling to apoptosis. The present study represents the biophysical investigation of oxidative stress, late apoptosis, and induced senescence among cancer cells after binding laboratory synthesized piperidine-based anthraquinone derivatives, 2, 6- Bis [(3-piperidino)acetamido)]anthracene-9,10-dione (N1P) and 2, 6-Bis [piperidino)propionamido]anthracene-9,10-dione (N2P), with G-quadruplex DNA. We employed biophysical approaches to explore the interaction of synthetic anthraquinone derivatives with quadruplex DNA sequences to influence biological activities in the presence of K[+] and Na[+] cations. The binding affinity for N2P and N1P are Kb = 5.8 × 10[6] M[-1] and Kb = 1.0 × 10[6] M[-1], respectively, leading to hypo-/hyper-chromism with 5-7 nm red shift and significant fluorescence quenching and changes in ellipticity resulting in external binding of both the ligands to G-quadruplex DNA. Ligand binding induced enhancement of thermostability of G4 DNA is greater in Na[+] environment (ΔTm = 34 °C) as compared to that in K[+] environment (ΔTm = 21 °C), thereby restricting telomerase binding access to telomeres. Microscopic images of treated cells indicated cellular shape, nuclear condensation, and fragmentation alterations. The findings pave the path for therapeutic research, given the great potential of modifying anthraquinone substituent groups towards improved efficacy, ROS generation, and G-quadruplex DNA selectivity.}, }
@article {pmid36038949, year = {2022}, author = {Kille, B and Balaji, A and Sedlazeck, FJ and Nute, M and Treangen, TJ}, title = {Multiple genome alignment in the telomere-to-telomere assembly era.}, journal = {Genome biology}, volume = {23}, number = {1}, pages = {182}, pmid = {36038949}, issn = {1474-760X}, support = {P01 AI152999/AI/NIAID NIH HHS/United States ; T15 LM007093/LM/NLM NIH HHS/United States ; }, mesh = {*Genome, Human ; *Genomics/methods ; Humans ; Nucleotides ; Telomere/genetics ; }, abstract = {With the arrival of telomere-to-telomere (T2T) assemblies of the human genome comes the computational challenge of efficiently and accurately constructing multiple genome alignments at an unprecedented scale. By identifying nucleotides across genomes which share a common ancestor, multiple genome alignments commonly serve as the bedrock for comparative genomics studies. In this review, we provide an overview of the algorithmic template that most multiple genome alignment methods follow. We also discuss prospective areas of improvement of multiple genome alignment for keeping up with continuously arriving high-quality T2T assembled genomes and for unlocking clinically-relevant insights.}, }
@article {pmid36038827, year = {2022}, author = {Fohringer, C and Hoelzl, F and Allen, AM and Cayol, C and Ericsson, G and Spong, G and Smith, S and Singh, NJ}, title = {Large mammal telomere length variation across ecoregions.}, journal = {BMC ecology and evolution}, volume = {22}, number = {1}, pages = {105}, pmid = {36038827}, issn = {2730-7182}, mesh = {Animals ; Animals, Wild/genetics ; *Deer/genetics ; *Ecosystem ; Female ; Humans ; Male ; Seasons ; Telomere/genetics ; }, abstract = {BACKGROUND: Telomere length provides a physiological proxy for accumulated stress in animals. While there is a growing consensus over how telomere dynamics and their patterns are linked to life history variation and individual experience, knowledge on the impact of exposure to different stressors at a large spatial scale on telomere length is still lacking. How exposure to different stressors at a regional scale interacts with individual differences in life history is also poorly understood. To better understand large-scale regional influences, we investigated telomere length variation in moose (Alces alces) distributed across three ecoregions. We analyzed 153 samples of 106 moose representing moose of both sexes and range of ages to measure relative telomere lengths (RTL) in white blood cells.<br><br>RESULTS: We found that average RTL was significantly shorter in a northern (montane) and southern (sarmatic) ecoregion where moose experience chronic stress related to severe summer and winter temperatures as well as high anthropogenic land-use compared to the boreal region. Our study suggests that animals in the northern boreal forests, with relatively homogenous land use, are less disturbed by environmental and anthropogenic stressors. In contrast, animals in areas experiencing a higher rate of anthropogenic and environmental change experience increased stress.<br><br>CONCLUSION: Although animals can often adapt to predictable stressors, our data suggest that some environmental conditions, even though predictable and ubiquitous, can generate population level differences of long-term stress. By measuring RTL in moose for the first time, we provide valuable insights towards our current understanding of telomere biology in free-ranging wildlife in human-modified ecosystems.}, }
@article {pmid36037299, year = {2022}, author = {Jentsch, A and Hoferichter, F and Raufelder, D and Hageman, G and Maas, L}, title = {The relation between sensory processing sensitivity and telomere length in adolescents.}, journal = {Brain and behavior}, volume = {12}, number = {9}, pages = {e2751}, pmid = {36037299}, issn = {2162-3279}, mesh = {Adolescent ; Biomarkers ; Body Mass Index ; Humans ; Perception ; *Telomere ; *Telomere Shortening ; }, abstract = {BACKGROUND: In the present study, we investigated the association between sensory processing sensitivity (SPS) and telomere length (TL), which is considered a biomarker of cellular aging. SPS is an individual characteristic describing increased perception and procession of inner or outer stimuli, and is positively related to self-perceived stress.<br><br>METHODS: We recruited 82 healthy adolescents aged 13-16 from secondary schools in Germany. SPS was measured with the Highly Sensitive Person Scale, and TL was determined by a multiplex quantitative PCR method.<br><br>RESULTS: Our results show that students with higher values of SPS are likely to have shorter telomeres (&#x3b2;&#xa0;=&#xa0;0.337, p&#xa0;=&#xa0;.001), when adjusting for sex, socioeconomic status, age, and body mass index. These findings are also independent of the negative impact of stress students might have perceived shortly before data collection.<br><br>CONCLUSIONS: Our analysis suggests that students who struggle with low sensory threshold are likely to have shorter telomeres.}, }
@article {pmid36036734, year = {2023}, author = {Salisbury, ML and Markin, CR and Wu, P and Cogan, JD and Mitchell, DB and Liu, Q and Loyd, JE and Lancaster, LH and Kropski, JA and Blackwell, TS}, title = {Peripheral Blood Telomere Attrition in Persons at Risk for Familial Pulmonary Fibrosis.}, journal = {American journal of respiratory and critical care medicine}, volume = {207}, number = {2}, pages = {208-211}, pmid = {36036734}, issn = {1535-4970}, support = {K23 HL141539/HL/NHLBI NIH HHS/United States ; R01 HL151016/HL/NHLBI NIH HHS/United States ; K08HL130595/HL/NHLBI NIH HHS/United States ; P01HL092870/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Idiopathic Pulmonary Fibrosis ; Mutation ; Telomere/genetics ; }, }
@article {pmid36036284, year = {2023}, author = {Khalil, D and Giurgescu, C and Misra, DP and Templin, T and Jenuwine, E and Drury, SS}, title = {Psychosocial Factors and Telomere Length Among Parents and Infants of Immigrant Arab American Families.}, journal = {Biological research for nursing}, volume = {25}, number = {1}, pages = {137-149}, doi = {10.1177/10998004221124145}, pmid = {36036284}, issn = {1552-4175}, mesh = {Infant ; Female ; Humans ; Child, Preschool ; Cross-Sectional Studies ; Pilot Projects ; *Mothers/psychology ; *Emigrants and Immigrants ; Arabs ; Telomere ; }, abstract = {Background: Immigrant Arab American families face multiple stressors related to migration and resettlement. Telomere length (TL) is an established biomarker of aging and psychosocial stress. No published studies have concurrently examined the association between maternal and paternal psychosocial factors and infants' TL. The purpose of this study was to: (1) compare mother, father, and infant TLs; (2) explore the association of maternal and paternal psychosocial factors (acculturative stress and depressive symptoms) with maternal and paternal TL; and (3) explore the association of maternal and paternal psychosocial factors with infants' TL among Arab American immigrants. Method: Using a cross-sectional exploratory design, a sample of 52 immigrant Arab American mother-father-infant triads were recruited from community centers. Data were collected in a single home visit when the infant was 6-24 months old. Each parent completed the study questionnaires addressing their psychosocial factors (acculturative stress, and depressive symptoms), then parents and infants provided buccal cell for TL measurement. Results: Maternal TL was positively correlated to infants' TL (r = .31, p = .04) and significantly shorter (p < .001). Paternal TL was not correlated with infant TL but was significantly shorter than infant's TL (p < .001). Maternal depression was significantly correlated with mothers' TL (r = .4, p = .007). Higher levels of maternal depressive symptoms were significantly associated with shorter infant TL when controlling for background characteristics. Conclusions: Our pilot study is the first study to examine maternal and paternal psychosocial factors related to migration and infants' TL. More research is needed to advance our understanding of the effects of immigration on the intergenerational transfer of stress and trauma.}, }
@article {pmid36035793, year = {2022}, author = {Wang, Y and Ferrucci, L and Seidman, MM and Liu, Y}, title = {An optimized proximity ligation assay to detect telomere dysfunction induced foci in human and mouse cells.}, journal = {STAR protocols}, volume = {3}, number = {3}, pages = {101610}, pmid = {36035793}, issn = {2666-1667}, mesh = {Animals ; Fluorescent Antibody Technique ; Humans ; In Situ Hybridization, Fluorescence ; Mice ; *Telomere ; }, abstract = {Telomere dysfunction-induced foci (TIF) can be measured by immunofluorescence, combined with telomere-fluorescent in situ hybridization. We modified this approach by combining the proximity ligation assay (PLA), which detects colocalization of two molecules in proximity through a signal amplification step and improves the fidelity and sensitivity of TIF detection in human and mouse cells. The protocol includes cell preparation, permeabilization, fixation, and blocking PLA detection of DNA damage response proteins within proximity with telomeres and optional PLA verification by immunofluorescence-based technique.}, }
@article {pmid36031719, year = {2022}, author = {Maher, TM}, title = {A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?.}, journal = {Respirology (Carlton, Vic.)}, volume = {27}, number = {11}, pages = {916-917}, doi = {10.1111/resp.14355}, pmid = {36031719}, issn = {1440-1843}, mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/diagnosis/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Shortening ; }, }
@article {pmid36030273, year = {2022}, author = {Yu, EY and Cheung, NV and Lue, NF}, title = {Connecting telomere maintenance and regulation to the developmental origin and differentiation states of neuroblastoma tumor cells.}, journal = {Journal of hematology &amp; oncology}, volume = {15}, number = {1}, pages = {117}, pmid = {36030273}, issn = {1756-8722}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Cell Differentiation ; Cell Proliferation ; Child ; Humans ; *Neuroblastoma ; *Telomerase ; Telomere ; Telomere Homeostasis ; }, abstract = {A cardinal feature that distinguishes clinically high-risk neuroblastoma from low-risk tumors is telomere maintenance. Specifically, neuroblastoma tumors with either active telomerase or alternative lengthening of telomeres exhibit aggressive growth characteristics that lead to poor outcomes, whereas tumors without telomere maintenance can be managed with observation or minimal treatment. Even though the need for cancer cells to maintain telomere DNA-in order to sustain cell proliferation-is well established, recent studies suggest that the neural crest origin of neuroblastoma may enforce unique relationships between telomeres and tumor malignancy. Specifically in neuroblastoma, telomere structure and telomerase activity are correlated with the adrenergic/mesenchymal differentiation states, and manipulating telomerase activity can trigger tumor cell differentiation. Both findings may reflect features of normal neural crest development. This review summarizes recent advances in the characterization of telomere structure and telomere maintenance mechanisms in neuroblastoma and discusses the findings in the context of relevant literature on telomeres during embryonic and neural development. Understanding the canonical and non-canonical roles of telomere maintenance in neuroblastoma could reveal vulnerabilities for telomere-directed therapies with potential applications to other pediatric malignancies.}, }
@article {pmid36028900, year = {2022}, author = {Tan, KT and Slevin, MK and Meyerson, M and Li, H}, title = {Identifying and correcting repeat-calling errors in nanopore sequencing of telomeres.}, journal = {Genome biology}, volume = {23}, number = {1}, pages = {180}, pmid = {36028900}, issn = {1474-760X}, support = {R01 HG010040/HG/NHGRI NIH HHS/United States ; U01 HG010961/HG/NHGRI NIH HHS/United States ; R35 CA197568/CA/NCI NIH HHS/United States ; U41 HG010972/HG/NHGRI NIH HHS/United States ; }, mesh = {Genomics ; High-Throughput Nucleotide Sequencing ; *Nanopore Sequencing ; *Nanopores ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Telomere ; }, abstract = {Nanopore long-read sequencing is an emerging approach for studying genomes, including long repetitive elements like telomeres. Here, we report extensive basecalling induced errors at telomere repeats across nanopore datasets, sequencing platforms, basecallers, and basecalling models. We find that telomeres in many organisms are frequently miscalled. We demonstrate that tuning of nanopore basecalling models leads to improved recovery and analysis of telomeric regions, with minimal negative impact on other genomic regions. We highlight the importance of verifying nanopore basecalls in long, repetitive, and poorly defined regions, and showcase how artefacts can be resolved by improvements in nanopore basecalling models.}, }
@article {pmid36014852, year = {2022}, author = {Opstad, TB and Alexander, J and Aaseth, JO and Larsson, A and Seljeflot, I and Alehagen, U}, title = {Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality-Sub-Study of a Randomized Clinical Trial.}, journal = {Nutrients}, volume = {14}, number = {16}, pages = {}, pmid = {36014852}, issn = {2072-6643}, mesh = {Aged ; Aged, 80 and over ; *Cardiovascular Diseases/mortality/physiopathology/prevention &amp; control ; Dietary Supplements ; Humans ; Leukocytes ; Prospective Studies ; *Selenium/pharmacology/therapeutic use ; *Telomere/drug effects/physiology ; *Ubiquinone/pharmacology/therapeutic use ; }, abstract = {Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q10 is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70-80 years, were included. Intervention time was 4 years, with 10 years' follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. -0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q10 supplementation associated with reduced cardiovascular mortality.}, }
@article {pmid36011306, year = {2022}, author = {Oudrhiri, N and M'kacher, R and Chaker, D and Colicchio, B and Borie, C and Jeandidier, E and Dieterlen, A and Griscelli, F and Bennaceur-Griscelli, A and Turhan, AG}, title = {Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome.}, journal = {Genes}, volume = {13}, number = {8}, pages = {}, pmid = {36011306}, issn = {2073-4425}, mesh = {Ataxia ; Brain Neoplasms ; Calcinosis ; Central Nervous System Cysts ; *DNA Repair-Deficiency Disorders ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Leukoencephalopathies ; Muscle Spasticity ; Retinal Diseases ; Seizures ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; }, abstract = {Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1-STN1-TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how CTC1 mutations may have an effect on telomere structure and function. For that purpose, we established the very first induced pluripotent stem cell lines (iPSCs) from a compound heterozygous patient with CP carrying deleterious mutations in both alleles of CTC1. Telomere dysfunction and chromosomal instability were assessed in both circulating lymphocytes and iPSCs from the patient and from healthy controls of similar age. The circulating lymphocytes and iPSCs from the CP patient were characterized by their higher telomere length heterogeneity and telomere aberrations compared to those in control cells from healthy donors. Moreover, in contrast to iPSCs from healthy controls, the high levels of telomerase were associated with activation of the alternative lengthening of telomere (ALT) pathway in CP-iPSCs. This was accompanied by inappropriate activation of the DNA repair proteins γH2AX, 53BP1, and ATM, as well as with accumulation of DNA damage, micronuclei, and anaphase bridges. CP-iPSCs presented features of cellular senescence and increased radiation sensitivity. Clonal dicentric chromosomes were identified only in CP-iPSCs after exposure to radiation, thus mirroring the role of telomere dysfunction in their formation. These data demonstrate that iPSCs derived from CP patients can be used as a model system for molecular studies of the CP syndrome and underscores the complexity of telomere dysfunction associated with the defect of DNA repair machinery in the CP syndrome.}, }
@article {pmid36010691, year = {2022}, author = {Derevyanko, A and Skowronska, A and Skowronski, MT and Kordowitzki, P}, title = {The Interplay between Telomeres, Mitochondria, and Chronic Stress Exposure in the Aging Egg.}, journal = {Cells}, volume = {11}, number = {16}, pages = {}, pmid = {36010691}, issn = {2073-4409}, mesh = {*Aging/genetics ; Female ; Humans ; Mitochondria/genetics/metabolism ; Oocytes/metabolism ; Pregnancy ; *Telomere ; Telomere Shortening ; }, abstract = {While at the organismal level, biological aging can be estimated by telomere length and DNA methylation signatures, reliable biomarkers that can predict reproductive age are much needed to gauge the quality of an oocyte. Reproductive medicine and fertility centers often merely quantitate the ovarian reserve to predict the likelihood of fertilization and pregnancy in women of advanced reproductive age. It is highly important to address the level of age-related decline in oocyte quality since it leads to an increased risk of miscarriages and aneuploidy. Conversely, the pathways behind oocyte aging remain, in large part, elusive. Telomere shortening upon chronic stress exposure regulates mitochondria function and biogenesis by various pathways; therefore, establishing a link between these two important players and extrapolating them for the aging of oocytes will be the purpose of our commentary.}, }
@article {pmid36009574, year = {2022}, author = {Opstad, TB and Solheim, S and Pettersen, AR and Kalstad, AA and Arnesen, H and Seljeflot, I}, title = {TERT and TET2 Genetic Variants Affect Leukocyte Telomere Length and Clinical Outcome in Coronary Artery Disease Patients-A Possible Link to Clonal Hematopoiesis.}, journal = {Biomedicines}, volume = {10}, number = {8}, pages = {}, pmid = {36009574}, issn = {2227-9059}, abstract = {Inherited and acquired mutations in hematopoietic stem cells can cause clonal expansion with increased risk of cardiovascular disease (CVD), a condition known for the clonal hematopoiesis of indeterminate potential (CHIP). Inherited genetic variants in two CHIP-associated genome loci, the telomerase gene telomerase enzyme reverse transcriptase (TERT) (rs7705526) and the epigenetic regulator ten-eleven translocation 2 (TET2) (rs2454206), were investigated in 1001 patients with stable coronary artery disease (CAD) (mean age 62 years, 22% women), with regards to cardiovascular outcome, comorbidities, and leukocyte telomere length. Over 2 years, mutated TERT increased the risk two-fold for major clinical events (MACEs) in all patients (p = 0.004), acute myocardial infarction (AMI) in male patients (p = 0.011), and stroke in female patients (p < 0.001). Mutated TET2 correlated with type 2 diabetes (p < 0.001), the metabolic syndrome (p = 0.002), as well as fasting glucose, HbA1c, and shorter telomeres (p = 0.032, p = 0.003, and p = 0.016, respectively). In conclusion, our results from stable CAD patients highlight TERTs' role in CVD, and underline TET2s' role in the epigenetic regulation of lifestyle-related diseases.}, }
@article {pmid36006930, year = {2022}, author = {Sharaf, R and Frampton, GM and Albacker, LA}, title = {Mutations in the TERC template sequence can be incorporated into the telomeres of human tumors.}, journal = {PloS one}, volume = {17}, number = {8}, pages = {e0272707}, pmid = {36006930}, issn = {1932-6203}, mesh = {Humans ; Mutation ; *Neoplasms/genetics ; RNA/genetics/metabolism ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; }, abstract = {Telomerase-mediated lengthening is a mechanism by which some cancer cells avoid senescence-mediated cell cycle arrest due to shortened telomeres. By reverse transcribing an RNA template, encoded by TERC, the enzyme telomerase synthesizes the elongation of telomeric DNA using the 3' end of the chromosome as a primer. TERC harbors a highly conserved template region consisting of 11 nucleotides spanning hg19 coordinates chr3:169482793-169482803. In human cell lines, when TERC was mutated to alter its template region, telomerase generated the predicted mutant telomeric repeats. However, it is unknown if this can occur in human clinical samples. Here, we report on the rare occurrence of two tumor samples where TERC template mutations were reflected in telomeric repeats.}, }
@article {pmid36005153, year = {2022}, author = {Tacheva, T and Zienolddiny-Narui, S and Dimov, D and Vlaykova, D and Miteva, I and Vlaykova, T}, title = {The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease.}, journal = {Current issues in molecular biology}, volume = {44}, number = {8}, pages = {3757-3769}, pmid = {36005153}, issn = {1467-3045}, abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.}, }
@article {pmid35996190, year = {2022}, author = {Retuerto, M and Lledó, A and Fernandez-Varas, B and Guerrero-López, R and Usategui, A and Lalueza, A and García-García, R and Mancebo, E and Paz-Artal, E and Sastre, L and Perona, R and Pablos, JL}, title = {Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities.}, journal = {Immunity &amp; ageing : I &amp; A}, volume = {19}, number = {1}, pages = {38}, pmid = {35996190}, issn = {1742-4933}, abstract = {BACKGROUND: Age and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL.<br><br>RESULTS: We analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n&#x2009;=&#x2009;169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1&#x2009;year later and compared with baseline TL. Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8&#x2009;months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease.<br><br>CONCLUSION: Shorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.}, }
@article {pmid35992857, year = {2022}, author = {Li, JH and Tao, YF and Shen, CH and Li, RD and Wang, Z and Xing, H and Ma, ES and Xue, HY and Zhang, QB and Ma, ZY and Wang, ZX}, title = {Integrated multi-omics analysis identifies ENY2 as a predictor of recurrence and a regulator of telomere maintenance in hepatocellular carcinoma.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {939948}, pmid = {35992857}, issn = {2234-943X}, abstract = {Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a high recurrence rate. Accurate prediction of recurrence risk is urgently required for tailoring personalized treatment programs for individual HCC patients in advance. In this study, we analyzed a gene expression dataset from an HCC cohort with 247 samples and identified five genes including ENY2, GPAA1, NDUFA4L2, NEDD9, and NRP1 as the variables for the prediction of HCC recurrence, especially the early recurrence. The Cox model and risks score were validated in two public HCC cohorts (GSE76427 and The Cancer Genome Atlas (TCGA)) and one cohort from Huashan Hospital, which included a total of 641 samples. Moreover, the multivariate Cox regression analysis revealed that the risk score could serve as an independent prognostic factor in the prediction of HCC recurrence. In addition, we found that ENY2, GPAA1, and NDUFA4L2 were significantly upregulated in HCC of the two validation cohorts, and ENY2 had significantly higher expression levels than another four genes in malignant cells, suggesting that ENY2 might play key roles in malignant cells. The cell line analysis revealed that ENY2 could promote cell cycle progression, cell proliferation, migration, and invasion. The functional analysis of the genes correlated with ENY2 revealed that ENY2 might be involved in telomere maintenance, one of the fundamental hallmarks of cancer. In conclusion, our data indicate that ENY2 may regulate the malignant phenotypes of HCC via activating telomere maintenance.}, }
@article {pmid35988638, year = {2022}, author = {Lynn, SE and Kern, MD and Serrurier, B and Sirman, A and Heidinger, BJ}, title = {Chill out: Environmentally relevant cooling challenge does not increase telomere loss during early life.}, journal = {General and comparative endocrinology}, volume = {329}, number = {}, pages = {114108}, doi = {10.1016/j.ygcen.2022.114108}, pmid = {35988638}, issn = {1095-6840}, mesh = {Animals ; Female ; *Corticosterone ; Stress, Physiological ; Telomere ; Telomere Shortening ; *Songbirds/physiology ; }, abstract = {In vertebrates, exposure to diverse stressors during early life activates a stress response that can initiate compensatory mechanisms or promote cellular damage with long-term fitness consequences. A growing number of studies associate exposure to stressors during early life with increased damage to telomeres (i.e., promoting the shortening of these highly conserved, repeating sequences of non-coding DNA at chromosome ends). However, some studies show no such relationship, suggesting that the nature, timing, and context of these challenges may determine the degree to which physiological mediators of the stress response act in a damage-mitigating or damage promoting way in relation to telomere dynamics. In free-living eastern bluebirds (Sialia sialis), we have previously demonstrated that bouts of offspring cooling that occur when brooding females leave the nest increase at least one such physiological mediator of the stress response (circulating glucocorticoids), suggesting that variation in patterns of maternal brooding may result in different impacts on telomere dynamics at a young age. Here we experimentally tested whether repeated bouts of ecologically relevant offspring cooling affected telomere dynamics during post-natal development. Rates of telomere shortening during the nestling stage were not affected by experimental cooling, but they were affected by brood size and the rate of growth during the nestling stage. Our data suggest that the effects of developmental stress exposure on offspring telomeres are often context-dependent and that not all challenges that increase physiological mediators of stress result in damage to telomeres. Under some conditions, physiological mediators of stress may instead act as protective regulators, allowing for optimization of fitness outcomes in the face of environmental challenges.}, }
@article {pmid35987624, year = {2022}, author = {Wang, T and Jia, Z and Li, S and Li, Y and Yu, T and Lu, T and Shi, Y}, title = {The association between leukocyte telomere length and chronic obstructive pulmonary disease is partially mediated by inflammation: a meta-analysis and population-based mediation study.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {320}, pmid = {35987624}, issn = {1471-2466}, mesh = {Aging ; Humans ; Inflammation/genetics ; Leukocytes ; Nutrition Surveys ; *Pulmonary Disease, Chronic Obstructive ; *Smoking ; Telomere ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the major health issues worldwide. Pathophysiological changes in COPD are mainly reflected in the deterioration of lung function with aging.<br><br>METHODS: Considering that telomere length is a hallmark of biological aging, we first performed a meta-analysis to summarize the current knowledge about the relationship between telomere length and COPD and then employed individual-level data from the continuous National Health and Nutrition Examination Survey (NHANES) to investigate whether telomere length could reflect accelerated aging in COPD and serve as an independent predictor. A mediation study was further performed to examine whether the association between telomeres and COPD could be mediated by inflammation, as one of the most important etiologies and characteristics of COPD.<br><br>RESULTS: The four studies included in our meta-analysis were with high heterogeneity (I[2]&#x2009;=&#x2009;95.7%, Phet&#x2009;<&#x2009;0.001), and the pooled relative risk for COPD comparing the shortest tertile versus the longest tertile was 4.06 (95% CI&#x2009;=&#x2009;1.38 to 11.96). Of the 6,378 subjects in the individual-level data analyses using NHANES, 455 were diagnosed with COPD, and multivariable-adjusted logistic regression also indicated that short telomere length was associated with COPD. Consistently, cubic regression spline analyses showed that long telomeres exhibited a significant association with a decreased risk of COPD. In the subsequent mediation analyses, C-reactive protein concentration, white blood cells count and blood neutrophil count, as inflammatory biomarkers, showed a significant indirect effect on the relationship between telomere length and COPD.<br><br>CONCLUSION: Accelerated aging in COPD could be characterized by excessive telomere shortening, and inflammatory response might be involved in the underlying mechanisms of COPD pathogenesis promoted by short telomere length. Telomere length measurement may facilitate clinical translational research and targeted therapy of COPD.}, }
@article {pmid35986545, year = {2022}, author = {Zafirovic, S and Macvanin, M and Stanimirovic, J and Obradovic, M and Radovanovic, J and Melih, I and Isenovic, E}, title = {Association Between Telomere Length and Cardiovascular Risk: Pharmacological Treatments Affecting Telomeres and Telomerase Activity.}, journal = {Current vascular pharmacology}, volume = {20}, number = {6}, pages = {465-474}, doi = {10.2174/1570161120666220819164240}, pmid = {35986545}, issn = {1875-6212}, mesh = {Humans ; *Telomerase/genetics/metabolism ; *Cardiovascular Diseases/diagnosis/drug therapy/genetics ; Risk Factors ; Telomere/genetics/metabolism ; Heart Disease Risk Factors ; }, abstract = {Telomeres represent the ends of chromosomes, and they are composed of an extensive number of - TTAGGG nucleotide sequence repeats in humans. Telomeres prevent chromosome degradation, participate in stabilization, and regulate the DNA repair system. Inflammation and oxidative stress have been identified as important processes causing cardiovascular disease and accelerating telomere shortening rate. This review investigates the link between telomere length and pathological vascular conditions from experimental and human studies. Also, we discuss pharmacological treatments affecting telomeres and telomerase activity.}, }
@article {pmid35983406, year = {2022}, author = {Hoffmann, J and Tabata, N and Mas-Peiro, S and Spyridopoulos, I and Sinning, JM and Berkowitsch, A and Martin-Ruiz, C and Al-Kassou, B and Herrmann, E and Dimmeler, S and Zeiher, AM and Vasa-Nicotera, M}, title = {Longer leukocyte telomere length is associated with myeloid inflammation and increased mortality after transcatheter aortic valve replacement.}, journal = {European heart journal open}, volume = {2}, number = {4}, pages = {oeac045}, pmid = {35983406}, issn = {2752-4191}, abstract = {AIMS: Inflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR.<br><br>METHODS AND RESULTS: LTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (P&#x2009;=&#x2009;0.017), paralleled by increased procalcitonin (PCT) serum levels (P&#x2009;=&#x2009;0.0006). This inflammatory reaction was accompanied by increased myeloid cells in the highest LTL tertile, mainly a rise in circulating neutrophils (P&#x2009;=&#x2009;0.0025) and monocytes (P&#x2009;=&#x2009;0.01). Multivariate analysis revealed LTL (HR 2.6, 95%CI 1.4-5.1, &#x2009;P=&#x2009;0.004) and PCT levels (HR 4.3, 95%CI 1.7-11.0, P&#x2009;=&#x2009;0.003) as independent predictors of mortality.<br><br>CONCLUSIONS: Longer LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.}, }
@article {pmid35977791, year = {2022}, author = {Romero-Haro, A&#xc1; and Morger, J and Haussmann, MF and Tschirren, B}, title = {Reproductive Strategies Affect Telomere Dynamics across the Life Course.}, journal = {The American naturalist}, volume = {200}, number = {3}, pages = {373-382}, doi = {10.1086/720440}, pmid = {35977791}, issn = {1537-5323}, mesh = {Adult ; Aging/genetics ; Animals ; *Coturnix/genetics ; Humans ; Infant, Newborn ; *Life Change Events ; Male ; Reproduction ; Telomere ; }, abstract = {AbstractBecause parental care has a heritable basis, the benefits of receiving increased parental provisioning early in life are genetically linked to the costs of providing increased parental provisioning at adulthood. Reproductive strategies thus result in distinct cost-benefit syndromes across the life course that may shape individual health and aging trajectories. Here we used an artificial selection approach in Japanese quail (Coturnix japonica) to test how reproductive strategies affect telomere length, a biomarker of somatic state, at different life stages. We show that males but not females from lines selected for low maternal investment (i.e., developing in a relatively small egg) had shorter telomeres at birth. These patterns were still weakly present at the end of the juvenile growth period. In contrast, significantly shorter telomeres were found in reproductively active adult birds from the high-investment lines, suggesting that telomere attrition was accelerated in these individuals once they had become reproductively active. Our study shows that reproductive strategies differentially affect telomere dynamics across the life course, highlighting the role of cross-generational constraints in shaping individual aging trajectories.}, }
@article {pmid35974160, year = {2022}, author = {Petermann-Rocha, F and Valera-Gran, D and Fernández-Pires, P and Martens, DS and Júlvez, J and Rodríguez-Dehli, C and Andiarena, A and Lozano, M and Fernández-Somoano, A and Lertxundi, A and Llop, S and Guxens, M and Nawrot, TS and Navarrete-Muñoz, EM}, title = {Children who sleep more may have longer telomeres: evidence from a longitudinal population study in Spain.}, journal = {Pediatric research}, volume = {}, number = {}, pages = {}, pmid = {35974160}, issn = {1530-0447}, abstract = {BACKGROUND: Inadequate sleep duration has been suggested as a chronic stressor associated with changes in telomere length (TL). This study aimed to explore the association between sleep duration and TL using the INMA birth cohort study data.<br><br>METHODS: A total of 1014 children were included in this study (cross-sectional: 686; longitudinal: 872). Sleep duration (h/day) was reported by caregivers at 4 years and classified into tertiles (7-10&#x2009;h/day; >10-11&#x2009;h/day; >11-14&#x2009;h/day). Leucocyte TL at 4 and 7-9 years were measured using quantitative PCR methods. Multiple robust linear regression models, through log-level regression models, were used to report the % of difference among tertiles of sleep duration.<br><br>RESULTS: In comparison to children who slept between >10 and 11&#x2009;h/day, those in the highest category (more than 11&#x2009;h/day) had 8.5% (95% CI: 3.56-13.6) longer telomeres at 4 years. Longitudinal analysis showed no significant association between sleep duration at 4 years and TL at 7-9 years.<br><br>CONCLUSION: Children who slept more hours per day had longer TL at 4 years independently of a wide range of confounder factors. Environmental conditions, such as sleep duration, might have a major impact on TL during the first years of life.<br><br>IMPACT: Telomere length was longer in children with longer sleep duration (>11&#x2009;h/day) independently of a wide range of confounder factors at age 4 and remained consistent by sex. Sleep routines are encouraged to promote positive child development, like the number of hours of sleep duration. Considering the complex biology of telomere length, future studies still need to elucidate which biological pathways might explain the association between sleep duration and telomere length.}, }
@article {pmid35968296, year = {2022}, author = {Maroon, JC}, title = {The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length-The difference between zero and one: A case report.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {949536}, pmid = {35968296}, issn = {1664-2295}, abstract = {INTRODUCTION: Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one.<br><br>METHODS: This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics.<br><br>RESULTS: Neurocognitive results showed a 3.1-3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7-15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session.<br><br>CONCLUSION: The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.}, }
@article {pmid35959813, year = {2022}, author = {Byrjalsen, A and Bygum, A and Lautrup, CK and Frederiksen, AL and Fialla, AD and Raaschou-Jensen, K and Bendstrup, E and Madsen, TN and Klarskov, M and Jelsig, AM}, title = {[Telomere biology disorders].}, journal = {Ugeskrift for laeger}, volume = {184}, number = {28}, pages = {}, pmid = {35959813}, issn = {1603-6824}, mesh = {Adult ; Biology ; Child ; *Diet, Ketogenic ; *Epilepsy/therapy ; Humans ; Telomere ; *Vagus Nerve Stimulation ; }, abstract = {This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.}, }
@article {pmid35953846, year = {2022}, author = {Kim, S and Chowdhury, T and Yu, HJ and Kahng, JY and Lee, CE and Choi, SA and Kim, KM and Kang, H and Lee, JH and Lee, ST and Won, JK and Kim, KH and Kim, MS and Lee, JY and Kim, JW and Kim, YH and Kim, TM and Choi, SH and Phi, JH and Shin, YK and Ku, JL and Lee, S and Yun, H and Lee, H and Kim, D and Kim, K and Hur, JK and Park, SH and Kim, SK and Park, CK}, title = {The telomere maintenance mechanism spectrum and its dynamics in gliomas.}, journal = {Genome medicine}, volume = {14}, number = {1}, pages = {88}, pmid = {35953846}, issn = {1756-994X}, mesh = {*Glioma/genetics ; Humans ; Mutation ; *Telomerase/genetics ; Telomere/genetics ; Telomere Homeostasis ; }, abstract = {BACKGROUND: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues.<br><br>METHODS: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups.<br><br>RESULTS: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression.<br><br>CONCLUSIONS: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.}, }
@article {pmid35950364, year = {2022}, author = {Lundsgaard, NU and Cramp, RL and Franklin, CE}, title = {Early exposure to UV radiation causes telomere shortening and poorer condition later in life.}, journal = {The Journal of experimental biology}, volume = {225}, number = {17}, pages = {}, pmid = {35950364}, issn = {1477-9145}, mesh = {Animals ; Anura/genetics ; Australia ; Larva/genetics ; Metamorphosis, Biological ; *Telomere Shortening ; *Ultraviolet Rays/adverse effects ; }, abstract = {Determining the contribution of elevated ultraviolet-B radiation (UVBR; 280-315 nm) to amphibian population declines is being hindered by a lack of knowledge about how different acute UVBR exposure regimes during early life-history stages might affect post-metamorphic stages via long-term carryover effects. We acutely exposed tadpoles of the Australian green tree frog (Litoria caerulea) to a combination of different UVBR irradiances and doses in a multi-factorial laboratory experiment, and then reared them to metamorphosis in the absence of UVBR to assess carryover effects in subsequent juvenile frogs. Dose and irradiance of acute UVBR exposure influenced carryover effects into metamorphosis in somewhat opposing manners. Higher doses of UVBR exposure in larvae yielded improved rates of metamorphosis. However, exposure at a high irradiance resulted in frogs metamorphosing smaller in size and in poorer condition than frogs exposed to low and medium irradiance UVBR as larvae. We also demonstrate some of the first empirical evidence of UVBR-induced telomere shortening in vivo, which is one possible mechanism for life-history trade-offs impacting condition post-metamorphosis. These findings contribute to our understanding of how acute UVBR exposure regimes in early life affect later life-history stages, which has implications for how this stressor may shape population dynamics.}, }
@article {pmid35949423, year = {2022}, author = {Yu, HJ and Koh, SH}, title = {Is Telomere Length Shortening a Risk Factor for Neurodegenerative Disorders?.}, journal = {Dementia and neurocognitive disorders}, volume = {21}, number = {3}, pages = {83-92}, pmid = {35949423}, issn = {2384-0757}, abstract = {Telomeres are located at the end of chromosomes. They are known to protect chromosomes and prevent cellular senescence. Telomere length shortening has been considered an important marker of aging. Many studies have reported this concept in connection with neurodegenerative disorders. Considering the role of telomeres, it seems that longer telomeres are beneficial while shorter telomeres are detrimental in preventing neurodegenerative disorders. However, several studies have shown that people with longer telomeres might also be vulnerable to neurodegenerative disorders. Before these conflicting results can be explained through large-scale longitudinal clinical studies on the role of telomere length in neurodegenerative disorders, it would be beneficial to simultaneously review these opposing results. Understanding these conflicting results might help us plan future studies to reveal the role of telomere length in neurodegenerative disorders. In this review, these contradictory findings are thoroughly discussed, with the aim to better understand the role of telomere length in neurodegenerative disorders.}, }
@article {pmid35948770, year = {2022}, author = {Olson, CL and Barbour, AT and Wuttke, DS}, title = {Filling in the blanks: how the C-strand catches up to the G-strand at replicating telomeres using CST.}, journal = {Nature structural &amp; molecular biology}, volume = {29}, number = {8}, pages = {730-733}, pmid = {35948770}, issn = {1545-9985}, support = {T32 GM008759/GM/NIGMS NIH HHS/United States ; }, mesh = {*Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomere-Binding Proteins/metabolism ; }, }
@article {pmid35947933, year = {2022}, author = {Natalini, JG and England, BR and Baker, JF and Chen, Q and Singh, N and Mahajan, TD and Roul, P and Thiele, GM and Sauer, BC and Mikuls, TR and Johnson, FB and Kawut, SM}, title = {Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans.}, journal = {Respiratory medicine}, volume = {201}, number = {}, pages = {106943}, doi = {10.1016/j.rmed.2022.106943}, pmid = {35947933}, issn = {1532-3064}, support = {IK2 CX002203/CX/CSRD VA/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; T32 HL007891/HL/NHLBI NIH HHS/United States ; }, mesh = {*Arthritis, Rheumatoid/complications/epidemiology/genetics ; Cross-Sectional Studies ; Female ; Humans ; *Lung Diseases, Interstitial/etiology/genetics ; Male ; Telomere/genetics ; Telomere Shortening ; *Veterans ; }, abstract = {BACKGROUND: Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking.<br><br>METHODS: Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort.<br><br>RESULTS: Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p <&#xa0;0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p&#xa0;=&#xa0;0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p&#xa0;=&#xa0;0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p&#xa0;=&#xa0;0.94).<br><br>CONCLUSION: Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.}, }
@article {pmid35947641, year = {2022}, author = {Macha, SJ and Koneru, B and Burrow, TA and Zhu, C and Savitski, D and Rahman, RL and Ronaghan, CA and Nance, J and McCoy, K and Eslinger, C and Reynolds, CP}, title = {Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function.}, journal = {Cancer research}, volume = {82}, number = {18}, pages = {3345-3358}, pmid = {35947641}, issn = {1538-7445}, support = {R01 CA264949/CA/NCI NIH HHS/United States ; R01 CA217251/CA/NCI NIH HHS/United States ; R01 CA221957/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Carcinoma ; Humans ; Irinotecan ; Mice ; *Neuroblastoma/drug therapy/genetics ; *Sarcoma/genetics ; *Telomerase/genetics ; Telomere/genetics/metabolism ; Telomere Homeostasis/genetics ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {UNLABELLED: A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length, which can be identified with robust biomarkers. ALT has been reported to be prevalent in high-risk neuroblastoma and certain sarcomas, and ALT cancers are a major clinical challenge that lack targeted therapeutic approaches. Here, we found ALT in a variety of pediatric and adult cancer histologies, including carcinomas. Patient-derived ALT cancer cell lines from neuroblastomas, sarcomas, and carcinomas were hypersensitive to the p53 reactivator eprenetapopt (APR-246) relative to telomerase-positive (TA+) models. Constitutive telomere damage signaling in ALT cells activated ataxia-telangiectasia mutated (ATM) kinase to phosphorylate p53, which resulted in selective ALT sensitivity to APR-246. Treatment with APR-246 combined with irinotecan achieved complete responses in mice xenografted with ALT neuroblastoma, rhabdomyosarcoma, and breast cancer and delayed tumor growth in ALT colon cancer xenografts, while the combination had limited efficacy in TA+ tumor models. A large number of adult and pediatric cancers present with the ALT phenotype, which confers a uniquely high sensitivity to reactivation of p53. These data support clinical evaluation of a combinatorial approach using APR-246 and irinotecan in ALT patients with cancer.<br><br>SIGNIFICANCE: This work demonstrates that constitutive activation of ATM in chemotherapy-refractory ALT cancer cells renders them hypersensitive to reactivation of p53 function by APR-246, indicating a potential strategy to overcome therapeutic resistance.}, }
@article {pmid35947638, year = {2022}, author = {Lemaître, JF and Gaillard, JM and Gilson, E}, title = {Telomeres as a sentinel of population decline in the context of global warming.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {35}, pages = {e2211349119}, pmid = {35947638}, issn = {1091-6490}, mesh = {Animals ; *Extinction, Biological ; *Global Warming ; *Lizards/genetics ; Population Dynamics ; Sentinel Species ; *Telomere/genetics ; }, }
@article {pmid35942347, year = {2022}, author = {Zhang, JM and Zou, L}, title = {Protocol to stimulate and delineate alternative lengthening of telomeres in human U2OS cells.}, journal = {STAR protocols}, volume = {3}, number = {3}, pages = {101594}, pmid = {35942347}, issn = {2666-1667}, mesh = {DNA Replication ; Humans ; *Telomerase/genetics ; *Telomere/genetics ; }, abstract = {Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe a protocol to stimulate the formation of ALT-associated PML bodies (APBs) and ALT activity by tethering PML-IV to telomeres in human U2OS cells. Through immunofluorescence, in situ hybridization, and microscopy, we analyze dynamics of telomere clustering, visualize recruitment of DNA repair proteins to APBs, and measure telomere DNA synthesis during ALT. This protocol provides a unique approach to delineate the ALT pathway. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).}, }
@article {pmid35939862, year = {2022}, author = {Woo, JMP and Parks, CG and Hyde, EE and Auer, PL and Simanek, AM and Konkel, RH and Taylor, J and Sandler, DP and Meier, HCS}, title = {Early life trauma and adult leucocyte telomere length.}, journal = {Psychoneuroendocrinology}, volume = {144}, number = {}, pages = {105876}, pmid = {35939862}, issn = {1873-3360}, support = {Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Adult ; Child ; Female ; Humans ; Leukocytes ; Life Change Events ; Prospective Studies ; *Telomere ; *Telomere Shortening ; }, abstract = {BACKGROUND: Telomere length, a biomarker of cell division and cellular aging, has been associated with multiple chronic disease endpoints. Experienced trauma over the life course may contribute to telomere shortening via mechanisms of stress embodiment. However, it is unclear how patterns of co-occurring trauma during sensitive periods (e.g., early life) throughout the life course may influence telomere shortening. We examine the relationship between co-occurring early life trauma on adult telomere length and the extent to which adulthood trauma, socioeconomic position, and health and lifestyle factors may mediate this relationship.<br><br>METHODS: We use data from a sample of participants in the Sister Study (N&#xa0;=&#xa0;740, analytic sample: n&#xa0;=&#xa0;602), a prospective cohort of U.S. self-identified females aged 35-74 years at enrollment (2003-2009) for whom leukocyte telomere length was measured in baseline blood samples. Participants reported their experience of 20 different types of trauma, from which we identified patterns of co-occurring early life trauma (before age 18) using latent class analysis. We estimated the direct and indirect effects of early life trauma on leukocyte telomere length using structural equation modeling, allowing for mediating adult pathways.<br><br>RESULTS: Approximately 47 % of participants reported early life trauma. High early life trauma was associated with shorter telomere length compared to low early life trauma (&#x3b2;&#xa0;=&#xa0;-0.11; 95 % CI: -0.22, -0.004) after adjusting for age and childhood socioeconomic position. The inverse association between early life trauma and adult leukocyte telomere length was largely attributable to the direct effect of early life trauma on telomere length (&#x3b2;&#xa0;=&#xa0;-0.12; 95 %CI: -0.23, -0.01). Mediating indirect pathways via adult trauma, socioeconomic position, and health metrics did not substantively contribute the overall association.<br><br>CONCLUSIONS: These findings highlight the role of patterns of co-occurring early life trauma on shortened telomere length independent of adult pathways.}, }
@article {pmid35939680, year = {2022}, author = {Dupoué, A and Blaimont, P and Angelier, F and Ribout, C and Rozen-Rechels, D and Richard, M and Miles, D and de Villemereuil, P and Rutschmann, A and Badiane, A and Aubret, F and Lourdais, O and Meylan, S and Cote, J and Clobert, J and Le Galliard, JF}, title = {Lizards from warm and declining populations are born with extremely short telomeres.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {33}, pages = {e2201371119}, pmid = {35939680}, issn = {1091-6490}, mesh = {*Aging/genetics ; Animals ; *Extinction, Biological ; Female ; *Global Warming ; *Lizards/genetics ; Population Dynamics ; Reproduction ; Risk ; *Telomere/genetics ; *Telomere Shortening ; }, abstract = {Aging is the price to pay for acquiring and processing energy through cellular activity and life history productivity. Climate warming can exacerbate the inherent pace of aging, as illustrated by a faster erosion of protective telomere DNA sequences. This biomarker integrates individual pace of life and parental effects through the germline, but whether intra- and intergenerational telomere dynamics underlies population trends remains an open question. Here, we investigated the covariation between life history, telomere length (TL), and extinction risk among three age classes in a cold-adapted ectotherm (Zootoca vivipara) facing warming-induced extirpations in its distribution limits. TL followed the same threshold relationships with population extinction risk at birth, maturity, and adulthood, suggesting intergenerational accumulation of accelerated aging rate in declining populations. In dwindling populations, most neonates inherited already short telomeres, suggesting they were born physiologically old and unlikely to reach recruitment. At adulthood, TL further explained females' reproductive performance, switching from an index of individual quality in stable populations to a biomarker of reproductive costs in those close to extirpation. We compiled these results to propose the aging loop hypothesis and conceptualize how climate-driven telomere shortening in ectotherms may accumulate across generations and generate tipping points before local extirpation.}, }
@article {pmid35939618, year = {2022}, author = {Quque, M and Ferreira, C and Sosa, S and Schull, Q and Zahn, S and Criscuolo, F and Bleu, J and Viblanc, VA}, title = {Cascading Effects of Conspecific Aggression on Oxidative Status and Telomere Length in Zebra Finches.}, journal = {Physiological and biochemical zoology : PBZ}, volume = {95}, number = {5}, pages = {416-429}, doi = {10.1086/721252}, pmid = {35939618}, issn = {1537-5293}, mesh = {Aggression/physiology ; Animals ; *Finches/physiology ; Oxidative Stress ; *Physical Conditioning, Animal ; Telomere ; }, abstract = {Living in social groups may exacerbate interindividual competition for territory, food, and mates, leading to stress and possible health consequences. Unfavorable social contexts have been shown to elevate glucocorticoid levels (often used as biomarkers of individual stress), but the downstream consequences of socially stressful environments are rarely explored. Our study experimentally tests the mechanistic links between social aggression, oxidative stress, and somatic maintenance in captive zebra finches (Taeniopygia guttata). Over 64 d, we measured the effects of aggression (received or emitted) on the individual oxidative status, body condition, and changes in relative telomere length (rTL) of birds living in high- and low-social-density conditions. Using path analyses, we found that birds living at high social density increased their aggressive behavior. Birds receiving the highest number of aggressions exhibited the strongest activation of antioxidant defenses and highest plasmatic levels of reactive oxygen metabolites. In turn, this prevented birds from maintaining or restoring telomere length between the beginning and the end of the experiment. Received aggression also had a direct negative effect on changes in rTL, unrelated to oxidative stress. In contrast, emitted aggression had no significant effect on individual oxidative stress or changes in rTL. Body condition did not appear to affect the physiological response to aggression or oxidative stress. At low density, we found trends that were similar to those at high density but nonsignificant. Our study sheds light on the causal chain linking the social environment and aggressive behavior to individual oxidative stress and telomere length. The long-term consequences of socially induced stress on fitness remain to be characterized.}, }
@article {pmid35938805, year = {2022}, author = {Moazamian, A and Gharagozloo, P and Aitken, RJ and Drevet, JR}, title = {OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: Sperm telomeres, oxidative stress, and infertility.}, journal = {Reproduction (Cambridge, England)}, volume = {164}, number = {6}, pages = {F125-F133}, doi = {10.1530/REP-22-0189}, pmid = {35938805}, issn = {1741-7899}, mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; *Infertility, Male/metabolism ; Semen/metabolism ; Spermatozoa/metabolism ; Oxidative Stress ; Telomere/metabolism ; Guanine/metabolism ; DNA ; Deoxyguanosine/metabolism ; Biomarkers/metabolism ; }, abstract = {IN BRIEF: Oxidative stress is recognized as an underlying driving factor of both telomere dysfunction and human subfertility/infertility. This review briefly reassesses telomere integrity as a fertility biomarker before proposing a novel, mechanistic rationale for the role of oxidative stress in the seemingly paradoxical lengthening of sperm telomeres with aging.<br><br>ABSTRACT: The maintenance of redox balance in the male reproductive tract is critical to sperm health and function. Physiological levels of reactive oxygen species (ROS) promote sperm capacitation, while excess ROS exposure, or depleted antioxidant defenses, yields a state of oxidative stress which disrupts their fertilizing capacity and DNA structural integrity. The guanine moiety is the most readily oxidized of the four DNA bases and gets converted to the mutagenic lesion 8-hydroxy-deoxyguanosine (8-OHdG). Numerous studies have also confirmed oxidative stress as a driving factor behind accelerated telomere shortening and dysfunction. Although a clear consensus has not been reached, clinical studies also appear to associate telomere integrity with fertility outcomes in the assisted reproductive technology setting. Intriguingly, while sperm cellular and molecular characteristics make them more susceptible to oxidative insult than any other cell type, they are also the only cell type in which telomere lengthening accompanies aging. This article focuses on the oxidative stress response pathways to propose a mechanism for the explanation of this apparent paradox.}, }
@article {pmid35934479, year = {2022}, author = {Paul, T and Myong, S}, title = {Helicase mediated vectorial folding of telomere G-quadruplex.}, journal = {Methods in enzymology}, volume = {672}, number = {}, pages = {283-297}, doi = {10.1016/bs.mie.2022.03.065}, pmid = {35934479}, issn = {1557-7988}, support = {R01 GM115631/GM/NIGMS NIH HHS/United States ; R01 CA207342/CA/NCI NIH HHS/United States ; RF1 NS113636/NS/NINDS NIH HHS/United States ; }, mesh = {DNA Helicases/metabolism ; *G-Quadruplexes ; Shelterin Complex ; *Telomerase/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/chemistry/genetics/metabolism ; }, abstract = {The G-rich single-stranded telomere overhang can self-fold into G-quadruplex (G4) structure both in vivo and in vitro. In somatic cells, telomeres shorten progressively due to the end-replication. In stem cells, however, telomeres are replenished by a special enzyme, telomerase which synthesizes single-stranded telomere overhang. The active extension by the telomerase releases G-rich overhang segmentally in 5' to 3' direction as the overhang folds into G4 structure after successive elongation. To replicate such vectorial G4 folding process, we employed a superhelicase, Rep-X to release the G-rich sequence gradually. Using single-molecule assay we demonstrated that the folded conformation achieved by the vectorial folding is inherently different from the post-folding where the entire overhang is allowed to fold at once. In addition, the vectorially folded overhangs are less stable and more accessible to a complementary C-rich strand and the telomere binding protein, POT1 compared to the post-folded state. The higher accessibility may have implications for the facile loading of shelterin proteins after DNA replication.}, }
@article {pmid35934145, year = {2022}, author = {Lai, X and Yuan, Y and Liu, M and Xiao, Y and Ma, L and Guo, W and Fang, Q and Yang, H and Hou, J and Yang, L and Yang, H and He, MA and Guo, H and Zhang, X}, title = {Individual and joint associations of co-exposure to multiple plasma metals with telomere length among middle-aged and older Chinese in the Dongfeng-Tongji cohort.}, journal = {Environmental research}, volume = {214}, number = {Pt 3}, pages = {114031}, doi = {10.1016/j.envres.2022.114031}, pmid = {35934145}, issn = {1096-0953}, mesh = {Aged ; *Aluminum ; Bayes Theorem ; China ; Humans ; *Manganese ; Middle Aged ; Telomere ; Vanadium/toxicity ; }, abstract = {Studies on associations of metals with leucocyte telomere length (LTL) were mainly limited to several most common toxic metals and single-metal effect, but the impact of other common metals and especially the overall joint associations and interactions of metal mixture with LTL are largely unknown. We included 15 plasma metals and LTL among 4906 participants from Dongfeng-Tongji cohort. Multivariable linear regression was used to estimate associations of individual metals with LTL. We also applied Bayesian kernel machine regression (BKMR) and quantile g-computation regression (Q-g) to evaluate the overall association and interactions, and identified the major contributors as well as the potential modifications by major characteristics. Multivariable linear regression found vanadium, copper, arsenic, aluminum and nickel were negatively associated with LTL, and a 2-fold change was related to 1.9%-5.1% shorter LTL; while manganese and zinc showed 3.7% and 4.0% longer LTL (all P < 0.05) in multiple-metal models. BKMR confirmed above metals and revealed a linearly inverse joint association between 15 metals and LTL. Q-g regression further indicated each quantile increase in mixture was associated with 5.2% shorter LTL (95% CI: -8.1%, -2.3%). Furthermore, manganese counteracted against aluminum and vanadium respectively (Pint<0.05). In addition, associations of vanadium, aluminum and metal mixture with LTL were more prominent in overweight participants. Our results are among the first to provide a new comprehensive view of metal mixture exposure on LTL attrition in the general population, including identifying the major components, metals interactions and the overall effects.}, }
@article {pmid35933575, year = {2022}, author = {Fan, Y and Guo, Y and Zhong, J and Chi, H and Zhao, X and Su, P and Gao, J and Chen, M}, title = {The association between visceral adiposity index and leukocyte telomere length in adults: results from National Health and Nutrition Examination Survey.}, journal = {Aging clinical and experimental research}, volume = {34}, number = {9}, pages = {2177-2183}, pmid = {35933575}, issn = {1720-8319}, mesh = {*Adiposity/genetics ; Humans ; *Leukocytes ; Nutrition Surveys ; Obesity, Abdominal ; Risk Factors ; Telomere/genetics ; United States ; }, abstract = {BACKGROUND: Leukocyte telomere length (LTL) is a robust marker of biological aging, which is associated with obesity. Recently, the visceral adiposity index (VAI) has been proposed as an indicator of adipose distribution and function.<br><br>OBJECTIVE: To evaluated the association between VAI and LTL in adult Americans.<br><br>METHODS: There were 3193 participants in U.S. National Health and Nutrition Examination Surveys (1999-2002) included in this analysis. LTL was measured using quantitative PCR (qPCR) and expressed as telomere to single-gene copy ratio (T/S ratio). We performed multiple logistic regression models to explore the association between VAI and LTL by adjusting for potential confounders.<br><br>RESULTS: Among all participants, VAI was associated with the shorter LTL (&#x3b2;: &#x2009;-&#x2009;14.81, 95% CI &#x2009;-&#x2009;22.28 to &#x2009;-&#x2009;7.34, p&#x2009;<&#x2009;0.001). There were significant differences of LTL in VAI tertiles (p&#x2009;<&#x2009;0.001). Participants in the higher VAI tertile had the shorter LTL (1.26&#x2009;&#x2264;&#x2009;VAI&#x2009;<&#x2009;2.46: &#x3b2;&#x2009;=&#x2009;&#x2009;-&#x2009;130.16, 95% CI [&#x2009;-&#x2009;183.44, &#x2009;-&#x2009;76.87]; VAI&#x2009;&#x2265;&#x2009;2.46: &#x3b2;&#x2009;=&#x2009;&#x2009;-&#x2009;216.12, 95% CI [&#x2009;-&#x2009;216.12, &#x2009;-&#x2009;81.42], p for trend:&#x2009;<&#x2009;0.001) comparing with the lower VAI tertile. We also found a non-linear relationship between VAI and LTL. VAI was negatively correlated with LTL when VAI was less than 2.84.<br><br>CONCLUSIONS: The present study demonstrates that VAI is independently associated with telomere length. A higher VAI is associated with shorter LTL. The results suggest that VAI may provide prediction for LTL and account for accelerating the biological aging.}, }
@article {pmid35932977, year = {2022}, author = {Zheng, Y and Zhang, N and Wang, Y and Wang, F and Li, G and Tse, G and Liu, T}, title = {Association between leucocyte telomere length and the risk of atrial fibrillation: An updated systematic review and meta-analysis.}, journal = {Ageing research reviews}, volume = {81}, number = {}, pages = {101707}, doi = {10.1016/j.arr.2022.101707}, pmid = {35932977}, issn = {1872-9649}, mesh = {*Atrial Fibrillation/epidemiology/genetics ; *Biological Products ; Female ; Humans ; Leukocytes ; Male ; Telomere/genetics ; Telomere Shortening ; }, abstract = {BACKGROUND AND AIMS: Advancing age is the most important risk factor of atrial fibrillation (AF). The shortening of telomere length is a biomarker of biologic aging. There is an increasing body of evidence that leucocyte telomere length (LTL) is associated with the risk of AF development. However, the results in these studies were controversial. The current systematic review and meta-analysis was conducted to examine the role of LTL in predicting the incidence of AF.<br><br>METHODS AND RESULTS: Observational studies reporting the association between LTL and the risk of AF were retrieved through 25th June, 2022 from PubMed and Embase. A total of twelve studies including 18,293 patients were included in the present analysis. Leucocyte telomere shortening was found to be an independent predictor of AF as a continuous variable in both univariate [OR:2.14; 95%CI(1.48,3.10); P&#xa0;<&#xa0;0.0001] and multivariate analyses [OR:1.41;95%CI(1.11,1.79); P&#xa0;=&#xa0;0.005], as well as categorical variable in multivariate analysis [OR:1.53; 95%CI(1.04,2.27); P&#xa0;=&#xa0;0.03]. Furthermore, leucocyte telomere shortening was significantly associated with recurrent AF [OR:4.32;95%CI(2.42,7.69); P&#xa0;<&#xa0;0.00001] but not new-onset AF [OR:1.14; 95%CI(0.90,1.45); P&#xa0;=&#xa0;0.29]. Leucocyte telomere shortening was also associated with an increased risk of persistent AF [OR:14.73;95%CI (3.16,68.67); P&#xa0;=&#xa0;0.0006] and paroxysmal AF [OR:2.74;95%CI(1.45,5.18); P&#xa0;=&#xa0;0.002]. Besides, LTL was an independent predictor for progression from paroxysmal AF to persistent AF [OR:3.2;95%CI(1.66,6.18); P&#xa0;=&#xa0;0.0005]. Differences between males [OR:1.99; 95%CI(1.29,3.06); P&#xa0;=&#xa0;0.002] and females [OR:0.86; 95%CI (0.29,2.56);P&#xa0;=&#xa0;0.79] were observed.<br><br>CONCLUSIONS: Leucocyte telomere shortening predicts the risk of AF, especially recurrent AF. The predictive value is more prominent in males than in females. Shortening in LTL can predict the progression from paroxysmal to persistent AF.}, }
@article {pmid35932478, year = {2022}, author = {Chik, HYJ and Sparks, AM and Schroeder, J and Dugdale, HL}, title = {A meta-analysis on the heritability of vertebrate telomere length.}, journal = {Journal of evolutionary biology}, volume = {35}, number = {10}, pages = {1283-1295}, pmid = {35932478}, issn = {1420-9101}, mesh = {Animals ; Phylogeny ; *Telomere/genetics ; *Vertebrates/genetics ; }, abstract = {Telomere dynamics are linked with both cellular and organismal senescence, and life history, individual quality and health. Telomere dynamics, particularly telomere length, have therefore garnered much research interest in evolutionary biology. To examine the evolution of telomere length, it is important to quantify its heritability, the proportion of total variation explained by additive genetic effects. Many studies have quantified telomere length heritability, but estimates are varied, and no general conclusion has been drawn. Additionally, it is unclear whether biological and methodological factors influence telomere length heritability estimates. We present the first meta-analysis of telomere length heritability, using 104 estimates from 43 studies over 18 vertebrate species. We calculated an overall mean heritability and examined how estimates varied by study, phylogeny, species-specific ecology, environmental setting, age at sampling, laboratory methods, statistical methods, sex and repeated measurements. Overall heritability was moderate (44.9%, 95% CI: 25.2-64.7%), and there was considerable heterogeneity in heritability estimates, in particular among studies and estimates. Laboratory method influenced heritability estimates, with in-gel hybridization TRF yielding higher heritabilities than qPCR and Southern blot TRF. There was also an effect from statistical method, with twin-based and SNP-based estimates lower than correlation-based or pedigree-based estimates. Our results highlight an overall heritable basis of telomere length, and we recommend future research on a wider range of taxa, and the use of variance-partitioning methods with relatedness or SNP data over correlation methods to minimize heritability estimation bias.}, }
@article {pmid35931358, year = {2022}, author = {Guo, Z and Zou, K and Li, X and Duan, X and Fan, Y and Liu, X and Wang, W}, title = {Relationship between miRNAs polymorphisms and peripheral blood leukocyte DNA telomere length in coke oven workers: A cross-sectional study.}, journal = {Environmental toxicology and pharmacology}, volume = {95}, number = {}, pages = {103941}, doi = {10.1016/j.etap.2022.103941}, pmid = {35931358}, issn = {1872-7077}, mesh = {*Coke/analysis ; Cross-Sectional Studies ; DNA ; DNA Damage ; Humans ; Leukocytes ; *MicroRNAs/genetics ; *Occupational Exposure/adverse effects/analysis ; *Polycyclic Aromatic Hydrocarbons/analysis ; Telomere/genetics ; }, abstract = {OBJECTIVE: The purpose of this study was to investigate the factors affecting telomere length (TL) in coke oven workers by analyzing the interaction between miRNAs polymorphisms and coke oven emissions (COEs) exposure.<br><br>METHODS: A total of 544 coke oven workers and 238 healthy controls were recruited. Peripheral blood was collected from the subjects, genomic DNA was extracted, leukocyte TL was detected by real-time quantitative polymerase chain reaction, and fifteen polymorphisms of eight miRNAs were genotyped by flight mass spectrometry.<br><br>RESULTS: Statistical analysis showed that the peripheral blood DNA TL in the exposure group was shorter than that in the control group (P&#xa0;<&#xa0;0.001). Generalized linear model found that COEs-exposure [&#x3b2; (95%CI) =&#xa0;-0.427 (-0.556, -0.299), P&#xa0;<&#xa0;0.001], genotype CC+CT for miR-612 rs1144925 [&#x3b2; (95%CI) =&#xa0;-0.367 (-0.630, -0.104), P&#xa0;=&#xa0;0.006], and the interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure [&#x3b2; (95% CI) =&#xa0;0.564 (0.108, 1.020), P&#xa0;=&#xa0;0.015] were associated with the shortened TL.<br><br>CONCLUSION: COEs-exposure and miR-612 rs1144925 TT could promote telomere shortening in coke oven workers. The interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure could protect telomere. This provides clues for further mechanistic studies between miRNA and telomere damage.}, }
@article {pmid35930283, year = {2022}, author = {Martens, DS and Sleurs, H and Dockx, Y and Rasking, L and Plusquin, M and Nawrot, TS}, title = {Association of Newborn Telomere Length With Blood Pressure in Childhood.}, journal = {JAMA network open}, volume = {5}, number = {8}, pages = {e2225521}, pmid = {35930283}, issn = {2574-3805}, mesh = {Adult ; Blood Pressure ; Child ; Child, Preschool ; Cohort Studies ; Female ; Humans ; *Hypertension ; Infant, Newborn ; Male ; *Placenta ; Pregnancy ; Prospective Studies ; Telomere ; United States ; }, abstract = {IMPORTANCE: Adult telomere length (TL) is a biological marker of aging associated with vascular health. TL at birth is associated with later life TL and may contain early biological information of later life cardiovascular health and disease.<br><br>OBJECTIVE: To evaluate whether newborn TL is associated with early life blood pressure differences in childhood.<br><br>This cohort study was part of the ENVIRONAGE (Environmental Influence on Aging in Early Life) study, a birth cohort of Belgian mother-child pairs with recruitment at birth and a median follow-up of 4.5 years conducted between October 2014 and July 2021. Participants included for analysis provided full data for evaluation at follow-up visit. Data analysis was conducted between August and September 2021.<br><br>MAIN OUTCOMES AND MEASURES: Cord blood and placental average relative TL were measured at birth using quantitative polymerase chain reaction (qPCR). Systolic, diastolic, and mean arterial pressure (MAP) were evaluated at follow-up. High childhood blood pressure (standardized for child age, sex, and height) was defined following the 2017 American Academy of Pediatrics guidelines. Multivariable adjusted linear and logistic regression models were used to associate newborn TL and blood pressure indicators in childhood.<br><br>RESULTS: This study included 485 newborn children (52.8% girls) with a mean (SD) age of 4.6 (0.4) years at the follow-up visit. Newborn TL was associated with lower blood pressure in childhood. A 1-IQR increase in cord blood TL was associated with a -1.54 mm Hg (95% CI, -2.36 to -0.72 mm Hg) lower diastolic blood pressure and -1.18 mm Hg (95% CI, -1.89 to -0.46 mm Hg) lower MAP. No association was observed with systolic blood pressure. Furthermore, a 1-IQR increase in cord blood TL was associated with lower odds of having high blood pressure at the age of 4 to 6 years (adjusted OR, 0.72; 95% CI, 0.53 to 0.98). In placenta, a 1-IQR increase in TL was associated with a -0.96 mm Hg (95% CI, -1.72 to -0.21 mm Hg) lower diastolic, -0.88 mm Hg (95% CI, -1.54 to -0.22 mm Hg) lower MAP, and a lower adjusted OR of 0.69 (95% CI, 0.52 to 0.92) for having a high blood pressure in childhood.<br><br>CONCLUSIONS AND RELEVANCE: In this prospective birth cohort study, variation in early life blood pressure at school-age was associated with TL at birth. Cardiovascular health may to some extent be programmed at birth, and these results suggest that TL entails a biological mechanism in this programming.}, }
@article {pmid35929966, year = {2022}, author = {Tummala, H and Walne, A and Dokal, I}, title = {The biology and management of dyskeratosis congenita and related disorders of telomeres.}, journal = {Expert review of hematology}, volume = {15}, number = {8}, pages = {685-696}, doi = {10.1080/17474086.2022.2108784}, pmid = {35929966}, issn = {1747-4094}, support = {MR/P018440/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Biology ; Danazol ; *Dyskeratosis Congenita/diagnosis/genetics/therapy ; Humans ; Mutation ; Oxymetholone ; *Telomerase ; Telomere/genetics/metabolism ; }, abstract = {BACKGROUND: Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders.<br><br>WHAT IS COVERED: Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future.<br><br>EXPERT VIEW: As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.}, }
@article {pmid35923948, year = {2022}, author = {Pepke, ML and Kvalnes, T and Ranke, PS and Araya-Ajoy, YG and Wright, J and Sæther, BE and Jensen, H and Ringsby, TH}, title = {Causes and consequences of variation in early-life telomere length in a bird metapopulation.}, journal = {Ecology and evolution}, volume = {12}, number = {8}, pages = {e9144}, pmid = {35923948}, issn = {2045-7758}, abstract = {Environmental conditions during early-life development can have lasting effects shaping individual heterogeneity in fitness and fitness-related traits. The length of telomeres, the DNA sequences protecting chromosome ends, may be affected by early-life conditions, and telomere length (TL) has been associated with individual performance within some wild animal populations. Thus, knowledge of the mechanisms that generate variation in TL, and the relationship between TL and fitness, is important in understanding the role of telomeres in ecology and life-history evolution. Here, we investigate how environmental conditions and morphological traits are associated with early-life blood TL and if TL predicts natal dispersal probability or components of fitness in 2746 wild house sparrow (Passer domesticus) nestlings from two populations sampled across 20 years (1994-2013). We retrieved weather data and we monitored population fluctuations, individual survival, and reproductive output using field observations and genetic pedigrees. We found a negative effect of population density on TL, but only in one of the populations. There was a curvilinear association between TL and the maximum daily North Atlantic Oscillation index during incubation, suggesting that there are optimal weather conditions that result in the longest TL. Dispersers tended to have shorter telomeres than non-dispersers. TL did not predict survival, but we found a tendency for individuals with short telomeres to have higher annual reproductive success. Our study showed how early-life TL is shaped by effects of growth, weather conditions, and population density, supporting that environmental stressors negatively affect TL in wild populations. In addition, shorter telomeres may be associated with a faster pace-of-life, as individuals with higher dispersal rates and annual reproduction tended to have shorter early-life TL.}, }
@article {pmid35920280, year = {2022}, author = {Borges, G and Criqui, M and Harrington, L}, title = {Tieing together loose ends: telomere instability in cancer and aging.}, journal = {Molecular oncology}, volume = {16}, number = {18}, pages = {3380-3396}, pmid = {35920280}, issn = {1878-0261}, support = {148936//CIHR/Canada ; }, mesh = {Aging/genetics ; Cellular Senescence/genetics ; Genomic Instability ; Humans ; *Neoplasms/genetics ; *Telomerase/genetics/metabolism ; Telomere/genetics/metabolism ; }, abstract = {Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.}, }
@article {pmid35920237, year = {2022}, author = {Gurvich, C and Thomas, N and Hudaib, AR and Van Rheenen, TE and Thomas, EHX and Tan, EJ and Neill, E and Carruthers, SP and Sumner, PJ and Romano-Silva, M and Bozaoglu, K and Kulkarni, J and Rossell, SL}, title = {The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders.}, journal = {Psychological medicine}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/S0033291722002148}, pmid = {35920237}, issn = {1469-8978}, abstract = {BACKGROUND: Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample.<br><br>METHODS: Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length.<br><br>RESULTS: Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group.<br><br>CONCLUSIONS: This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.}, }
@article {pmid35920029, year = {2022}, author = {Vernasco, BJ and Watts, HE}, title = {Telomere length predicts timing and intensity of migratory behaviour in a nomadic songbird.}, journal = {Biology letters}, volume = {18}, number = {8}, pages = {20220176}, pmid = {35920029}, issn = {1744-957X}, mesh = {Animal Migration/physiology ; Animals ; *Finches ; Psychomotor Agitation ; Seasons ; *Songbirds/genetics ; Telomere ; Telomere Shortening ; }, abstract = {Our understanding of state-dependent behaviour is reliant on identifying physiological indicators of condition. Telomeres are of growing interest for understanding behaviour as they capture differences in biological state and residual lifespan. To understand the significance of variable telomere lengths for behaviour and test two hypotheses describing the relationship between telomeres and behaviour (i.e. the causation and the selective adoption hypotheses), we assessed if telomere lengths are longitudinally repeatable traits related to spring migratory behaviour in captive pine siskins (Spinus pinus). Pine siskins are nomadic songbirds that exhibit highly flexible, facultative migrations, including a period of spring nomadism. Captive individuals exhibit extensive variation in spring migratory restlessness and are an excellent system for mechanistic studies of migratory behaviour. Telomere lengths were found to be significantly repeatable (R = 0.51) over four months, and shorter pre-migratory telomeres were associated with earlier and more intense expression of spring nocturnal migratory restlessness. Telomere dynamics did not vary with migratory behaviour. Our results describe the relationship between telomere length and migratory behaviour and provide support for the selective adoption hypothesis. More broadly, we provide a novel perspective on the significance of variable telomere lengths for animal behaviour and the timing of annual cycle events.}, }
@article {pmid35918419, year = {2022}, author = {Huang, MY and Madhani, HD}, title = {Telomere transposon takeover in Cryptococcus.}, journal = {Nature microbiology}, volume = {7}, number = {8}, pages = {1108-1109}, pmid = {35918419}, issn = {2058-5276}, mesh = {Automation ; *Cryptococcus/genetics ; Telomere ; }, }
@article {pmid35914599, year = {2022}, author = {Passos, JDC and Felisbino, K and Laureano, HA and Guiloski, IC}, title = {Occupational exposure to pesticides and its association with telomere length - A systematic review and meta-analysis.}, journal = {The Science of the total environment}, volume = {849}, number = {}, pages = {157715}, doi = {10.1016/j.scitotenv.2022.157715}, pmid = {35914599}, issn = {1879-1026}, mesh = {Biomarkers ; Humans ; *Occupational Exposure/adverse effects/analysis ; *Pesticides/toxicity ; Telomere ; }, abstract = {BACKGROUND: Telomere length is a common biomarker for the cumulative effect of environmental factors on aging-related diseases, therefore an association has been hypothesized between occupational exposure to pesticides and shorter telomere length.<br><br>OBJECTIVE: This study is a systematic review and meta-analysis aiming to examine the association between telomere length and occupational exposure to pesticides.<br><br>METHODS: We systematically searched in SciELO, PubMed, Scopus, Embase, Cochrane, Lilacs, Science Direct, and Web of Science databases for all observational studies containing measurements of telomere length on groups occupationally exposed to pesticides. Data were synthesized through qualitative synthesis and meta-analysis. We estimated the associations between exposed and non-exposed groups by using the natural log of the response ratio (lnRR). Heterogeneity was quantified using the Cochran Q test and I[2] statistics.<br><br>RESULTS: Six studies were included in the qualitative synthesis and meta-analysis, with a total of 480 participants exposed to pesticides. The time of exposure evaluated 391 participants that had a range of 5 to >30 years of occupational exposure. Most studies presented shorter telomere length in the occupationally exposed group. From the six studies included in the meta-analysis, three presented telomere length measurement as a single copy gene (T/S), and three presented telomere length measurement as base pairs (bp). The statistical analysis pooled estimates (log ratio of means) of the telomere length in both measurements (T/S and bp) showed a shortening of telomere length in the exposed group when compared with the non-exposed (control) group. Two of six studies reported longer telomere length in the group exposed to pesticides.<br><br>DISCUSSION: Our findings suggest an association between occupational exposure to pesticides and shorter telomere length. However, we found a small number of studies to include in our meta-analysis, being required more high-quality studies to strengthen our findings and conclusions.}, }
@article {pmid35912187, year = {2022}, author = {Mushtaq, I and Bhat, GR and Rah, B and Besina, S and Zahoor, S and Wani, MA and Shah, MA and Bashir, S and Farooq, M and Rather, RA and Afroze, D}, title = {Telomere Attrition With Concomitant hTERT Overexpression Involved in the Progression of Gastric Cancer May Have Prognostic and Clinical Implications in High-Risk Population Group From North India.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {919351}, pmid = {35912187}, issn = {2234-943X}, abstract = {Genetic instabilities exacerbated by the dysfunction of telomeres can lead to the development of cancer. Nearly 90% of all human malignancies are linked with telomere dysregulation and overexpression of telomerase, an enzyme that catalyzes the synthesis of telomeric DNA repeats at the ends of chromosomes. The burden of gastric cancer continues to inflict a deterring impact on the global health scenario, accounting for over one million new cases in 2020. The disease is asymptomatic in its early stages of progression, which is attributed to the poor prognosis and overall surge in mortality rate worldwide. Exploiting telomere physiology can provide extensive mechanistic insight into telomere-associated gastric cancer progression and its use as a target in a variety of therapeutic interventions. In this study, we aimed to evaluate the clinical implications of c-Myc, human telomerase reverse transcriptase (hTERT) expression, and telomere length in patients with gastric cancer. A total of 57 gastric cancer cases and adjacent controls were included in the study. RT-PCR and immunohistochemistry were used to assess the expression levels of c-Myc and hTERT. The relative telomere length was measured by MMQPCR using the Cawthon method. Our results indicated that the shorter telomere and increased hTERT expression were associated with gastric cancer progression. The study also highlighted the role of short telomeres and increased expression of hTERT in gastric cancer progression and its association with various etiological risk factors, transcriptional activators, and overall survival among the ethnic Kashmiri population of North India.}, }
@article {pmid35911771, year = {2022}, author = {Liao, Q and He, J and Tian, FF and Bi, FF and Huang, K}, title = {A causal relationship between leukocyte telomere length and multiple sclerosis: A Mendelian randomization study.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {922922}, pmid = {35911771}, issn = {1664-3224}, mesh = {Genome-Wide Association Study ; Humans ; Leukocytes ; *Mendelian Randomization Analysis ; *Multiple Sclerosis/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; }, abstract = {OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory autoimmune and degenerative disorder of the central nervous system. Telomeres are protective structures located at the ends of linear chromosomes, and leukocyte telomere length (LTL) is closely connected with cell aging and senescence. However, the relationship between LTL and the risk of MS remains unknown.<br><br>METHODS: We performed a two-sample Mendelian randomization (MR) to evaluate whether LTL was causally associated with MS risk.<br><br>RESULTS: In our MR analysis, 12 LTL-related variants were selected as valid instrumental variables, and a causal relationship between LTL and MS was suggested. The risk of MS nearly doubled as the genetically predicted LTL shortened by one standard deviation (SD) under the inverse variance weighted (IVW) fixed effect model (odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.52-2.62, p = 6.01e-07). Similar estimated causal effects were also observed under different MR models. The MR-Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.005, stand error (SE) = 0.03, p = 0.87). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis also indicated no directional pleiotropy or outliers for any LTL-related IVs (p-global test = 0.13). In addition, a leave-one-out sensitivity analysis showed similar findings, which further emphasized the validity and stability of the causal relationship.<br><br>CONCLUSIONS: Our results suggest a potential causal effect of LTL on the risk of MS. Genetically predicted shorter LTL could increase the risk of MS in the European population. LTL should be noted and emphasized in the pathogenesis and treatment of MS.}, }
@article {pmid35910300, year = {2022}, author = {Aviv, A}, title = {The telomere tumult: meaning and metrics in population studies.}, journal = {The lancet. Healthy longevity}, volume = {3}, number = {5}, pages = {e308-e309}, pmid = {35910300}, issn = {2666-7568}, support = {R01 HL134840/HL/NHLBI NIH HHS/United States ; U01 AG066529/AG/NIA NIH HHS/United States ; }, mesh = {*Benchmarking ; *Biological Specimen Banks ; Health Behavior ; Leukocytes ; Telomere/genetics ; United Kingdom ; }, }
@article {pmid35903361, year = {2022}, author = {Son, N and Cui, Y and Xi, W}, title = {Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {931785}, pmid = {35903361}, issn = {1664-8021}, abstract = {Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168-1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046-1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332-0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.}, }
@article {pmid35902621, year = {2022}, author = {Bae, JS and Lee, JW and Joung, JG and Cho, HW and Ju, HY and Yoo, KH and Koo, HH and Sung, KW}, title = {Clinical significance of germline telomere length and associated genetic factors in patients with neuroblastoma.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {12954}, pmid = {35902621}, issn = {2045-2322}, mesh = {Genetic Markers ; *Genome-Wide Association Study ; Humans ; Leukocytes, Mononuclear ; *Neuroblastoma/genetics ; Polymorphism, Single Nucleotide ; Telomere/genetics ; }, abstract = {Studies investigating the relationship between germline telomere length and the clinical characteristics of tumors are very limited. This study evaluated the relationship between germline telomere length and the clinical characteristics of neuroblastoma. In addition, a genome-wide association study (GWAS) was performed to investigate the genetic factors associated with germline telomere length. The germline telomere length of peripheral blood mononuclear cells from 186 patients with neuroblastoma was measured by quantitative polymerase chain reaction. The association between germline telomere length and clinical characteristics, including long-term survival, was investigated. For the GWAS, genotyping was performed with a high-density bead chip (Illumina, San Diego, CA, USA). After strict quality-control checks of the samples, an association analysis was conducted. The result showed that longer germline telomeres were significantly associated with longer event-free survival (P = 0.032). To identify significantly assocated genetic markers for germline telomere length, genome wide association analysis was performed. As a result, several single nucleotide polymorphisms located in HIVEP3, LRRTM4, ADGRV1, RAB30, and CHRNA4 genes were discovered. During gene-based analysis (VEGAS2 tool), the CNTN4 gene had the most significant association with germline telomere length (P = 1.0E-06). During gene ontology analysis, susceptible genes associated with germline telomere length were mainly distributed in neurite morphogenesis and neuron development. A longer germline telomere length is associated with favorable prognostic factors at diagnosis and eventually better event-free survival in patients with neuroblastoma. In addition, the GWAS demonstrated that genetic markers and genes related to germline telomere length are associated with neurite morphogenesis and neuron development. Further research with larger cohorts of patients and functional investigations are needed.}, }
@article {pmid35897312, year = {2022}, author = {Liu, Y and Liu, S and Xin, J and Qian, P and Guo, S and Xu, X and Wang, D and Yang, L}, title = {Telomere Length and Hearing Loss: A Two-Sample Mendelian Randomization.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {15}, pages = {}, pmid = {35897312}, issn = {1660-4601}, mesh = {Genome-Wide Association Study ; *Hearing Loss/epidemiology/genetics ; Humans ; *Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Telomere ; }, abstract = {BACKGROUND: Observational studies have suggested that there may be an association between telomere length (TL) and hearing loss (HL). However, inferring causality from observational studies is subject to residual confounding effects, reverse causation, and bias. This study adopted a two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between TL and increased risk of HL.<br><br>METHODS: A total of 16 single nucleotide polymorphisms (SNPs) associated with TL were identified from a genome-wide association study (GWAS) meta-analysis of 78,592 European participants and applied to our modeling as instrumental variables. Summary-level data for hearing loss (HL), age-related hearing loss (ARHL), and noise-induced hearing loss (NIHL) were obtained from the recent largest available GWAS and five MR analyses were used to investigate the potential causal association of genetically predicted TL with increased risk for HL, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode. In addition, sensitivity analysis, pleiotropy, and heterogeneity tests were also used to evaluate the robustness of our findings.<br><br>RESULTS: There was no causal association between genetically predicted TL and HL or its subtypes (by the IVW method, HL: odds ratio (OR) = 1.216, p = 0.382; ARHL: OR = 0.934, p = 0.928; NIHL: OR = 1.003, p = 0.776). Although heterogenous sites rs2736176, rs3219104, rs8105767, and rs2302588 were excluded for NIHL, the second MR analysis was consistent with the first analysis (OR = 1.003, p = 0.572).<br><br>CONCLUSION: There was no clear causal relationship between shorter TLs and increased risk of HL or its subtypes in this dataset.}, }
@article {pmid35892638, year = {2022}, author = {Scarabino, D and Veneziano, L and Fiore, A and Nethisinghe, S and Mantuano, E and Garcia-Moreno, H and Bellucci, G and Solanky, N and Morello, M and Zanni, G and Corbo, RM and Giunti, P}, title = {Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {35892638}, issn = {2076-3921}, abstract = {SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.}, }
@article {pmid35887427, year = {2022}, author = {Quenu, M and Treindl, AD and Lee, K and Takemoto, D and Thünen, T and Ashrafi, S and Winter, D and Ganley, ARD and Leuchtmann, A and Young, CA and Cox, MP}, title = {Telomere-to-Telomere Genome Sequences across a Single Genus Reveal Highly Variable Chromosome Rearrangement Rates but Absolute Stasis of Chromosome Number.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {8}, number = {7}, pages = {}, pmid = {35887427}, issn = {2309-608X}, abstract = {Genome rearrangements in filamentous fungi are prevalent but little is known about the modalities of their evolution, in part because few complete genomes are available within a single genus. To address this, we have generated and compared 15 complete telomere-to-telomere genomes across the phylogeny of a single genus of filamentous fungi, Epichloë. We find that the striking distinction between gene-rich and repeat-rich regions previously reported for isolated species is ubiquitous across the Epichloë genus. We built a species phylogeny from single-copy gene orthologs to provide a comparative framing to study chromosome composition and structural change through evolutionary time. All Epichloë genomes have exactly seven nuclear chromosomes, but despite this conserved ploidy, analyses reveal low synteny and substantial rearrangement of gene content across the genus. These rearrangements are highly lineage-dependent, with most occurring over short evolutionary distances, with long periods of structural stasis. Quantification of chromosomal rearrangements shows they are uncorrelated with numbers of substitutions and evolutionary distances, suggesting that different modes of evolution are acting to create nucleotide and chromosome-scale changes.}, }
@article {pmid35886017, year = {2022}, author = {Zimnitskaya, OV and Petrova, MM and Lareva, NV and Cherniaeva, MS and Al-Zamil, M and Ivanova, AE and Shnayder, NA}, title = {Leukocyte Telomere Length as a Molecular Biomarker of Coronary Heart Disease.}, journal = {Genes}, volume = {13}, number = {7}, pages = {}, pmid = {35886017}, issn = {2073-4425}, mesh = {Adult ; Biomarkers ; *Cardiovascular Diseases ; *Coronary Disease/genetics ; Humans ; Leukocytes ; Telomere/genetics ; }, abstract = {BACKGROUND: This work is a review of preclinical and clinical studies of the role of telomeres and telomerase in the development and progression of coronary heart disease (CHD).<br><br>MATERIALS AND METHODS: A search for full-text publications (articles, reviews, meta-analyses, Cochrane reviews, and clinical cases) in English and Russian was carried out in the databases PubMed, Oxford University Press, Scopus, Web of Science, Springer, and E-library electronic library using keywords and their combinations. The search depth is 11 years (2010-2021).<br><br>RESULTS: The review suggests that the relative leukocyte telomere length (LTL) is associated with the development of socially significant and widespread cardiovascular diseases such as CHD and essential hypertension. At the same time, the interests of researchers are mainly focused on the study of the relative LTL in CHD.<br><br>CONCLUSIONS: Despite the scientific and clinical significance of the analyzed studies of the relative length of human LTL as a biological marker of cardiovascular diseases, their implementation in real clinical practice is difficult due to differences in the design and methodology of the analyzed studies, as well as differences in the samples by gender, age, race, and ethnicity. The authors believe that clinical studies of the role of the relative length of leukocyte telomeres in adult patients with coronary heart disease are the most promising and require large multicenter studies with a unified design and methodology.}, }
@article {pmid35884905, year = {2022}, author = {Lauriola, A and Davalli, P and Marverti, G and Caporali, A and Mai, S and D'Arca, D}, title = {Telomere Dysfunction Is Associated with Altered DNA Organization in Trichoplein/Tchp/Mitostatin (TpMs) Depleted Cells.}, journal = {Biomedicines}, volume = {10}, number = {7}, pages = {}, pmid = {35884905}, issn = {2227-9059}, abstract = {Recently, we highlighted a novel role for the protein Trichoplein/TCHP/Mitostatin (TpMs), both as mitotic checkpoint regulator and guardian of chromosomal stability. TpMs-depleted cells show numerical and structural chromosome alterations that lead to genomic instability. This condition is a major driving force in malignant transformation as it allows for the cells acquiring new functional capabilities to proliferate and disseminate. Here, the effect of TpMs depletion was investigated in different TpMs-depleted cell lines by means of 3D imaging and 3D Structured illumination Microscopy. We show that TpMs depletion causes alterations in the 3D architecture of telomeres in colon cancer HCT116 cells. These findings are consistent with chromosome alterations that lead to genomic instability. Furthermore, TpMs depletion changes the spatial arrangement of chromosomes and other nuclear components. Modified nuclear architecture and organization potentially induce variations that precede the onset of genomic instability and are considered as markers of malignant transformation. Our present observations connect the tumor suppression ability of TpMs with its novel functions in maintaining the proper chromosomal segregation as well as the proper telomere and nuclear architecture. Further investigations will investigate the connection between alterations in telomeres and nuclear architecture with the progression of human tumors with the aim of developing personalized therapeutic interventions.}, }
@article {pmid35880304, year = {2022}, author = {Curtis, EM and Codd, V and Nelson, C and D'Angelo, S and Wang, Q and Allara, E and Kaptoge, S and Matthews, PM and Tobias, JH and Danesh, J and Cooper, C and Samani, NJ and Harvey, NC}, title = {Telomere Length and Risk of Incident Fracture and Arthroplasty: Findings From UK Biobank.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {37}, number = {10}, pages = {1997-2004}, pmid = {35880304}, issn = {1523-4681}, support = {209233/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MC_PC_21001/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; MC_PC_21003/MRC_/Medical Research Council/United Kingdom ; 201268/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Female ; Male ; Humans ; Middle Aged ; Hand Strength ; *Arthroplasty, Replacement, Hip ; Biological Specimen Banks ; *Arthroplasty, Replacement, Knee ; *Fractures, Bone/epidemiology/genetics ; Bone Density ; Telomere ; United Kingdom/epidemiology ; Risk Factors ; *Osteoporotic Fractures/epidemiology ; *Hip Fractures/epidemiology ; }, abstract = {We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leukocyte telomere length (LTL) was measured in baseline samples using a validated polymerase chain reaction (PCR) method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio (HR) for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity, and menopause (women). In further analyses we adjusted for either estimated bone mineral density (eBMD) from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance), or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean ± standard deviation (SD) age 56.4 ± 8.0 and 57.0 ± 8.3 years, respectively. During follow-up there were 5619 fractures; 5285 hip and 4261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men (HR/SD 0.93; 95% confidence interval [CI], 0.88-0.97) and women (0.92; 95% CI, 0.88-0.96), and hip arthroplasty in men (0.91; 95% CI, 0.87-0.95), but not women (0.98; 95% CI, 0.94-1.01). Longer LTL was weakly associated with reduced risk of any incident fracture in women (HR/SD 0.96; 95% CI, 0.93-1.00) with less evidence in men (0.98; 95% CI, 0.93-1.02). Associations with incident outcomes were not materially altered by adjustment for heel eBMD, grip strength, gait speed, fat mass, or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeletal systems might influence later life musculoskeletal outcomes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).}, }
@article {pmid35879401, year = {2022}, author = {Topiwala, A and Taschler, B and Ebmeier, KP and Smith, S and Zhou, H and Levey, DF and Codd, V and Samani, NJ and Gelernter, J and Nichols, TE and Burgess, S}, title = {Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.}, journal = {Molecular psychiatry}, volume = {27}, number = {10}, pages = {4001-4008}, pmid = {35879401}, issn = {1476-5578}, support = {/WT_/Wellcome Trust/United Kingdom ; I01 CX001849/CX/CSRD VA/United States ; BRC-1215-20010/DH_/Department of Health/United Kingdom ; 216462/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; G1001354/MRC_/Medical Research Council/United Kingdom ; MR/K013351/1/MRC_/Medical Research Council/United Kingdom ; R01 EB026859/EB/NIBIB NIH HHS/United States ; BRC-1215-20014/DH_/Department of Health/United Kingdom ; 100309/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Mendelian Randomization Analysis ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Alcohol Drinking/genetics ; Ethanol ; Telomere/genetics ; }, abstract = {Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.}, }
@article {pmid35878015, year = {2022}, author = {Zhan, Y and Kang, X}, title = {Disentangling the Causal Effect of Telomere Length in Systemic Lupus Erythematosus Using Genetic Variants as Instruments.}, journal = {Arthritis &amp; rheumatology (Hoboken, N.J.)}, volume = {74}, number = {12}, pages = {1890-1892}, doi = {10.1002/art.42313}, pmid = {35878015}, issn = {2326-5205}, mesh = {Humans ; *Lupus Erythematosus, Systemic/genetics ; Telomere/genetics ; Causality ; }, }
@article {pmid35876482, year = {2022}, author = {}, title = {Corrigendum to: TERT promoter C228T mutation in neural progenitors confers growth advantage following telomere shortening in vivo.}, journal = {Neuro-oncology}, volume = {24}, number = {11}, pages = {2008}, doi = {10.1093/neuonc/noac178}, pmid = {35876482}, issn = {1523-5866}, }
@article {pmid35872157, year = {2022}, author = {Heaphy, CM and Singhi, AD}, title = {The diagnostic and prognostic utility of incorporating DAXX, ATRX, and alternative lengthening of telomeres to the evaluation of pancreatic neuroendocrine tumors.}, journal = {Human pathology}, volume = {129}, number = {}, pages = {11-20}, doi = {10.1016/j.humpath.2022.07.015}, pmid = {35872157}, issn = {1532-8392}, support = {R37 CA263622/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adaptor Proteins, Signal Transducing/genetics/metabolism ; Biomarkers, Tumor/genetics ; Co-Repressor Proteins/metabolism ; In Situ Hybridization, Fluorescence ; Molecular Chaperones/metabolism ; *Neuroendocrine Tumors/diagnosis/genetics/pathology ; Nuclear Proteins/genetics/metabolism ; *Pancreatic Neoplasms/diagnosis/genetics/metabolism ; Prognosis ; *Telomere/pathology ; X-linked Nuclear Protein/genetics ; }, abstract = {Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and an ill-defined pathobiology. Although many PanNETs are indolent and remain stable for years, a subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of PanNETs presents a treatment dilemma. Current prognostic systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients diagnosed with a PanNET. Recent studies have identified alterations in death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (ATRX), as well as alternative lengthening of telomeres (ALT), as promising prognostic biomarkers. This review summarizes the identification, clinical utility, and specific nuances in testing for DAXX/ATRX by immunohistochemistry and ALT by telomere-specific fluorescence in situ hybridization in PanNETs. Furthermore, a discussion on diagnostic indications for DAXX, ATRX, and ALT status is provided to include the distinction between PanNETs and pancreatic neuroendocrine carcinomas (PanNECs), and determining pancreatic origin for metastatic neuroendocrine tumors in the setting of an unknown primary.}, }
@article {pmid35862346, year = {2022}, author = {Nadri, P and Ansari-Mahyari, S and Jafarpour, F and Mahdavi, AH and Tanhaei Vash, N and Lachinani, L and Dormiani, K and Nasr-Esfahani, MH}, title = {Melatonin accelerates the developmental competence and telomere elongation in ovine SCNT embryos.}, journal = {PloS one}, volume = {17}, number = {7}, pages = {e0267598}, pmid = {35862346}, issn = {1932-6203}, mesh = {Animals ; Blastocyst/metabolism ; Culture Media/metabolism ; Embryonic Development/genetics ; *Melatonin/metabolism/pharmacology ; *Nuclear Transfer Techniques/veterinary ; RNA, Messenger/metabolism ; Sheep/genetics ; Telomere ; }, abstract = {SCNT embryos suffer from poor developmental competence (both in vitro and in vivo) due to various defects such as oxidative stress, incomplete epigenetic reprogramming, and flaws in telomere rejuvenation. It is very promising to ameliorate all these defects in SCNT embryos by supplementing the culture medium with a single compound. It has been demonstrated that melatonin, as a multitasking molecule, can improve the development of SCNT embryos, but its function during ovine SCNT embryos is unclear. We observed that supplementation of embryonic culture medium with 10 nM melatonin for 7 days accelerated the rate of blastocyst formation in ovine SCNT embryos. In addition, the quality of blastocysts increased in the melatonin-treated group compared with the SCNT control groups in terms of ICM, TE, total cell number, and mRNA expression of NANOG. Mechanistic studies in this study revealed that the melatonin-treated group had significantly lower ROS level, apoptotic cell ratio, and mRNA expression of CASPASE-3 and BAX/BCL2 ratio. In addition, melatonin promotes mitochondrial membrane potential and autophagy status (higher number of LC3B dots). Our results indicate that melatonin decreased the global level of 5mC and increased the level of H3K9ac in the treated blastocyst group compared with the blastocysts in the control group. More importantly, we demonstrated for the first time that melatonin treatment promoted telomere elongation in ovine SCNT embryos. This result offers the possibility of better development of ovine SCNT embryos after implantation. We concluded that melatonin can accelerate the reprogramming of telomere length in sheep SCNT embryos, in addition to its various beneficial effects such as increasing antioxidant capacity, reducing DNA damage, and improving the quality of derived blastocysts, all of which led to a higher in vitro development rate.}, }
@article {pmid35862118, year = {2022}, author = {Brandt, M and Dörschmann, H and Khraisat, S and Knopp, T and Ringen, J and Kalinovic, S and Garlapati, V and Siemer, S and Molitor, M and Göbel, S and Stauber, R and Karbach, SH and Münzel, T and Daiber, A and Wenzel, P}, title = {Telomere Shortening in Hypertensive Heart Disease Depends on Oxidative DNA Damage and Predicts Impaired Recovery of Cardiac Function in Heart Failure.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {79}, number = {10}, pages = {2173-2184}, doi = {10.1161/HYPERTENSIONAHA.121.18935}, pmid = {35862118}, issn = {1524-4563}, mesh = {Animals ; DNA ; *Heart Failure ; *Hypertension ; Mice ; NADPH Oxidases/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Telomere Shortening ; }, abstract = {BACKGROUND: Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial hypertension are associated with dysregulation of the neurohormonal axis. How neurohormonal activation is linked to telomere shortening in the pathogenesis of HF is incompletely understood.<br><br>METHODS: Cardiomyocyte telomere length was assessed in a mouse model of hypertensive HF induced by excess neurohormonal activation (AngII [angiotensin II] infusion, high salt diet, and uninephrectomy), in AngII-stimulated cardiomyocytes and in endomyocardial biopsies from patients with HF. Superoxide production, expression of NOX2 (NADPH oxidase 2) and PRDX1 (peroxiredoxin 1) and HDAC6 (histone deacetylase 6) activity were assessed.<br><br>RESULTS: Telomere shortening occurred in vitro and in vivo, correlating with both left ventricular (LV) dilatation and LV systolic function impairment. Telomere shortening coincided with increased superoxide production, increased NOX2 expression, increased HDAC6 activity, loss of the telomere-specific antioxidant PRDX1, and increased oxidative DNA-damage. NOX2 knockout prevented PRDX1 depletion, DNA-damage and telomere shortening confirming this enzyme as a critical source of reactive oxygen species. Cotreatment with the NOX inhibitor apocynin ameliorated hypertensive HF and telomere shortening. Similarly, treatment with the HDAC6 inhibitor tubastatin A, which increases PRDX1 bioavailability, prevented telomere shortening in adult cardiomyocytes. To explore the clinical relevance of our findings, we examined endomyocardial biopsies from an all-comer population of patients with HF with reduced ejection fraction. Here, cardiomyocyte telomere length predicted the recovery of cardiac function.<br><br>CONCLUSIONS: Cardiomyocyte telomere shortening and oxidative damage in heart failure with reduced ejection fraction induced by excess neurohormonal activation depends on NOX2-derived superoxide and may help to stratify HF therapy.}, }
@article {pmid35861921, year = {2022}, author = {Kayacık Günday, &#xd6; and Özdemir Erdoğan, M and Pehlivan, A and Yılmazer, M}, title = {The effect of metformin treatment on leukocyte telomere length in patients with polycystic ovary syndrome: a prospective case-contr