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24 Feb 2021 at 01:48
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Bibliography on: Telomeres


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Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

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Citations The Papers (from PubMed®)


RevDate: 2021-02-23

Mehta SR, Iudicello JE, Lin J, et al (2021)

Telomere length is associated with HIV infection, methamphetamine use, inflammation, and comorbid disease risk.

Drug and alcohol dependence, 221:108639 pii:S0376-8716(21)00134-4 [Epub ahead of print].

BACKGROUND: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.

METHODS: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).

RESULTS: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).

CONCLUSIONS: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.

RevDate: 2021-02-22

Poláková E, Záhonová K, Albanaz ATS, et al (2021)

Diverse telomeres in trypanosomatids.

Parasitology pii:S0031182021000378 [Epub ahead of print].

RevDate: 2021-02-20

Bi J, Wu M, Liu Y, et al (2021)

Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study.

Ecotoxicology and environmental safety, 213:112037 pii:S0147-6513(21)00148-2 [Epub ahead of print].

OBJECTIVE: Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life. Newborn TL is sensitive to maternal metals concentrations, while study about the association between maternal manganese (Mn) concentrations and newborn TL was not found. Our study aimed to investigate whether newborn TL is related to maternal Mn concentrations.

METHODS: Data were collected from a birth cohort study of 762 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. We measured the Mn concentrations in spot urine samples collected during three trimesters by inductively coupled plasma mass spectrometry (ICP-MS) and relative cord blood TL by quantitative real-time polymerase chain reaction (qPCR). We applied multiple informant models to investigate the associations between maternal Mn concentrations and cord blood TL.

RESULTS: The geometric mean of creatinine-corrected urinary Mn concentrations were 1.58 μg/g creatinine, 2.53 μg/g creatinine, and 2.62 μg/g creatinine in the first, second, and third trimester, respectively. After adjusting for potential confounders, a doubling of maternal urinary Mn concentration during the second trimester was related to a 2.10% (95% CI: 0.25%, 3.99%) increase in cord blood TL. Mothers with the highest tertile of urinary Mn concentrations during the second trimester had a 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL than those with the lowest tertile. This association was more evident in male infants. No relationship was found between maternal urinary Mn concentrations and cord blood TL during the first and third trimesters in our study.

CONCLUSIONS: Our findings suggested that maternal Mn concentration during the second trimester was positively associated with newborn TL. These results might provide an epidemiology evidence on the protective role of maternal Mn for newborn TL and offer clues for the early prevention of telomere shortening related diseases.

RevDate: 2021-02-20

Lim CJ, TR Cech (2021)

Publisher Correction: Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.

RevDate: 2021-02-20

Augereau A, Mariotti M, Pousse M, et al (2021)

Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen.

Science advances, 7(8): pii:7/8/eabe0174.

The naked mole rat (NMR), a long-lived and cancer-resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment.

RevDate: 2021-02-20

Córdoba-Lanús E, Cazorla-Rivero S, García-Bello MA, et al (2021)

Telomere length dynamics over 10-years and related outcomes in patients with COPD.

Respiratory research, 22(1):56.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been proposed as a disease of accelerated aging. Several cross-sectional studies have related a shorter telomere length (TL), a marker of biological aging, with COPD outcomes. Whether accelerated telomere shortening over time relates to worse outcomes in COPD patients, is not known.

METHODS: Relative telomere length (T/S) was determined by qPCR in DNA samples from peripheral blood in 263 patients at baseline and up to 10 years post enrolment. Yearly clinical and lung function data of 134 patients with at least two-time measures of T/S over this time were included in the analysis.

RESULTS: At baseline, T/S inversely correlated with age (r = - 0.236; p < 0.001), but there was no relationship between T/S and clinical and lung function variables (p > 0.05). Over 10 years of observation, there was a median shortening of TL of 183 bp/year for COPD patients. After adjusting for age, gender, active smoking and mean T/S, patients that shortened their telomeres the most over time, had worse gas exchange, more lung hyperinflation and extrapulmonary affection during the follow-up, (PaO2 p < 0.0001; KCO p = 0.042; IC/TLC p < 0.0001; 6MWD p = 0.004 and BODE index p = 0.009). Patients in the lowest tertile of T/S through the follow-up period had an increased risk of death [HR = 5.48, (1.23-24.42) p = 0.026].

CONCLUSIONS: This prospective study shows an association between accelerated telomere shortening and progressive worsening of pulmonary gas exchange, lung hyperinflation and extrapulmonary affection in COPD patients. Moreover, persistently shorter telomeres over this observation time increase the risk for all-cause mortality.

RevDate: 2021-02-19

Puttabyatappa M, Ciarelli JN, Chatoff AG, et al (2021)

Developmental Programming: Metabolic Tissue-Specific Changes in Endoplasmic Reticulum Stress, Mitochondrial Oxidative and Telomere Length Status induced by Prenatal Testosterone Excess in the Female Sheep.

Molecular and cellular endocrinology pii:S0303-7207(21)00051-4 [Epub ahead of print].

Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver / muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial oxidative phosphorylation (OxPhos), number, and function, ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age. Prenatal T treatment led to: (a) reduction in mitochondrial number and OxPhos complexes and increase in ER stress markers in muscle; (b) increase in fibrosis with trend towards increase in short telomere fragments in liver (c) depot-specific mitochondrial changes with OxPhos complexes namely increase in SAT and reduction in PRAT and increase in mitochondrial number in ECAT; (d) depot-specific ER stress marker changes with increase in VAT, reduction in SAT, contrasting changes in ECAT and no changes in PRAT; and (d) reduced shorter telomere fragments in SAT, ECAT and PRAT. These changes indicate insulin resistance may be driven by mitochondrial and ER dysfunction in muscle, fibrosis and premature senescence in liver, and depot-specific changes in mitochondrial function and ER stress without involving cellular senescence in adipose tissue. These findings provide mechanistic insights into pathophysiology of metabolic dysfunction among female offspring from hyperandrogenic pregnancies.

RevDate: 2021-02-18

Akincilar SC, Chan CHT, Ng QF, et al (2021)

Non-canonical roles of canonical telomere binding proteins in cancers.

Cellular and molecular life sciences : CMLS [Epub ahead of print].

Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role. While targeting telomerase activity appears to be an attractive therapeutic option, this approach has failed in clinical trials due to undesirable cytotoxic effects on stem cells. To circumvent this concern, an alternative strategy could be to target the molecules involved in the non-canonical functions of telomeric proteins. In this review, we will focus on emerging evidence that has demonstrated the non-canonical roles of telomeric proteins and their impact on tumorigenesis. Furthermore, we aim to address current knowledge gaps in telomeric protein functions and propose future research approaches that can be undertaken to achieve this.

RevDate: 2021-02-18

Katoto PDMC, Kayembe-Kitenge T, Pollitt KJG, et al (2021)

Telomere length and outcome of treatment for pulmonary tuberculosis in a gold mining community.

Scientific reports, 11(1):4031.

Telomere length (TL) is a marker of ageing and mitochondrial DNA (mtDNA) is an early marker of inflammation caused by oxidative stress. We determined TL and mtDNA content among active pulmonary tuberculosis (PTB) patients to assess if these cellular biomarkers differed between artisanal miners and non-miners, and to assess if they were predictive of treatment outcome. We conducted a prospective cohort study from August 2018 to May 2019 involving newly diagnosed PTB patients at three outpatient TB clinics in a rural Democratic Republic of Congo. We measured relative TL and mtDNA content in peripheral blood leukocytes (at inclusion) via qPCR and assessed their association with PTB treatment outcome. We included 129 patients (85 miners and 44 non-miners) with PTB (median age 40 years; range 5-71 years, 22% HIV-coinfected). For each increase in year and HIV-coinfection, TL shortened by - 0.85% (- 0.19 to - 0.52) (p ≤ 0.0001) and - 14% (- 28.22 to - 1.79) (p = 0.02) respectively. Independent of these covariates, patients with longer TL were more likely to have successful TB treatment [adjusted hazard ratio; 95% CI 1.27 for a doubling of leucocyte telomere length at baseline; 1.05-1.44] than patients with a shorter TL. Blood mtDNA content was not predictive for PTB outcome. For a given chronological age, PTB patients with longer telomeres at time of diagnosis were more likely to have successful PTB treatment outcome.

RevDate: 2021-02-18

Kim C, Sung S, Kim JS, et al (2021)

Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells.

Nature communications, 12(1):1097.

Telomeres are part of a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes to protect chromosomal ends; however, in some species or telomerase-defective situations, an alternative lengthening of telomeres (ALT) mechanism is used. ALT mainly utilises recombination-based replication mechanisms and the constituents of ALT-based telomeres vary depending on models. Here we show that mouse telomeres can exploit non-telomeric, unique sequences in addition to telomeric repeats. We establish that a specific subtelomeric element, the mouse template for ALT (mTALT), is used for repairing telomeric DNA damage as well as for composing portions of telomeres in ALT-dependent mouse embryonic stem cells. Epigenomic and proteomic analyses before and after ALT activation reveal a high level of non-coding mTALT transcripts despite the heterochromatic nature of mTALT-based telomeres. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributes to the maintenance of telomere stability by regulating telomeric transcription. These findings provide a molecular basis to study the evolution of new structures in telomeres.

RevDate: 2021-02-17

Raghunandan M, Geelen D, Majerova E, et al (2021)

NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres.

The EMBO journal [Epub ahead of print].

About 10% of cancer cells employ the "alternative lengthening of telomeres" (ALT) pathway instead of re-activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT+ cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPAS33) at ALT telomeres by promoting the hnRNPA1- and DNA-PK-dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT+ cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from hTR's non-canonical function in modulating telomeric p-RPAS33 . Collectively, our study shines new light on the interference between telomerase- and ALT-dependent pathways and unravels a crucial role for hTR and NHP2 in DDR regulation at ALT telomeres.

RevDate: 2021-02-17

Gutierrez-Rodrigues F, Alves-Paiva RM, Scatena NF, et al (2021)

Association between leukocyte telomere length and sex by quantile regression analysis.

Hematology, transfusion and cell therapy pii:S2531-1379(21)00005-5 [Epub ahead of print].

INTRODUCTION: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex.

METHODS: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis.

RESULTS: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p < 0.0001 vs. 45 pb kb per year, p < 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model.

CONCLUSION: The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.

RevDate: 2021-02-15

Sparks AM, Spurgin LG, van der Velde M, et al (2021)

Telomere heritability and parental age at conception effects in a wild avian population.

Molecular ecology [Epub ahead of print].

Individual variation in telomere length is predictive of health and mortality risk across a range of species. However, the relative influence of environmental and genetic variation on individual telomere length in wild populations remains poorly understood. Heritability of telomere length has primarily been calculated using parent-offspring regression which can be confounded by shared environments. To control for confounding variables, quantitative genetic "animal models" can be used, but few studies have applied animal models in wild populations. Furthermore, parental age at conception may also influence offspring telomere length, but most studies have been cross-sectional. We investigated within- and between-parental age at conception effects and heritability of telomere length in the Seychelles warbler using measures from birds caught over 20 years and a multigenerational pedigree. We found a weak negative within-paternal age at conception effect (as fathers aged, their offspring had shorter telomeres) and a weak positive between-maternal age at conception effect (females that survived to older ages had offspring with longer telomeres). Animal models provided evidence that heritability and evolvability of telomere length were low in this population, and that variation in telomere length was not driven by early-life effects of hatch period or parental identities. Quantitative polymerase chain reaction plate had a large influence on telomere length variation and not accounting for it in the models would have underestimated heritability. Our study illustrates the need to include and account for technical variation in order to accurately estimate heritability, as well as other environmental effects, on telomere length in natural populations.

RevDate: 2021-02-16

Shen M, Young A, C Autexier (2021)

PCNA, a focus on replication stress and the alternative lengthening of telomeres pathway.

DNA repair, 100:103055 pii:S1568-7864(21)00011-2 [Epub ahead of print].

The maintenance of telomeres, which are specialized stretches of DNA found at the ends of linear chromosomes, is a crucial step for the immortalization of cancer cells. Approximately 10-15 % of cancer cells use a homologous recombination-based mechanism known as the Alternative Lengthening of Telomeres (ALT) pathway to maintain their telomeres. Telomeres in general pose a challenge to DNA replication owing to their repetitive nature and potential for forming secondary structures. Telomeres in ALT+ cells especially are subject to elevated levels of replication stress compared to telomeres that are maintained by the enzyme telomerase, in part due to the incorporation of telomeric variant repeats at ALT+ telomeres, their on average longer lengths, and their modified chromatin states. Many DNA metabolic strategies exist to counter replication stress and to protect stalled replication forks. The role of proliferating cell nuclear antigen (PCNA) as a platform for recruiting protein partners that participate in several of these DNA replication and repair pathways has been well-documented. We propose that many of these pathways may be active at ALT+ telomeres, either to facilitate DNA replication, to manage replication stress, or during telomere extension. Here, we summarize recent evidence detailing the role of PCNA in pathways including DNA secondary structure resolution, DNA damage bypass, replication fork restart, and DNA damage synthesis. We propose that an examination of PCNA and its post-translational modifications (PTMs) may offer a unique lens by which we might gain insight into the DNA metabolic landscape that is distinctively present at ALT+ telomeres.

RevDate: 2021-02-13

Choi JY, Abdulkina LR, Yin J, et al (2021)

Natural variation in plant telomere length is associated with flowering time.

The Plant cell pii:6122721 [Epub ahead of print].

Telomeres are highly repetitive DNA sequences found at the ends of chromosomes that protect the chromosomes from deterioration duringcell division. Here, using whole-genome re-sequencing and terminal restriction fragment assays, we found substantial natural intraspecific variation in telomere length in Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays). Genome-wide association study (GWAS) mapping in A. thaliana identified 13 regions with GWAS-significant associations underlying telomere length variation, including a region that harbors the telomerase reverse transcriptase (TERT) gene. Population genomic analysis provided evidence for a selective sweep at the TERT region associated with longer telomeres. We found that telomere length is negatively correlated with flowering time variation not only in A. thaliana, but also in maize and rice, indicating a link between life-history traits and chromosome integrity. Our results point to several possible reasons for this correlation, including the possibility that longer telomeres may be more adaptive in plants that have faster developmental rates (and therefore flower earlier). Our work suggests that chromosomal structure itself might be an adaptive trait associated with plant life-history strategies.

RevDate: 2021-02-15

Lee SW, Lim KH, Lee KJ, et al (2021)

No association between telomere length and osteonecrosis of the femoral head.

BMC musculoskeletal disorders, 22(1):176.

BACKGROUND: Telemore length (TL) shortening has been found in many diseases. However, clinical characteristics of TL shortening in osteonecrosis of the femoral head (ONFH) has not been investigated. Therefore, we studied whether TL changes have clinicopathological values in ONFH.

METHODS: The TL in the synovial tissues of 36 ONFH and 127 control patients (femoral neck fracture) was examined by quantitative real-time PCR as relative length, Δ Ct value. In addition, the correlation between TL and clinical features of ONFH and controls was analyzed.

RESULTS: The average TL in the femoral tissues was 1.46 ± 3.12 (standard deviation). The average TL in the ONFH and control tissues was 1.92 ± 4.11 and 1.34 ± 2.78, respectively, however, the difference was absent (p = 0.324). Furthermore, a shorter TL was tended to be associated with erythrocyte sedimentation rate (100% vs. 61.5%, p = 0.073); however, the association was not statistically significant.

CONCLUSIONS: In this study, we demonstrated that there is no association between the TL and clinicopathologic characteristics of ONFH patients. However, further studies considering the genetic factors are needed to be performed.

RevDate: 2021-02-12

Blagosklonny MV (2021)

DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.

Aging, 13: pii:202674 [Epub ahead of print].

Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.

RevDate: 2021-02-16

Quintana-Sosa M, León-Mejía G, Luna-Carrascal J, et al (2021)

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay biomarkers and telomere length analysis in relation to inorganic elements in individuals exposed to welding fumes.

Ecotoxicology and environmental safety, 212:111935 pii:S0147-6513(21)00046-4 [Epub ahead of print].

During the welding activities many compounds are released, several of these cause oxidative stress and inflammation and some are considered carcinogenic, in fact the International Agency for Research on Cancer established that welding fumes are carcinogenic to humans. The aim of the present study was to analyze the cytotoxic and genotoxic potential of exposure to welding fumes and to determine concentrations of metals in blood and urine of occupationally exposed workers. We included 98 welders and 100 non-exposed individuals. Our results show significant increase in the frequency of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD) and necrotic cells (NECR) in cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, as well as in the telomere length (TL) of the exposed individuals with respect to the non-exposed group. In the analysis of the concentrations of inorganic elements using PIXE method, were found higher concentrations of Cr, Fe and Cu in the urine, and Cr, Fe, Mg, Al, S, and Mn in the blood in the exposed group compared to the non-exposed group. A significant correlation was observed between MN and age and between NPB and years of exposure. Additionally, we found a significant correlation for TL in relation to MN, NPB, age and years of exposure in the exposed group. Interestingly, a significant correlation between MN and the increase in the concentration of Mg, S, Fe and Cu in blood samples of the exposed group, and between MN and Cr, Fe, Ni and Cu in urine. Thus, our findings may be associated with oxidative and inflammatory damage processes generated by the components contained in welding fumes, suggesting a high occupational risk in welding workers.

RevDate: 2021-02-14

Baquero JM, Benítez-Buelga C, Rajagopal V, et al (2021)

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.

Scientific reports, 11(1):3490.

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

RevDate: 2021-02-14

Mei Y, Deng Z, Vladimirova O, et al (2021)

TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity.

Scientific reports, 11(1):3509.

Telomere dysfunction causes chromosomal instability which is associated with many cancers and age-related diseases. The non-coding telomeric repeat-containing RNA (TERRA) forms a structural and regulatory component of the telomere that is implicated in telomere maintenance and chromosomal end protection. The basic N-terminal Gly/Arg-rich (GAR) domain of telomeric repeat-binding factor 2 (TRF2) can bind TERRA but the structural basis and significance of this interaction remains poorly understood. Here, we show that TRF2 GAR recognizes G-quadruplex features of TERRA. We show that small molecules that disrupt the TERRA-TRF2 GAR complex, such as N-methyl mesoporphyrin IX (NMM) or genetic deletion of TRF2 GAR domain, result in the loss of TERRA, and the induction of γH2AX-associated telomeric DNA damage associated with decreased telomere length, and increased telomere aberrations, including telomere fragility. Taken together, our data indicates that the G-quadruplex structure of TERRA is an important recognition element for TRF2 GAR domain and this interaction between TRF2 GAR and TERRA is essential to maintain telomere stability.

RevDate: 2021-02-10

Banevicius M, Gedvilaite G, Vilkeviciute A, et al (2021)

Association of relative leukocyte telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, TRF2) with atrophic age-related macular degeneration.

Ophthalmic genetics [Epub ahead of print].

Background: In an experimental model, telomere shortening inhibits neovascularization. It is thus possible that telomere shortening might have a role in the pathogenesis of geographic atrophy in case of age-related macular degeneration (AMD). This is why we aimed to find any associated differences of telomere length and genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TNKS2, and TRF2) in patients with atrophic AMD compared to healthy controls. Methods: The study enrolled patients with atrophic AMD (n = 56) and healthy (n = 73) 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 a real-time polymerase chain reaction method. The results were assessed using the statistical analysis method of "IBM SPSS Statistics 20.0". Results: We found statistically significantly higher T/S in atrophic AMD patients than in healthy controls (T/S, median (IQR): 1.638 (1.110) vs. 0.764 (0.801), p < .001). Also, statistically significant differences were found in TRF1 rs10107605 allele (A and C) distributions between the atrophic AMD and control groups (88.36% and 11.64% vs. 95.54% and 4.46%, respectively, p = .041), as well as between the short telomere and long telomere groups (86.92% and 13.08% vs. 96.09% and 3.91%, respectively, p = .008). Conclusions: Our research revealed the leukocyte telomere length having a role in atrophic AMD development, also the association between TRF1 rs10107605 and the telomere length.

RevDate: 2021-02-10

Nettle D, Gadalla SM, Lai TP, et al (2021)

Telomere length measurement for longitudinal analysis: implications of assay precision.

American journal of epidemiology pii:6132159 [Epub ahead of print].

Researchers increasingly wish to test hypotheses concerning the impact of environmental or disease exposures on telomere length (TL), and use longitudinal study designs to do so. In population studies, TL is usually measured using a quantitative polymerase chain reaction (qPCR)-based method. This method has been validated by presenting a correlation with a gold standard method such as Southern blotting (SB) in cross-sectional datasets. However, in a cross-section, the range of true variation in TL is large, and measurement error is introduced only once. In a longitudinal study, the target variation of interest is small, and measurement error is introduced both at baseline and follow-up. We present a small dataset (n = 20) where leukocyte TL was measured 6.6 years apart by both qPCR and SB. The cross-sectional correlations between qPCR and SB were high both at baseline (r = 0.90) and follow-up (r = 0.85), yet their correlation for TL change was poor (r = 0.48). Moreover, the qPCR but not SB data showed strong signatures of measurement error. Through simulation, we show that the statistical power gain from performing a longitudinal analysis is much greater for SB than qPCR. We discuss implications for optimal study design and analysis.

RevDate: 2021-02-11

Bevelacqua JJ, Welsh J, Mortazavi SAR, et al (2021)

Space Medicine: Why Do Recently Published Papers about Telomere Length Alterations Increase our Uncertainty Rather than Reduce it?.

Journal of biomedical physics & engineering, 11(1):103-108.

There is a growing interest in examining alterations in telomere length as a reliable biomarker of general health, as well as a marker for predicting later morbidity and mortality. Substantial evidence shows that telomere length is associated with aging; telomere shortening acts as a "counting mechanism" that drives replicative senescence by limiting the mitotic potential of normal (but not malignant) cells. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. This discussion includes three major research areas regarding telomere length: environmental stressors, aging, and life span. Our review suggests that activation of telomerase activity due to stressors in space might be a double-edged sword with both favorable and unfavorable consequences. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. In this Correspondence, we attempt to answer the question of why recently published papers about telomere length alterations increase our uncertainty rather than reduce it. The selection of an effect's consequence must clearly elucidate the experimental conditions as well as associated stressors. Both positive and negative consequences must be clearly addressed in order to bolster the conclusions, as well as identify future research directions.

RevDate: 2021-02-13

Lim CJ, TR Cech (2021)

Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.

Nature reviews. Molecular cell biology [Epub ahead of print].

The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the 'telomere replisome') and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1-STN1-TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.

RevDate: 2021-02-09

Gonzalez de la Rosa PM, Thomson M, Trivedi U, et al (2021)

A telomere-to-telomere assembly of Oscheius tipulae and the evolution of rhabditid nematode chromosomes.

G3 (Bethesda, Md.), 11(1):.

Eukaryotic chromosomes have phylogenetic persistence. In many taxa, each chromosome has a single functional centromere with essential roles in spindle attachment and segregation. Fusion and fission can generate chromosomes with no or multiple centromeres, leading to genome instability. Groups with holocentric chromosomes (where centromeric function is distributed along each chromosome) might be expected to show karyotypic instability. This is generally not the case, and in Caenorhabditis elegans, it has been proposed that the role of maintenance of a stable karyotype has been transferred to the meiotic pairing centers, which are found at one end of each chromosome. Here, we explore the phylogenetic stability of nematode chromosomes using a new telomere-to-telomere assembly of the rhabditine nematode Oscheius tipulae generated from nanopore long reads. The 60-Mb O. tipulae genome is resolved into six chromosomal molecules. We find the evidence of specific chromatin diminution at all telomeres. Comparing this chromosomal O. tipulae assembly with chromosomal assemblies of diverse rhabditid nematodes, we identify seven ancestral chromosomal elements (Nigon elements) and present a model for the evolution of nematode chromosomes through rearrangement and fusion of these elements. We identify frequent fusion events involving NigonX, the element associated with the rhabditid X chromosome, and thus sex chromosome-associated gene sets differ markedly between species. Despite the karyotypic stability, gene order within chromosomes defined by Nigon elements is not conserved. Our model for nematode chromosome evolution provides a platform for investigation of the tensions between local genome rearrangement and karyotypic evolution in generating extant genome architectures.

RevDate: 2021-02-09

Glapa-Nowak A, Mutt SJ, Lisowska A, et al (2021)

Leukocyte Telomere Length Is Not Reduced in Children and Adults with Cystic Fibrosis but Associates with Clinical Characteristics-A Cross-Sectional Study.

Journal of clinical medicine, 10(4): pii:jcm10040590.

We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5-10 (34 CF; 36 HS) and 114 adults aged 18-45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686-0.950) vs. 0.831 (0.707-0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715-0.931) vs. 0.703 (0.574-0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664-0.910) vs. 0.943 (0.813-1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status (p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643-0.905) vs. 0.950 (0.783-1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648-0.908) vs. 0.832 (0.748-1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = -0.251; p = 0.0239), as well as number of hospitalization days (rho = -0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.

RevDate: 2021-02-08

On K, Crevel G, Cotterill S, et al (2021)

Drosophila telomere capping protein HOAP interacts with DSB sensor proteins Mre11 and Nbs.

Genes to cells : devoted to molecular & cellular mechanisms [Epub ahead of print].

In eukaryotes, specific DNA-protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex. This capping complex is essential for the inhibition of the DNA damage response (DDR) at telomeres and contributes to genome integrity. In Drosophila the central factors of telomere capping complex are HOAP and HipHop. Furthermore, a DDR protein complex Mre11-Rad50-Nbs (MRN) is known to be important for the telomere association of HOAP and HipHop. However, whether MRN interacts with HOAP and HipHop, and the telomere recognition mechanisms of HOAP and HipHop are poorly understood. Here, we show that Nbs interacts with Mre11 and transports the Mre11-Rad50 complex from the cytoplasm to the nucleus. In addition, we report that HOAP interacts with both Mre11 and Nbs. The N-terminal region of HOAP is essential for its co-localization with HipHop. Finally, we reveal that Nbs interacts with the N-terminal region of HOAP.

RevDate: 2021-02-08

Zhang N, Li Y, Lai TP, et al (2021)

Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells.

Chromosoma [Epub ahead of print].

Telomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1-10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.

RevDate: 2021-02-10

Ge J, Li C, Sun H, et al (2021)

Telomere Dysfunction in Oocytes and Embryos From Obese Mice.

Frontiers in cell and developmental biology, 9:617225.

Maternal obesity impairs oocyte quality and embryo development. However, the potential molecular pathways remain to be explored. In the present study, we examined the effects of obesity on telomere status in oocytes and embryos obtained from mice fed with high-fat diet (HFD). Of note, telomere shortening was observed in both oocytes and early embryos from obese mice, as evidenced by the reduced expression of telomerase reverse transcriptase and activity of telomerase. Moreover, quantitative analysis of telomere dysfunction-induced foci (TIFs) revealed that maternal obesity induces the defective telomeres in oocytes and embryos. Meanwhile, the high frequency of aneuploidy was detected in HFD oocytes and embryos as compared to controls, accompanying with the increased incidence of apoptotic blastocysts. In conclusion, these results indicate that telomere dysfunction might be a molecular pathway mediating the effects of maternal obesity on oocyte quality and embryo development.

RevDate: 2021-02-10

Vaiserman A, D Krasnienkov (2020)

Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.

Frontiers in genetics, 11:630186.

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.

RevDate: 2021-02-07

Xu M, Axhemi A, Malgowska M, et al (2021)

Active and passive destabilization of G-quadruplex DNA by the telomere POT1-TPP1 complex.

Journal of molecular biology pii:S0022-2836(21)00040-1 [Epub ahead of print].

Chromosome ends are protected by guanosine-rich telomere DNA that forms stable G-quadruplex (G4) structures. The heterodimeric POT1-TPP1 complex interacts specifically with telomere DNA to shield it from illicit DNA damage repair and to resolve secondary structure that impedes telomere extension. The mechanism by which POT1-TPP1 accomplishes these tasks is poorly understood. Here, we establish the kinetic framework for POT1-TPP1 binding and unfolding of telomere G4 DNA. Our data identify two modes of POT1-TPP1 destabilization of G4 DNA that are governed by protein concentration. At low concentrations, POT1-TPP1 passively captures transiently unfolded G4s. At higher concentrations, POT1-TPP1 proteins bind to G4s to actively destabilize the DNA structures. Cancer-associated POT1-TPP1 mutations impair multiple reaction steps in this process, resulting in less efficient destabilization of G4 structures. The mechanistic insight highlights the importance of cell cycle dependent expression and localization of the POT1-TPP1 complex and distinguishes diverse functions of this complex in telomere maintenance.

RevDate: 2021-02-06

Hecker M, Fitzner B, Jäger K, et al (2021)

Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes.

Molecular neurobiology [Epub ahead of print].

Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.

RevDate: 2021-02-05

Kosebent EG, S Ozturk (2021)

The spatiotemporal expression of TERT and telomere repeat binding proteins in the postnatal mouse testes.

Andrologia [Epub ahead of print].

Telomeres consist of repetitive DNA sequences and telomere-associated proteins. Telomeres located at the ends of eukaryotic chromosomes undergo shortening due to DNA replication, genotoxic factors and reactive oxygen species. The short telomeres are elongated by the enzyme telomerase expressed in the germ line, embryonic and stem cells. Telomerase is in the structure of ribonucleoprotein composed of telomerase reverse transcriptase (TERT), telomerase RNA component (Terc) and other components. Among telomere-associated proteins, telomeric repeat binding factor 1 (TRF1) and 2 (TRF2) exclusively bind to the double-stranded telomeric DNA to regulate its length. However, protection of telomeres 1 (POT1) interacts with the single-stranded telomeric DNA to protect from DNA damage response. Herein, we characterised the spatial and temporal expression of the TERT, TRF1, TRF2 and POT1 proteins in the postnatal mouse testes at the ages of 6, 8, 16, 20, 29, 32 and 88 days by using immunohistochemistry. Significant differences in the spatiotemporal expression patterns and levels of these proteins were determined in the postnatal testes (p < .05). These findings indicate that TERT and telomere repeat binding proteins seem to be required for maintaining the length and structural integrity of telomeres in the spermatogenic cells from newborn to adult terms.

RevDate: 2021-02-05

Meshkani SE, Kooshki A, Alahabadi A, et al (2021)

Dietary pattern and telomere length in preschool children in a middle-income country.

Maternal & child nutrition [Epub ahead of print].

Telomere length (TL) has been associated with lifestyle and dietary pattern. However, the available evidence on this association in children is scarce, especially in low- and middle-income countries (LMICs). Therefore, this study aimed to evaluate the association of dietary pattern and leukocyte TL (LTL) in preschool children, Sabzevar, Iran (2017). This cross-sectional study was based on 187 preschool children (aged 5 to 7) recruited from 27 kindergartens. Nutrition information including amounts of consumed dairy products, meat and processed meat products, nuts and seeds, white bread and refined grains, fruits, vegetables, simple sugars, fats and drinks was obtained through a questionnaire. Linear mixed-effects models were fitted with polymerase chain reaction (PCR) plate ID and kindergartens as random effects to estimate the association of each food group consumption with LTL, controlled for relevant covariates. Higher consumption of dairy products and sugar was associated with shorter LTL (β = -0.180, 95% confidence interval [CI]: -0.276, -0.085, P value <0.001 and β = -0.139, 95% CI: -0.193, -0.086, P value <0.001, respectively). An increase in consumption of fish, nuts and seeds, coloured fruits, green leafy vegetables, cruciferous vegetables and olive was significantly associated with the increase in relative LTL. The associations for the consumption of legumes, other fruits, yellow and orange vegetables, red meat, egg, white bread and refined grains, solid and liquid fats, processed meats, potato chips, carbonated drinks, tea (black) and soft drinks groups were not statistically significant. Our findings showed that there was an association between the consumption of certain food groups with LTL.

RevDate: 2021-02-05

Lister-Shimauchi EH, Dinh M, Maddox P, et al (2021)

Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations.

Communications biology, 4(1):158.

Deficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.

RevDate: 2021-02-13

McGrath SL, Huang SH, K Kobryn (2021)

Single stranded DNA annealing is a conserved activity of telomere resolvases.

PloS one, 16(2):e0246212.

Bacterial species of the genera Agrobacterium and Borrelia possess chromosomes terminated by hairpin telomeres. Replication produces dimeric replication intermediates fused via replicated telomere junctions. A specialized class of enzymes, referred to as telomere resolvases, promotes the resolution of the replicated intermediate into linear monomers terminated by hairpin telomeres. Telomere resolution is catalyzed via DNA cleavage and rejoining events mechanistically similar to those promoted by topoisomerase-IB and tyrosine recombinase enzymes. Examination of the borrelial telomere resolvase, ResT, revealed unanticipated multifunctionality; aside from its expected telomere resolution activity ResT possessed a singled-stranded DNA (ssDNA) annealing activity that extended to both naked ssDNA and ssDNA complexed with its cognate single-stranded DNA binding protein (SSB). At present, the role this DNA annealing activity plays in vivo remains unknown. We have demonstrated here that single-stranded DNA annealing is also a conserved property of the agrobacterial telomere resolvase, TelA. This activity in TelA similarly extends to both naked ssDNA and ssDNA bound by its cognate SSB. TelA's annealing activity was shown to stem from the N-terminal domain; removal of this domain abolished annealing without affecting telomere resolution. Further, independent expression of the N-terminal domain of TelA produced a functional annealing protein. We suggest that the apparent conservation of annealing activity in two telomere resolvases, from distantly related bacterial species, implies a role for this activity in hairpin telomere metabolism. Our demonstration of the separation of the telomere resolution and annealing activities of TelA provides a platform for future experiments aimed at identifying the role DNA annealing performs in vivo.

RevDate: 2021-02-15
CmpDate: 2021-02-15

Engin AB, A Engin (2021)

The Connection Between Cell Fate and Telomere.

Advances in experimental medicine and biology, 1275:71-100.

Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.

RevDate: 2021-02-11

Červenák F, Sepšiová R, Nosek J, et al (2021)

Step-by-Step Evolution of Telomeres: Lessons from Yeasts.

Genome biology and evolution, 13(2):.

In virtually every eukaryotic species, the ends of nuclear chromosomes are protected by telomeres, nucleoprotein structures counteracting the end-replication problem and suppressing recombination and undue DNA repair. Although in most cases, the primary structure of telomeric DNA is conserved, there are several exceptions to this rule. One is represented by the telomeric repeats of ascomycetous yeasts, which encompass a great variety of sequences, whose evolutionary origin has been puzzling for several decades. At present, the key questions concerning the driving force behind their rapid evolution and the means of co-evolution of telomeric repeats and telomere-binding proteins remain largely unanswered. Previously published studies addressed mostly the general concepts of the evolutionary origin of telomeres, key properties of telomeric proteins as well as the molecular mechanisms of telomere maintenance; however, the evolutionary process itself has not been analyzed thoroughly. Here, we aimed to inspect the evolution of telomeres in ascomycetous yeasts from the subphyla Saccharomycotina and Taphrinomycotina, with special focus on the evolutionary origin of species-specific telomeric repeats. We analyzed the sequences of telomeric repeats from 204 yeast species classified into 20 families and as a result, we propose a step-by-step model, which integrates the diversity of telomeric repeats, telomerase RNAs, telomere-binding protein complexes and explains a propensity of certain species to generate the repeat heterogeneity within a single telomeric array.

RevDate: 2021-02-02

Onat T, Çaltekin MD, Inandiklioglu N, et al (2021)

Telomere Length in Idiopathic Recurrent Pregnancy Loss.

Zeitschrift fur Geburtshilfe und Neonatologie [Epub ahead of print].

OBJECTIVE: Telomere length is used as an indicator of biological aging. It is well known that one of the most remarkable risk factors of recurrent pregnancy losses is advanced maternal age. The objective of this study was to investigate the correlation between idiopathic recurrent pregnancy loss and telomere length.

METHOD: The study group included 40 women, while the control group consisted of 41 healthy women whose age and body mass index were matched. A venous blood sample was taken from all participants into EDTA tubes in the early follicular phase, and telomere length was measured through the qPCR technique.

RESULTS: When the mean TL of the groups was compared, it was determined that TL was significantly shorter among the iRPL group (7763.89±924.58 base pair) compared to the control group (8398.84±1102.95 base pair) (p<0.006). Whereas FSH and E2 were higher in the iRPL group, TAFC was lower (p<0.001). When the correlation between telomere length and endocrine parameters was statistically tested in the iRPL group, a negative correlation was found between FSH and telomere length (r=-0.437; p<0.001).

CONCLUSION: Shortened telomere length might play a role in the etiology of iRPL. We are of the opinion that patients with RPL should be screened for the presence of cardiovascular diseases and other chronic diseases, as is the case for POF.

RevDate: 2021-02-14

Dragović G, Andjić M, Toljić B, et al (2021)

Correlation between metabolic syndrome and relative telomere length shortening in HIV/AIDS patients on combined antiretroviral therapy.

Experimental gerontology, 147:111269 pii:S0531-5565(21)00044-9 [Epub ahead of print].

BACKGROUND: Components of the metabolic syndrome (MetS) play an important role in the accelerated aging process. Relative telomere length (RTL) is a marker of biological aging. The aim of our study was to determine RTL and its possible association with MetS and the components of MetS in HIV-infected patients treated with cART.

METHODS: We included 24 HIV-infected men, all Caucasians, with successful cART (<50 HIV-RNA copies/mL) and on stable cART for at least 24 months. The presence of MetS and its components was determined by the criteria prescribed by the International Diabetes Federation. RTL was determined by Real-Time PCR and ΔΔCt method. We performed a multiple linear regression modeling on log-transformed RTL (dependant variable) to evaluate which components of the metabolic syndrome as well as cART duration and cART type, had an impact on RTL.

RESULTS: Eleven (45.8%) patients had and 13 (54.2%) had not MetS. All patients, had an undetectable viral RNA and a relatively good immune status. The mean RTL was 0.62 ± 0.15 and 0.95 ± 0.36 in patients with and without MetS, respectively (p = 0.01). Multiple linear regression model showed no significant association between duration of cART, cART type and RTL (p = 0.2165, p = 0.8628, respectively). The same analysis showed that an increase in number of MetS components was associated with shorter telomere length (β = -0.4982, p = 0.042).

CONCLUSIONS: We showed for the first time association between RTL shortening in HIV-infected men with metabolic syndrome. Furthermore, our study also indicated that an increment of metabolic syndrome components is strongly associated with shorter telomere length.

RevDate: 2021-02-11

de Fluiter KS, Codd V, Denniff M, et al (2021)

Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life.

PloS one, 16(2):e0246400.

OBJECTIVE: Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition.

STUDY DESIGN: In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound.

RESULTS: LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes.

CONCLUSION: We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.

RevDate: 2021-02-02

Benetos A, Lai TP, Toupance S, et al (2021)

The Nexus between Telomere Length and Lymphocyte Count in Seniors hospitalized with Covid-19.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6126483 [Epub ahead of print].

Profound T-cell lymphopenia is the hallmark of severe Covid-19. T-cell proliferation is telomere length (TL)-dependent and telomeres shorten with age. Older Covid-19 patients, we hypothesize, are therefore at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting of the terminal restriction fragments (SB) in peripheral blood mononuclear cells of 17 Covid-19 and 21 non-Covid-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields two key metrics: the proportion of telomeres with different lengths (expressed in %), and their mean, TeSLA mTL (expressed in kb). Lymphocyte count (10 9/L) was 0.91 ± 0.42 in Covid-19 patients and 1.50 ± 0.50 in non-Covid-19 patients (P < 0.001). In Covid-19 patients, but not in non-Covid-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (P = 0.005) and positively correlated with TeSLA mTL (P = 0.03). Lymphocyte count was not significantly correlated with SB mTL in either Covid-19 or non-Covid-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to Covid-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

RevDate: 2021-02-02

Jebaraj BMC, S Stilgenbauer (2020)

Telomere Dysfunction in Chronic Lymphocytic Leukemia.

Frontiers in oncology, 10:612665.

Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell's replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.

RevDate: 2021-01-31

Wirth A, Wolf B, Huang CK, et al (2021)

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

GeroScience [Epub ahead of print].

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.

RevDate: 2021-02-10

Vodicka P, Andera L, Opattova A, et al (2021)

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction.

Cancers, 13(3):.

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

RevDate: 2021-01-29

Sperka T, Song Z, Morita Y, et al (2021)

Author Correction: Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction.

RevDate: 2021-01-29

Stone RC, Aviv A, R Paus (2021)

Telomere Dynamics and Telomerase in the Biology of Hair Follicles and their Stem Cells as a Model for Aging Research.

The Journal of investigative dermatology pii:S0022-202X(20)32399-X [Epub ahead of print].

In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.

RevDate: 2021-01-31

Saud Z, Kortsinoglou AM, Kouvelis VN, et al (2021)

Telomere length de novo assembly of all 7 chromosomes and mitogenome sequencing of the model entomopathogenic fungus, Metarhizium brunneum, by means of a novel assembly pipeline.

BMC genomics, 22(1):87.

BACKGROUND: More accurate and complete reference genomes have improved understanding of gene function, biology, and evolutionary mechanisms. Hybrid genome assembly approaches leverage benefits of both long, relatively error-prone reads from third-generation sequencing technologies and short, accurate reads from second-generation sequencing technologies, to produce more accurate and contiguous de novo genome assemblies in comparison to using either technology independently. In this study, we present a novel hybrid assembly pipeline that allowed for both mitogenome de novo assembly and telomere length de novo assembly of all 7 chromosomes of the model entomopathogenic fungus, Metarhizium brunneum.

RESULTS: The improved assembly allowed for better ab initio gene prediction and a more BUSCO complete proteome set has been generated in comparison to the eight current NCBI reference Metarhizium spp. genomes. Remarkably, we note that including the mitogenome in ab initio gene prediction training improved overall gene prediction. The assembly was further validated by comparing contig assembly agreement across various assemblers, assessing the assembly performance of each tool. Genomic synteny and orthologous protein clusters were compared between Metarhizium brunneum and three other Hypocreales species with complete genomes, identifying core proteins, and listing orthologous protein clusters shared uniquely between the two entomopathogenic fungal species, so as to further facilitate the understanding of molecular mechanisms underpinning fungal-insect pathogenesis.

CONCLUSIONS: The novel assembly pipeline may be used for other haploid fungal species, facilitating the need to produce high-quality reference fungal genomes, leading to better understanding of fungal genomic evolution, chromosome structuring and gene regulation.

RevDate: 2021-02-06

Han X, Kubota R, Tanaka KI, et al (2021)

The correlation of salivary telomere length and single nucleotide polymorphisms of the ADIPOQ, SIRT1 and FOXO3A genes with lifestyle-related diseases in a Japanese population.

PloS one, 16(1):e0243745.

BACKGROUND: It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate.

OBJECTIVE: The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves.

METHODS: In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university.

RESULTS: In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype.

CONCLUSION: Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.

RevDate: 2021-02-09

Heidinger BJ, Slowinski SP, Sirman AE, et al (2021)

Experimentally elevated testosterone shortens telomeres across years in a free-living songbird.

Molecular ecology [Epub ahead of print].

Reproductive investment often comes at a cost to longevity, but the mechanisms that underlie these long-term effects are not well understood. In male vertebrates, elevated testosterone has been shown to increase reproductive success, but simultaneously to decrease survival. One factor that may contribute to or serve as a biomarker of these long-term effects of testosterone on longevity is telomeres, which are often positively related to lifespan and have been shown to shorten in response to reproduction. In this longitudinal study, we measured the effects of experimentally elevated testosterone on telomere shortening in free-living, male dark-eyed juncos (Junco hyemalis carolinensis), a system in which the experimental elevation of testosterone has previously been shown to increase reproductive success and reduce survival. We found a small, significant effect of testosterone treatment on telomeres, with testosterone-treated males exhibiting significantly greater telomere shortening with age than controls. These results are consistent with the hypothesis that increased telomere shortening may be a long-term cost of elevated testosterone exposure. As both testosterone and telomeres are conserved physiological mechanisms, our results suggest that their interaction may apply broadly to the long-term costs of reproduction in male vertebrates.

RevDate: 2021-01-27

Ooi DSQ, Dorajoo R, Gurung RL, et al (2021)

Association of leukocyte telomere length with obesity-related traits in Asian children with early-onset obesity.

Pediatric obesity [Epub ahead of print].

BACKGROUND: Leukocyte telomere length (LTL) is associated with obesity and obesity-related traits, and there are ethnic-specific determinants of LTL.

OBJECTIVE: To evaluate LTL associations with obesity and metabolic parameters in Asian children with early-onset obesity.

METHODS: Genomic DNA was extracted from peripheral blood leukocytes of a cohort of children with (N = 371) and without obesity (N = 23), and LTL was measured using quantitative PCR (qPCR). Blood plasma was used for metabolic phenotyping. Statistical analysis was performed using SPSS and STATA.

RESULTS: Children with obesity had shorter LTL (coefficient = -0.683, PAdj = 1.24 × 10-3) as compared to children who were lean. LTL was found to be associated with waist circumference (coefficient = -0.326, PAdj = 0.044) and skin-fold measures (coefficient between 0.267 and 0.301, PAdj between 4.27 × 10-4 and 7.06 × 10-7) in children with obesity. However, no significant associations were observed between LTL and metabolic parameters, and between LTL and inflammatory cytokines. LTL also did not significantly mediate the risk of non-alcoholic fatty liver disease (NAFLD) in children with obesity.

CONCLUSIONS: We showed for the first time that Asian children with severe obesity had shorter LTL, and the shortening of LTL was associated with other adiposity measures including waist circumference and skin-fold measurements.

RevDate: 2021-01-30

Kim B, Ryu KJ, Lee S, et al (2021)

Changes in telomere length and senescence markers during human ovarian tissue cryopreservation.

Scientific reports, 11(1):2238.

Ovarian tissue cryopreservation is considered as a useful option to preserve fertility for cancer patients. This study purposed to evaluate the change of telomere length and senescence markers during human ovarian tissue cryopreservation. Ovarian tissues were obtained from women who underwent benign ovarian surgery in the gynecology research unit of a university hospital with prior consent and IRB approval. DNA was extracted from the ovarian tissues using a DNeasy tissue kit and telomere lengths in the DNA samples were determined by real time PCR before and after cryopreservation. All tissues were stained with hematoxylin-eosin and subjected to immunohistochemistry and TUNEL assays. Other senescence markers, including p53, p16, p21, and phospho-pRb proteins, were evaluated using western blot analysis. Ovarian tissues were collected from ten patients and prepared for slow freezing with the same size of diameter 4 mm and 1 mm thickness. Mean age of patients was 26.7 ± 6.2 years (range, 16-34 years), and ovarian tissues were cryopreserved and thawed 4 weeks after cryopreservation. The mean telomere length was significantly decreased after cryopreservation (9.57 ± 1.47 bp vs. 8.34 ± 1.83 bp, p = 0.001). Western blot analysis revealed that p53, p16, and p21 proteins increased and phospho-pRb protein expression decreased after ovarian tissue cryopreservation. Ovarian tissue cryopreservation and transplantation is regarded as one of promising options for fertility preservation. However, clinicians and researchers should be aware of possible irreversible DNA changes such as shortening of telomere length and alterations of other senescence markers in human ovarian tissues.

RevDate: 2021-02-05
CmpDate: 2021-02-05

Zhang S, Yu X, Zhang Y, et al (2021)

Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation.

Nature communications, 12(1):594.

Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.

RevDate: 2021-01-27

Pitkänen N, Pahkala K, Rovio SP, et al (2021)

Effects of Randomized Controlled Infancy-Onset Dietary Intervention on Leukocyte Telomere Length-The Special Turku Coronary Risk Factor Intervention Project (STRIP).

Nutrients, 13(2): pii:nu13020318.

Reduced telomere length (TL) is a biological marker of aging. A high inter-individual variation in TL exists already in childhood, which is partly explained by genetics, but also by lifestyle factors. We examined the influence of a 20-year dietary/lifestyle intervention on TL attrition from childhood to early adulthood. The study comprised participants of the longitudinal randomized Special Turku Coronary Risk Factor Intervention Project (STRIP) conducted between 1990 and 2011. Healthy 7-month-old children were randomized to the intervention group (n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group (n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years (n = 232; intervention n = 108, control n = 124). Yearly TL attrition rate was calculated. The participants of the intervention group had slower yearly TL attrition rate compared to the controls (intervention: mean = -7.5 bp/year, SD = 24.4 vs. control: mean = -15.0 bp/year, SD = 30.3; age, sex and baseline TL adjusted β = 0.007, SE = 0.004, p = 0.040). The result became stronger after additional adjustments for dietary fat quality and fiber intake, serum lipid and insulin concentrations, systolic blood pressure, physical activity and smoking (β = 0.013, SE = 0.005, p = 0.009). A long-term intervention focused mainly on dietary fat quality may affect the yearly TL attrition rate in healthy children/adolescents.

RevDate: 2021-01-27

Henckel E, James A, Konradsen JR, et al (2021)

A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia.

Children (Basel, Switzerland), 8(2): pii:children8020080.

Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson's correlation: -0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.

RevDate: 2021-01-27

D'Amico-Willman KM, Anderson ES, Gradziel TM, et al (2021)

Relative Telomere Length and Telomerase Reverse Transcriptase (TERT) Expression Are Associated with Age in Almond (Prunus dulcis [Mill.] D.A.Webb).

Plants (Basel, Switzerland), 10(2): pii:plants10020189.

While all organisms age, our understanding of how aging occurs varies among species. The aging process in perennial plants is not well-defined, yet can have implications on production and yield of valuable fruit and nut crops. Almond exhibits an age-related disorder known as non-infectious bud failure (BF) that affects vegetative bud development, indirectly affecting kernel yield. This species and disorder present an opportunity to address aging in a commercially relevant and vegetatively propagated perennial crop. The hypothesis tested in this study was that relative telomere length and/or telomerase reverse transcriptase (TERT) expression can serve as biomarkers of aging in almond. Relative telomere lengths and expression of TERT, a subunit of the enzyme telomerase, were measured via qPCR methods using bud and leaf samples collected from distinct age cohorts over a two-year period. Results from this work show a marginal but significant association between both relative telomere length and TERT expression, and age, suggesting that as almonds age, telomeres shorten and TERT expression decreases. This work provides information on potential biomarkers of perennial plant aging, contributing to our knowledge of this process. In addition, these results provide opportunities to address BF in almond breeding and nursery propagation.

RevDate: 2021-01-30

Caslini C, Connelly JA, Serna A, et al (2021)

Erratum for Caslini et al., "MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription".

Molecular and cellular biology, 41(2): pii:41/2/e00566-20.

RevDate: 2021-01-26

Adler BL, Boin F, Wolters PJ, et al (2021)

Autoantibodies targeting telomere-associated proteins in systemic sclerosis.

Annals of the rheumatic diseases pii:annrheumdis-2020-218918 [Epub ahead of print].

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.

METHODS: Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.

RESULTS: In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.

CONCLUSIONS: Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.

RevDate: 2021-02-15

Needham BL (2021)

Newborn telomere length and the early life origins of age-related disease.

EBioMedicine, 64:103214 pii:S2352-3964(21)00007-4 [Epub ahead of print].

RevDate: 2021-02-15

Adli A, Hosseini SM, Lari Najafi M, et al (2021)

Polycyclic aromatic hydrocarbons exposures and telomere length: A cross-sectional study on preschool children.

Environmental research, 195:110757 pii:S0013-9351(21)00051-7 [Epub ahead of print].

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with shorter telomere length (TL), a marker of ageing at cellular level. However, the available evidence on this association among children is still scarce. We therefore aimed to assess, the relationship between urinary 1-hydroxipayrene (1-OHP), a marker of exposure to PAHs, and relative leukocyte TL (LTL) in children at preschool age. Our study was based on 200 children enrolled from 27 randomly-selected kindergartens in the city of Sabzevar, Iran (2017). 1-OHP levels in the participants' urine samples were measured using solid phase extraction (SPE) method and high-performance liquid chromatography (HPLC). Moreover, real-time PCR was used to measure the LTL in the participants' blood samples. Linear mixed effects models, controlled for relevant covariates, were applied to investigate the association of 1-OHP concentration and LTL. The median (interquartile range (IQR)) of relative LTL and urinary 1-OHP were 0.83 (0.7) and 257 (375.5) ng/L, respectively. In the fully adjusted model, an IQR increase in urinary 1-OHP was related to -0.05 (95% confidence interval (CI): 0.09, -0.01, P-value = 0.02) decrease in relative LTL. This association was similar among boys and girls; however, we observed indications for a stronger association for those children whose parents had university education. Our study suggested an inverse relationship between urinary 1-OHP and LTL in children at preschool age. However, further longitudinal research with repeated measures of PAHs and LTL are needed to confirm these findings.

RevDate: 2021-02-16

Grill S, J Nandakumar (2020)

Molecular mechanisms of telomere biology disorders.

The Journal of biological chemistry, 296:100064 pii:S0021-9258(20)00050-2 [Epub ahead of print].

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

RevDate: 2021-01-22

Subecz C, Sun JS, L Roger (2021)

Effect of DNA repair inhibitor AsiDNA on the incidence of telomere fusion in crisis.

Human molecular genetics pii:6106230 [Epub ahead of print].

Telomere fusions lead to a state of genomic instability, and are thought to drive clonal evolution and tumorigenesis. Telomere fusions occur via both Classical and Alternative Non-Homologous End Joining repair pathways. AsiDNA is a DNA repair inhibitor that acts by mimicking a DNA double strand break (DSB) and hijacking the recruitment of proteins involved in various DNA repair pathways. In this study, we investigated whether the inhibition of DSB-repair pathways by AsiDNA could prevent telomere fusions during crisis. The present study showed that AsiDNA decreased the frequency of telomere fusions without affecting the rate of telomere erosion. Further, it indicated that AsiDNA does not impact the choice of the repair pathway used for the fusion of short dysfunctional telomeres. AsiDNA is thought to prevent short telomeres from fusing by inhibiting DNA repair. An alternative, non-mutually exclusive possibility is that cells harbouring fusions preferentially die in the presence of AsiDNA, thus resulting in a reduction in fusion frequency. This important work could open the way for investigating the use of AsiDNA in the treatment of tumours that have short dysfunctional telomeres and/or are experiencing genomic instability.

RevDate: 2021-02-08
CmpDate: 2021-02-08

Lippert TP, Marzec P, Idilli AI, et al (2021)

Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres.

Nature communications, 12(1):512.

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

RevDate: 2021-02-06

Han S, Ma X, J Fang (2021)

[Clinical Application and Challenges of Telomere and Telomerase Research 
in Lung Cancer].

Zhongguo fei ai za zhi = Chinese journal of lung cancer, 24(1):25-30.

Lung cancer is one of the malignant tumors with high incidence rate and high mortality worldwide. Telomere and telomerase are closely related to the occurrence and development of lung cancer. Although telomerase may not be the direct cause of carcinogenesis, it plays a key role in maintaining telomere length and tumor growth. The length of most tumors, including lung cancer, is shortened. The change of telomere length is related to the risk of lung cancer, and may become the therapeutic target and predictive index. Target drugs for telomere and telomerase signaling pathway are constantly being explored, and drugs represented by telomerase inhibitors are expected to be used in clinical treatment of lung cancer in the future. However, the research on telomere and telomerase is far from enough. The bypass mechanism of telomere length maintenance may be the direction of further research.

RevDate: 2021-01-27

Levstek T, Redenšek S, Trošt M, et al (2021)

Assessment of the Telomere Length and Its Effect on the Symptomatology of Parkinson's Disease.

Antioxidants (Basel, Switzerland), 10(1):.

Telomeres, which are repetitive sequences that cap the end of the chromosomes, shorten with each cell division. Besides cellular aging, there are several other factors that influence telomere length (TL), in particular, oxidative stress and inflammation, which play an important role in the pathogenesis of neurodegenerative brain diseases including Parkinson's disease (PD). So far, the majority of studies have not demonstrated a significant difference in TL between PD patients and healthy individuals. However, studies investigating the effect of TL on the symptomatology and disease progression of PD are scarce, and thus, warranted. We analyzed TL of peripheral blood cells in a sample of 204 PD patients without concomitant autoimmune diseases and analyzed its association with several PD related phenotypes. Monochrome multiplex quantitative PCR (mmqPCR) was used to determine relative TL given as a ratio of the amount of DNA between the telomere and albumin as the housekeeping gene. We found a significant difference in the relative TL between PD patients with and without dementia, where shorter TL presented higher risk for dementia (p = 0.024). However, the correlation was not significant after adjustment for clinical factors (p = 0.509). We found no correlations between TLs and the dose of dopaminergic therapy when the analysis was adjusted for genetic variability in inflammatory or oxidative factors. In addition, TL influenced time to onset of motor complications after levodopa treatment initiation (p = 0.0134), but the association did not remain significant after adjustment for age at inclusion and disease duration (p = 0.0781). Based on the results of our study we conclude that TL contributes to certain PD-related phenotypes, although it may not have a major role in directing the course of the disease. Nevertheless, this expends currently limited knowledge regarding the association of the telomere attrition and the disease severity or motor complications in Parkinson's disease.

RevDate: 2021-01-30

Lindrose AR, McLester-Davis LWY, Tristano RI, et al (2021)

Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature.

PloS one, 16(1):e0245582.

Use of telomere length (TL) as a biomarker for various environmental exposures and diseases has increased in recent years. Various methods have been developed to measure telomere length. Polymerase chain reaction (PCR)-based methods remain wide-spread for population-based studies due to the high-throughput capability. While several studies have evaluated the repeatability and reproducibility of different TL measurement methods, the results have been variable. We conducted a literature review of TL measurement cross-method comparison studies that included a PCR-based method published between January 1, 2002 and May 25, 2020. A total of 25 articles were found that matched the inclusion criteria. Papers were reviewed for quality of methodologic reporting of sample and DNA quality, PCR assay characteristics, sample blinding, and analytic approaches to determine final TL. Overall, methodologic reporting was low as assessed by two different reporting guidelines for qPCR-based TL measurement. There was a wide range in the reported correlation between methods (as assessed by Pearson's r) and few studies utilized the recommended intra-class correlation coefficient (ICC) for assessment of assay repeatability and methodologic comparisons. The sample size for nearly all studies was less than 100, raising concerns about statistical power. Overall, this review found that the current literature on the relation between TL measurement methods is lacking in validity and scientific rigor. In light of these findings, we present reporting guidelines for PCR-based TL measurement methods and results of analyses of the effect of assay repeatability (ICC) on statistical power of cross-sectional and longitudinal studies. Additional cross-laboratory studies with rigorous methodologic and statistical reporting, adequate sample size, and blinding are essential to accurately determine assay repeatability and replicability as well as the relation between TL measurement methods.

RevDate: 2021-01-30

Belfort MB, Qureshi F, Litt J, et al (2021)

Telomere length shortening in hospitalized preterm infants: A pilot study.

PloS one, 16(1):e0243468.

Leukocyte telomere length is a biomarker of aging-related health risks. Hospitalized preterm infants frequently experience elevated oxidative stress and inflammation, both of which contribute to telomere shortening. Our aim was to examine changes in telomere length during neonatal intensive care unit (NICU) hospitalization in a cohort of preterm infants <32 weeks' gestation. We conducted a longitudinal study of 10 infants (mean gestational age 27 weeks, range 23.5 to 29, at birth). We isolated DNA from dried blood spots and used Real Time Quantitative PCR to measure relative leukocyte telomere length in triplicate at three time points for each participant. From birth to discharge, infants experienced an average decline in relative telomere length of 0.021 units per week (95% CI -0.040, -0.0020; p = 0.03), after adjustment for gestational age at birth. Our results suggest a measurable decline in telomere length during NICU hospitalization. We speculate that telomere length change may convey information about NICU exposures that carry short- and long-term health risks.

RevDate: 2021-02-11

Barbé-Tuana FM, Grun LK, Pierdoná V, et al (2021)

Shorter telomeres in children with severe asthma, an indicative of accelerated aging.

Aging, 13(2):1686-1691.

Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.

RevDate: 2021-01-20

Huang Z, Liu C, Ruan Y, et al (2021)

Dynamics of leukocyte telomere length in adults aged 50 and older: a longitudinal population-based cohort study.

GeroScience [Epub ahead of print].

It is well established from previous cross-sectional studies that telomeres shorten with age. However, due to a considerable inter-individual variation in telomere length (TL), its relationship with biological aging is difficult to unpick. Longitudinal repeated assessments of TL changes within individuals should augment our understanding of TL dynamics in aging. This study disentangles within- and inter-individual effects of age on leukocyte telomere length (LTL) dynamics in a large population-based cohort of older adults. A total of 4053 subjects aged 50 and older from the WHO Study on global AGEing and adult health (SAGE) in Shanghai were studied. Relative LTL (T/S ratio) was measured at baseline (2009-2010) and follow-up (2017-2018) by quantitative real-time polymerase chain reaction. We used linear random slope models to analyze LTL dynamics in relation to age and sex and within-subject centering method to distinguish within- versus between-subject effects. We observed LTL shortening in 66.32%, maintenance in 11.23%, and elongation in 22.45% of the study participants. LTL declined significantly with age both cross-sectionally and longitudinally. More importantly, the longitudinal decline in LTL was much greater than the cross-sectional decline (- 0.017 (p < 0.001) versus - 0.002 (p < 0.001) per year). Furthermore, women had a lower within-subject LTL shortening rate than men (- 0.014 versus - 0.020 per year, p < 0.001). The within-individual longitudinal decline in LTL was much greater than the inter-individual cross-sectional decline, indicating that chronological age might impose a greater impact on LTL shortening than other influencing factors combined. Moreover, women showed a lower within-individual LTL shortening rate than men.

RevDate: 2021-01-20

Monsen RC, Chakravarthy S, Dean WL, et al (2021)

The solution structures of higher-order human telomere G-quadruplex multimers.

Nucleic acids research pii:6104436 [Epub ahead of print].

Human telomeres contain the repeat DNA sequence 5'-d(TTAGGG), with duplex regions that are several kilobases long terminating in a 3' single-stranded overhang. The structure of the single-stranded overhang is not known with certainty, with disparate models proposed in the literature. We report here the results of an integrated structural biology approach that combines small-angle X-ray scattering, circular dichroism (CD), analytical ultracentrifugation, size-exclusion column chromatography and molecular dynamics simulations that provide the most detailed characterization to date of the structure of the telomeric overhang. We find that the single-stranded sequences 5'-d(TTAGGG)n, with n = 8, 12 and 16, fold into multimeric structures containing the maximal number (2, 3 and 4, respectively) of contiguous G4 units with no long gaps between units. The G4 units are a mixture of hybrid-1 and hybrid-2 conformers. In the multimeric structures, G4 units interact, at least transiently, at the interfaces between units to produce distinctive CD signatures. Global fitting of our hydrodynamic and scattering data to a worm-like chain (WLC) model indicates that these multimeric G4 structures are semi-flexible, with a persistence length of ∼34 Å. Investigations of its flexibility using MD simulations reveal stacking, unstacking, and coiling movements, which yield unique sites for drug targeting.

RevDate: 2021-01-23

Konečná K, Sováková PP, Anteková K, et al (2021)

Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure.

International journal of molecular sciences, 22(1):.

Involvement of epigenetic mechanisms in the regulation of telomeres and transposable elements (TEs), genomic regions with the protective and potentially detrimental function, respectively, has been frequently studied. Here, we analyzed telomere lengths in Arabidopsis thaliana plants of Columbia, Landsberg erecta and Wassilevskija ecotypes exposed repeatedly to the hypomethylation drug zebularine during germination. Shorter telomeres were detected in plants growing from seedlings germinated in the presence of zebularine with a progression in telomeric phenotype across generations, relatively high inter-individual variability, and diverse responses among ecotypes. Interestingly, the extent of telomere shortening in zebularine Columbia and Wassilevskija plants corresponded to the transcriptional activation of TEs, suggesting a correlated response of these genomic elements to the zebularine treatment. Changes in lengths of telomeres and levels of TE transcripts in leaves were not always correlated with a hypomethylation of cytosines located in these regions, indicating a cytosine methylation-independent level of their regulation. These observations, including differences among ecotypes together with distinct dynamics of the reversal of the disruption of telomere homeostasis and TEs transcriptional activation, reflect a complex involvement of epigenetic processes in the regulation of crucial genomic regions. Our results further demonstrate the ability of plant cells to cope with these changes without a critical loss of the genome stability.

RevDate: 2021-02-12

Molbert N, Angelier F, Alliot F, et al (2021)

Fish from urban rivers and with high pollutant levels have shorter telomeres.

Biology letters, 17(1):20200819.

Environmental pressures, such as urbanization and exposure to pollutants may jeopardize survival of free-living animals. Yet, much remains to be known about physiological and ecological responses to currently-released pollutants, especially in wild vertebrate ectotherms. We tested the effect of urbanization and pollution (phthalates, organochlorine and pyrethroid pesticides, polychlorobiphenyls, polybromodiphenylethers, polycyclic aromatic hydrocarbons, and some of their metabolites) on telomere length, a suggested biomarker of life expectancy, in the European chub, Squalius cephalus, from urban and agricultural rivers of the Marne hydrographic network, France. We showed that telomere length was reduced in chub from urban rivers. Moreover, among the wide range of anthropogenic contaminants investigated, high levels of phthalate metabolites in liver were associated with shorter telomeres. This study suggests that urbanization and chemical pollution may compromise survival of wild fish, by accelerating telomere attrition.

RevDate: 2021-02-02

Vedder O, Moiron M, Bichet C, et al (2021)

Telomere length is heritable and genetically correlated with lifespan in a wild bird.

Molecular ecology [Epub ahead of print].

Telomeres are protective caps at the end of eukaryotic chromosomes that shorten with age and in response to stressful or resource-demanding conditions. Their length predicts individual health and lifespan across a wide range of animals, but whether the observed positive association between telomere length and lifespan is environmentally induced, or set at conception due to a shared genetic basis, has not been tested in wild animals. We applied quantitative genetic "animal models" to longitudinal telomere measurements collected over a 10-year period from individuals of a wild seabird (common tern; Sterna hirundo) with known pedigree. We found no variation in telomere shortening with age among individuals at the phenotypic and genetic level, and only a small permanent environmental effect on adult telomere length. Instead, we found telomere length to be highly heritable and strongly positively genetically correlated with lifespan. Such heritable differences between individuals that are set at conception may present a hitherto underappreciated component of variation in somatic state.

RevDate: 2021-01-18

Samavat H, Luu HN, Beckman KB, et al (2021)

Leukocyte telomere length, cancer incidence and all-cause mortality among Chinese adults: Singapore Chinese Health Study.

International journal of cancer, 148(2):352-362.

Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.

RevDate: 2021-01-16

Zhang JM, Genois MM, Ouyang J, et al (2021)

Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies.

Molecular cell pii:S1097-2765(20)30951-5 [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we induced telomere clustering in ALT-associated PML bodies (APBs) and a POLD3-dependent ATR response at telomeres, showing that BIR generates replication stress. Ablation of BLM helicase activity in APBs abolishes telomere synthesis but causes multiple chromosome bridges between telomeres, revealing a function of BLM in processing inter-telomere BIR intermediates. Interestingly, the accumulation of BLM in APBs requires its own helicase activity and POLD3, suggesting that BIR triggers a feedforward loop to further recruit BLM. Enhancing BIR induces PIAS4-mediated TRF2 SUMOylation, and PIAS4 loss deprives APBs of repair proteins and compromises ALT telomere synthesis. Thus, a BLM-driven and PIAS4-mediated feedforward loop operates in APBs to perpetuate BIR, providing a critical mechanism to extend ALT telomeres.

RevDate: 2021-01-26

Samad MA, Saiman MZ, Abdul Majid N, et al (2021)

Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116.

Molecules (Basel, Switzerland), 26(2):.

Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.

RevDate: 2021-02-14

Gala K, E Khattar (2021)

Long non-coding RNAs at work on telomeres: Functions and implications in cancer therapy.

Cancer letters, 502:120-132 pii:S0304-3835(21)00002-1 [Epub ahead of print].

Long non-coding RNAs (lncRNAs) are known to regulate various biological processes including cancer. Cancer cells possess limitless replicative potential which is attained by telomere length maintenance while normal somatic cells have a limited lifespan because their telomeres shorten with every cell division ultimately triggering replicative senescence. Two lncRNAs have been observed to play a key role in telomere length maintenance. First is the lncRNA TERC (telomerase RNA component) which functions as a template for telomeric DNA synthesis in association with telomerase reverse transcriptase (TERT) which serves as the catalytic component. Together they constitute the telomerase complex which functions as a reverse transcriptase to elongate telomeres. Second lncRNA that helps in regulating telomere length is the telomeric repeat-containing RNA (TERRA) which is transcribed from the subtelomeric region and extends to the telomeric region. TERC and TERRA exhibit important functions in cancer with implications in precision oncology. In this review, we discuss various aspects of these important lncRNAs in humans and their role in cancer along with recent advancements in their anticancer therapeutic application.

RevDate: 2021-01-25

Chakravarti D, LaBella KA, RA DePinho (2021)

Telomeres: history, health, and hallmarks of aging.

Cell, 184(2):306-322.

The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.

RevDate: 2021-01-16

Liddiard K, Grimstead JW, Cleal K, et al (2021)

Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response.

NAR cancer, 3(1):zcaa044.

Identifying attributes that distinguish pre-malignant from senescent cells provides opportunities for targeted disease eradication and revival of anti-tumour immunity. We modelled a telomere-driven crisis in four human fibroblast lines, sampling at multiple time points to delineate genomic rearrangements and transcriptome developments that characterize the transition from dynamic proliferation into replicative crisis. Progression through crisis was associated with abundant intra-chromosomal telomere fusions with increasing asymmetry and reduced microhomology usage, suggesting shifts in DNA repair capacity. Eroded telomeres also fused with genomic loci actively engaged in transcription, with particular enrichment in long genes. Both gross copy number alterations and transcriptional responses to crisis likely underpin the elevated frequencies of telomere fusion with chromosomes 9, 16, 17, 19 and most exceptionally, chromosome 12. Juxtaposition of crisis-regulated genes with loci undergoing de novo recombination exposes the collusive contributions of cellular stress responses to the evolving cancer genome.

RevDate: 2021-01-15

Henslee G, Williams C, Liu P, et al (2021)

Identification and characterization of novel ACD variants: Modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Cold Spring Harbor molecular case studies pii:mcs.a005454 [Epub ahead of print].

Telomere biology disorders (TBDs), largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominant and autosomal recessive TBDs. TPP1 is responsible for recruitment of telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1): c.505_507delGAG, p.E169del; and c.619delG, p.D207Tfs*22; as well as a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening. Further analysis of lymphoblastoid cell lines revealed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.D207Tfs*22, or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.

RevDate: 2021-01-26

Lejawa M, Osadnik K, Osadnik T, et al (2021)

Association of Metabolically Healthy and Unhealthy Obesity Phenotypes with Oxidative Stress Parameters and Telomere Length in Healthy Young Adult Men. Analysis of the MAGNETIC Study.

Antioxidants (Basel, Switzerland), 10(1):.

Obesity is a significant factor related to metabolic disturbances that can lead to metabolic syndrome (MetS). Metabolic dysregulation causes oxidative stress, which affects telomere structure. The current study aimed to evaluate the relationships between telomere length, oxidative stress and the metabolically healthy and unhealthy phenotypes in healthy young men. Ninety-eight participants were included in the study (49 healthy slim and 49 obese patients). Study participants were divided into three subgroups according to body mass index and metabolic health. Selected oxidative stress markers were measured in serum. Relative telomere length (rTL) was measured using quantitative polymerase chain reaction. The analysis showed associations between laboratory markers, oxidative stress markers and rTL in metabolically healthy and unhealthy participants. Total oxidation status (TOS), total antioxidant capacity (TAC) and rTL were significantly connected with metabolically unhealthy obesity. TAC was associated with metabolically healthy obesity. Telomeres shorten in patients with metabolic dysregulation related to oxidative stress and obesity linked to MetS. Further studies among young metabolically healthy and unhealthy individuals are needed to determine the pathways related to metabolic disturbances that cause oxidative stress that leads to MetS.

RevDate: 2021-01-26

Sławińska N, R Krupa (2021)

Molecular Aspects of Senescence and Organismal Ageing-DNA Damage Response, Telomeres, Inflammation and Chromatin.

International journal of molecular sciences, 22(2):.

Cells can become senescent in response to stress. Senescence is a process characterised by a stable proliferative arrest. Sometimes it can be beneficial-for example, it can suppress tumour development or take part in tissue repair. On the other hand, studies show that it is also involved in the ageing process. DNA damage response (DDR) is triggered by DNA damage or telomere shortening during cell division. When left unresolved, it may lead to the activation of senescence. Senescent cells secrete certain proteins in larger quantities. This phenomenon is referred to as senescence-associated secretory phenotype (SASP). SASP can induce senescence in other cells; evidence suggests that overabundance of senescent cells contributes to ageing. SASP proteins include proinflammatory cytokines and metalloproteinases, which degrade the extracellular matrix. Shortening of telomeres is another feature associated with organismal ageing. Older organisms have shorter telomeres. Restoring telomerase activity in mice not only slowed but also partially reversed the symptoms of ageing. Changes in chromatin structure during senescence include heterochromatin formation or decondensation and loss of H1 histones. During organismal ageing, cells can experience heterochromatin loss, DNA demethylation and global histone loss. Cellular and organismal ageing are both complex processes with many aspects that are often related. The purpose of this review is to bring some of these aspects forward and provide details regarding them.

RevDate: 2021-01-26

Selvaraju V, Phillips M, Fouty A, et al (2021)

Telomere Length as a Biomarker for Race-Related Health Disparities.

Genes, 12(1):.

Disparities between the races have been well documented in health and disease in the USA. Recent studies show that telomere length, a marker of aging, is associated with obesity and obesity-related diseases, such as heart disease and diabetes. The current study aimed to evaluate the connection between telomere length ratio, blood pressure, and childhood obesity. The telomere length ratio was measured in 127 children from both European American (EA) and African American (AA) children, aged 6-10 years old. AA children had a significantly high relative telomere to the single copy gene (T/S) ratio compared to EA children. There was no significant difference in the T/S ratio between normal weight (NW) and overweight/obese (OW/OB) groups of either race. Blood pressure was significantly elevated in AA children with respect to EA children. Hierarchical regression analysis adjusted for race, gender, and age expressed a significant relationship between the T/S ratio and diastolic pressure. Low T/S ratio participants showed a significant increase in systolic pressure, while a high T/S ratio group showed an increase in diastolic pressure and heart rate of AA children. In conclusion, our findings show that AA children have high T/S ratio compared to EA children. The high T/S ratio is negatively associated with diastolic pressure.

RevDate: 2021-02-05

Lee HH, Okuzono SS, Kim ES, et al (2020)

Optimism and telomere length among African American adults in the Jackson Heart Study.

Psychoneuroendocrinology, 125:105124 pii:S0306-4530(20)30547-3 [Epub ahead of print].

BACKGROUND: Optimism is linked with greater longevity in both White and African American populations. Optimism may enhance longevity by slowing cellular aging, for which leukocyte telomere shortening is a biomarker. However, limited studies have examined the association of optimism with leukocyte telomere length among African Americans.

METHODS: Data are from 723 men and 1244 women participating in the Jackson Heart Study (age = 21-93 years). We used multivariable linear regression models to conduct cross-sectional analyses examining whether higher optimism was associated with longer mean absolute leukocyte telomere length (assayed with Southern blot analysis). Models adjusted for sociodemographic characteristics, depressive symptomatology, health conditions, and health behavior-related factors. We also considered potential effect modification by key factors.

RESULTS: In the age-adjusted model, optimism, measured as a continuous variable, was not associated with leukocyte telomere length (β = 0.01, 95%CI: -0.02, 0.04). This association remained null in the fully-adjusted model (β = 0.02, 95%CI: -0.02, 0.05) and was also null when considering optimism as a binary measure (higher vs. lower optimism). We found no evidence of effect modification by sex, age, body mass index, income, or chronic conditions.

CONCLUSIONS: Optimism was not associated with leukocyte telomere length among African American adults. Future studies should investigate alternate biological and behavioral mechanisms that may explain the optimism-health association.

RevDate: 2021-01-12

McCulloch MJ, Ward Gauthier NA, L Vaillancourt (2021)

Use of telomere fingerprinting to identify clonal lineages of Colletotrichum fioriniae in Kentucky mixed-fruit orchards.

Plant disease [Epub ahead of print].

Multiple species in the fungal genus Colletotrichum cause anthracnose fruit rot diseases that are responsible for major yield losses of as much as 100%. Individual species of Colletotrichum typically have broad host ranges and can infect multiple fruit species. Colletotrichum fioriniae causes anthracnose fruit rots of apples, blueberries and strawberries in Kentucky orchards where these fruits grow in close proximity. This raises the possibility of cross-infection, which may have significant management implications. The potential occurrence of cross-infection was investigated by using telomere fingerprinting to identify C. fioriniae clones in several mixed-fruit orchards. Telomere fingerprints were highly polymorphic among a test group of C. fioriniae strains and effectively defined clonal lineages. Fingerprints were compared among apple, blueberry and strawberry isolates of C. fioriniae from three different orchards and similarity matrices were calculated to build phylograms for each orchard group. Multiple clonal lineages of C. fioriniae were identified within each orchard on the same fruit host. Related lineages were found among isolates from different hosts, but the results did not provide direct evidence for cross-infection of different fruit species by the same clones. Recovery of the same clonal lineages within orchards across multiple years suggested that local dispersal was important in pathogen population structure and that C. fioriniae strains persisted within orchards over time. Isolates from blueberry were less diverse than isolates from apple, perhaps related to more intensive anthracnose management protocols on apple versus blueberry. Telomere fingerprinting is a valuable tool for understanding population dynamics of Colletotrichum fruit rot fungi.

RevDate: 2021-01-12

Lee JS, La J, Aziz S, et al (2021)

Molecular Markers of Telomere Dysfunction and Senescence are Common Findings in the Usual Interstitial Pneumonia Pattern of Lung Fibrosis.

Histopathology [Epub ahead of print].

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a genetically-mediated, age-associated, progressive form of pulmonary fibrosis characterized pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (Non-IPF UIP) whose clinical course is similarly poor, suggesting common molecular drivers.

METHODS: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissue from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared.

RESULTS: Histopathologic changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, noncaseating granulomas, airway centered inflammation or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs compared to age-similar, unused donor, controls. Molecular markers of senescence (p16, p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localized expression of these proteins to AECII cells. The MUC5B promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients and MUC5B protein expression was similar in IPF and non-IPF UIP lungs.

CONCLUSIONS: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

RevDate: 2021-01-15

Evans JR, Torres-Pérez JV, Miletto Petrazzini ME, et al (2021)

Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).

Scientific reports, 11(1):339.

Individual differences in personality are associated with variation in healthy aging. Health behaviours are often cited as the likely explanation for this association; however, an underlying biological mechanism may also exist. Accelerated leukocyte telomere shortening is implicated in multiple age-related diseases and is associated with chronic activation of the hypothalamus-pituitary-adrenal (HPA) axis, providing a link between stress-related personality differences and adverse health outcomes. However, the effects of the HPA axis are tissue specific. Thus, leukocyte telomere length may not accurately reflect telomere length in disease-relevant tissues. Here, we examined the correlation between stress reactivity and telomere length in heart and brain tissue in young (6-9 month) and aging (18 month) zebrafish. Stress reactivity was assessed by tank diving and through gene expression. Telomere length was assessed using quantitative PCR. We show that aging zebrafish have shorter telomeres in both heart and brain. Telomere length was inversely related to stress reactivity in heart but not brain of aging individuals. These data support the hypotheses that an anxious predisposition contributes to accelerated telomere shortening in heart tissue, which may have important implications for our understanding of age-related heart disease, and that stress reactivity contributes to age-related telomere shortening in a tissue-specific manner.

RevDate: 2021-02-06

Crocco P, De Rango F, Dato S, et al (2021)

Telomere length as a function of age at population level parallels human survival curves.

Aging, 13(1):204-218.

Telomeres are subject to age related shortening which can be accelerated by oxidative stress and inflammation. Many studies have reported an inverse correlation between telomere length and survival, but such inverse correlation has not been always confirmed in different populations. We analyzed the trend of Leukocyte Telomere Length (LTL) as a function of age in a cohort of 516 subjects aged 65-106 years from Southern Italy. The trend of LTL obtained was quite similar to demographic survival curves reported with data of western societies. We observed a decrease of LTL after 70 years of age and then an increase after 92 years, in agreement with the sharp decrease of survival after 70 years of age and its increase after 90 years, due to the deceleration of mortality at old ages. Our data suggest that a generalized LTL attrition after 70 years of age, associated to organismal decline, affects most of the population. Such generalized attrition may exacerbate senescence in these subjects, predisposing them to high mortality risk. Conversely, the subjects with better physical conditions, experience a lower attrition and, consequently, a delayed senescence, contributing to the deceleration of mortality which has been observed among very old subjects in modern societies.

RevDate: 2021-02-15
CmpDate: 2021-01-27

Sanchez-Vazquez R, Guío-Carrión A, Zapatero-Gaviria A, et al (2021)

Shorter telomere lengths in patients with severe COVID-19 disease.

Aging, 13(1):1-15.

The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.

RevDate: 2021-01-25

Martens DS, Van Der Stukken C, Derom C, et al (2021)

Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.

EBioMedicine, 63:103164.

BACKGROUND: Telomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood.

METHODS: Telomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n = 273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n = 164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards.

FINDINGS: In children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r = 0.71, P < 0.0001;) and placenta (r = 0.60, P < 0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r = 0.46, P < 0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation.

INTERPRETATION: The high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life.

FUNDING: European Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).

RevDate: 2021-01-10

Cheng F, Luk AO, Wu H, et al (2021)

Shortened Relative Leukocyte Telomere Length is Associated with All-cause Mortality in Type 2 Diabetes- Analysis from the Hong Kong Diabetes Register.

Diabetes research and clinical practice pii:S0168-8227(21)00002-4 [Epub ahead of print].

AIMS: Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.

METHODS: Consecutive Chinese patients with type 2 diabetes (N=5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.

RESULTS: The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1,925 subjects who subsequently died compared with the remaining subjects (4.3±1.2 vs. 4.7±1.2, P<0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P<0.001), which remained significant after adjusting for traditional risk factors.

CONCLUSIONS: Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.

RevDate: 2021-01-08

Sethuram R, Bazzi AA, Salih SM, et al (2021)

Peripheral lymphocyte telomere dysfunction: a valid surrogate marker for female fertility?.

Fertility and sterility, 115(1):85-86.

RevDate: 2021-01-11

Liu X, Liu X, Shi Q, et al (2021)

Association of telomere length and telomerase methylation with n-3 fatty acids in preschool children with obesity.

BMC pediatrics, 21(1):24.

BACKGROUND: Telomeres play a crucial role in cellular survival and its length is a predictor for onset of chronic non-communicable diseases. Studies on association between telomeres and obesity in children have brought discrepant results and the underlying mechanisms and influential factors are to be elucidated. This study aimed to investigate changes in telomere length and telomerase reverse transcriptase (TERT) DNA methylation, and further to determine their correlation with n-3 polyunsaturated fatty acids (PUFAs) in preschool children with obesity.

METHODS: Forty-six preschool children with obesity aged 3 to 4 years were included in the study, with equal numbers of age- and gender-matched children with normal weight as control. Leukocyte telomere length was determined by the ratio of telomeric product and single copy gene obtained using real-time qPCR. DNA methylation of TERT promoter was analyzed by bisulfite sequencing. Fatty acids in erythrocytes were measured by gas chromatography with a total of 15 fatty acids analyzed. The total saturated fatty acids (SFAs), total n-6 PUFAs, total n-3 PUFAs, and the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) were calculated. Then the correlation between leukocyte telomere length, TERT promoter methylation and fatty acids was determined.

RESULTS: In preschool children with obesity, leukocyte telomeres were shortened and had a negative association with the body mass index. The methylated fractions in 13 of 25 CpG sites in the TERT promoter were increased by approximately 3 to 35% in the children with obesity compared to the normal weight children. Erythrocyte lauric acid and total SFAs, lenoleic acid and total n-6 PUFAs were higher, and DHA was lower in the children with obesity than those in the children with normal weight. Correlative analysis showed that leukocyte telomere length had a positive association with total SFAs and DHA, and a negative association with the AA/DHA ratio. However, no association between erythrocyte DHA and the TERT promoter methylation was found.

CONCLUSION: These data indicate that the reduced body DHA content and increased AA/DHA ratio may be associated with shortened leukocyte telomeres in child obesity, which is probably not involved in the TERT promoter methylation.

RevDate: 2021-01-11

Kalungi A, Kinyanda E, Womersley JS, et al (2021)

TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.

BMC medical genomics, 14(1):15.

BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years).

RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months.

CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.

RevDate: 2021-01-25

Godhamgaonkar AA, Sundrani DP, SR Joshi (2021)

Role of maternal nutrition and oxidative stress in placental telomere attrition in women with preeclampsia.

Hypertension in pregnancy, 40(1):63-74.

Background:Maternal nutrition influences the growth and development of the fetus and influences pregnancy outcome. We have earlier demonstrated altered maternal nutrition and increased oxidative stress in women with preeclampsia. Oxidative stress is known to be associated with reduced telomere length and short telomere aggregates. Increased telomere attrition leads to increased cellular senescence and tissue ageing. Methods:The present review focuses on the role of maternal nutrition and oxidative stress in telomere attrition in preeclampsia. Results and Conclusion:Future studies need to examine the association between maternal nutritional status in early pregnancy, oxidative stress and telomere attrition in preeclampsia.

RevDate: 2021-01-11
CmpDate: 2021-01-08

Fan YL, Q Ye (2020)

[A concise review of telomere and telomerase-related genetic markers in fibrotic lung diseases].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 38(12):952-956.

Fibrotic lung diseases are a heterogeneous group of diffuse parenchymal lung diseases caused by various factors. Pulmonary fibrosis is one of the common pathological changes of advanced fibrotic lung diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disorder with unknown etiology. IPF mainly affects the elderly that is considered as an aging related disease. Telomeres are specialized structures at the ends of chromosomes. Telomere shortening results in cellular senescence or apoptosis. Telomerase is a ribonucleoprotein complex that maintains telomere length and genome stability. The telomere shortening and mutations in telomere-related genes are associated with incidence and prognosis of pulmonary fibrosis. Here, a concise review of telomere and telomerase-related genomic markers in IPF and other fibrotic lung diseases is written.

RevDate: 2021-01-22

Elmadawy MA, Abdullah OA, El Gazzar WB, et al (2021)

Telomere length and signal joint T-cell receptor rearrangement excision circles as biomarkers for chronological age estimation.

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals [Epub ahead of print].

BACKGROUND: Chronological age estimation is a challenging marker in the field of forensic medicine. The current study aimed to investigate the accuracy of signal joint T-cell receptor rearrangement excision circles (sjTRECs) quantification and telomere length measurement as methods for estimating chronological age.

METHODS: Telomere length was estimated in the DNA derived from the buccal cells through estimating the telomeric restriction fragment (TRF) length using TeloTTAGGG Telomere Length Assay while the sjTRECs quantification was carried out on DNA isolated from the blood samples using qPCR.

RESULTS: The TRF length was shortened with increased age (r = -0.722, p < 0.001). The sjTRECs were also decreased with increased age (r = -0.831, p < 0.001). Stronger coefficient and lower standard error of the estimate was obtained when multiple regression analysis for age prediction based on the values of both methods was applied (r = -0.876, p < 0.001).

RevDate: 2021-01-14
CmpDate: 2021-01-14

Viswanath P, Batsios G, Mukherjee J, et al (2021)

Non-invasive assessment of telomere maintenance mechanisms in brain tumors.

Nature communications, 12(1):92.

Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.

RevDate: 2021-01-15

Starnino L, Dupuis G, Busque L, et al (2021)

The associations of hostility and defensiveness with telomere length are influenced by sex and health status.

Biology of sex differences, 12(1):2.

BACKGROUND: Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex.

METHODS: One thousand thirty-six individuals (Mage = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook-Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants.

RESULTS: A hostility by sex interaction emerged (β = - .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = - .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = - .43, p = .049).

CONCLUSION: Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.

RevDate: 2021-01-05

Li X, Liu J, Zhou G, et al (2021)

BDE-209 and DBDPE induce male reproductive toxicity through telomere-related cell senescence and apoptosis in SD rat.

Environment international, 146:106307.

Decabrominated diphenyl ether (BDE-209) and decabromodiphenyl ethane (DBDPE) are common flame retardants utilized in many kinds of electronic and textile products. Due to their persistence and bioaccumulation, BDE-209 and DBDPE extensively exist in the surrounding environment and wild animals. Previous studies have indicated that BDE-209 could induce male reproductive toxicity, whereas those of DBDPE remains relatively rare. In this study, we investigated the effects of both BDE-209 and DBDPE on reproductive system in male SD rats, and explored the potential mechanisms under the reproductive toxicity of BDE-209 and DBDPE. Male rats were orally administered with BDE-209 and DBDPE (0, 5, 50 and 500 mg/kg/day) for a 28-day exposure experiment. The current results showed that BDE-209 and DBDPE led to testicular damage in physiological structure, decreased the sperm number and motility, and increased the sperm malformation rates in rat. Moreover, BDE-209 and DBDPE could damage the telomeric function by shortening telomere length and reducing telomerase activity, which consequently caused cell senescence and apoptosis in testis of rat. This could contribute to the decline of sperm quality and quantity. In conclusion, BDE-209 and DBDPE led to reproductive toxicity by inducing telomere dysfunction and the related cell senescence and apoptosis in testis of SD rat. Comparatively, BDE-209 had more severe effects on male reproduction. Our findings may provide new insight into the potential deleterious effects of BFRs on male reproductive health.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Good Beginner's Books

Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

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