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29 Sep 2023 at 01:58
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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.

Created with PubMed® Query: telomere.q.txt NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-09-28

Sivasangari K, Sivamaruthi BS, Chaiyasut C, et al (2023)

Maternal stress-induced changes in adolescent and adult offspring: Neurobehavioural improvement and telomere maintenance.

Heliyon, 9(10):e20385.

Maternal stress (MS) during gestation is known to increase the risk for the development of behavioural and physiological disorders and advances cellular aging. In this study, we investigated whether the supplementation of standardized Bacopa monnieri extract (CDRI-08/BME) or l-Carnosine (L-C) to the mother exposed to social stress during gestation modify the effect on their offspring's neurobehaviour, antioxidant defence gene expression, telomere length, and telomere biology. To test this, timed pregnant rats were subjected to social stress during the gestational day (GD) 16-18. A subset of stressed pregnant rats received either BME [80 mg/kg in 0.5% gum acacia (per-orally; p.o)] or L-C [1 mg/kg (p.o)] every day from GD-10 to until their pup's attained postnatal day (PND)-23. We observed that MS induced anxiety-like behaviour, altered inter-limb coordination, antioxidant defence genes [Superoxide dismutase (SOD1,2), Catalase (CAT), Glutathione peroxidase-3 (GPX3)], telomerase reverse transcriptase (TERT), shelterin complex subunits (TRF1, RAP1B, POT1) protein level and shorten telomere length. Notably, supplementation of BME/L-C dampens the MS, thus the effect on neurobehaviour, antioxidant defence gene expression, and telomere biology is minimized in their offspring. Together, our results suggest that supplementation of BME/L-C during gestation dampens the MS and reduced oxidative stress-mediated changes in telomere shortening/biology and associated neurobehaviour in offspring born following MS.

RevDate: 2023-09-28

Vukašinović A, Klisic A, Ostanek B, et al (2023)

Redox Status and Telomere-Telomerase System Biomarkers in Patients with Acute Myocardial Infarction Using a Principal Component Analysis: Is There a Link?.

International journal of molecular sciences, 24(18): pii:ijms241814308.

In the present study, we examined redox status parameters in arterial and venous blood samples, its potential to predict the prognosis of acute myocardial infarction (AMI) patients assessed through its impact on the comprehensive grading SYNTAX score, and its clinical accuracy. Potential connections between common blood biomarkers, biomarkers of redox status, leukocyte telomere length, and telomerase enzyme activity in the acute myocardial infarction burden were assessed using principal component analysis (PCA). This study included 92 patients with acute myocardial infarction. Significantly higher levels of advanced oxidation protein products (AOPP), superoxide anion (O2[•-]), ischemia-modified albumin (IMA), and significantly lower levels of total oxidant status (TOS) and total protein sulfhydryl (SH-) groups were found in arterial blood than in the peripheral venous blood samples, while biomarkers of the telomere-telomerase system did not show statistical significance in the two compared sample types (p = 0.834 and p = 0.419). To better understand the effect of the examined biomarkers in the AMI patients on SYNTAX score, those biomarkers were grouped using PCA, which merged them into the four the most contributing factors. The "cholesterol-protein factor" and "oxidative-telomere factor" were independent predictors of higher SYNTAX score (OR = 0.338, p = 0.008 and OR = 0.427, p = 0.035, respectively), while the ability to discriminate STEMI from non-STEMI patients had only the "oxidative-telomere factor" (AUC = 0.860, p = 0.008). The results show that traditional cardiovascular risk factors, i.e., high total cholesterol together with high total serum proteins and haemoglobin, are associated with severe disease progression in much the same way as a combination of redox biomarkers (pro-oxidant-antioxidant balance, total antioxidant status, IMA) and telomere length.

RevDate: 2023-09-28

Han X, Hirschel A, Tsapekos M, et al (2023)

In Vitro Assessment of Gold Nanoparticles on Telomerase Activity and Telomere Length in Human Fibroblasts.

International journal of molecular sciences, 24(18): pii:ijms241814273.

Telomerase activity coincides with lengthening of the ends of chromosomes known as telomeres. Telomere length is used as a marker for cellular aging. Telomeres shorten over time as cells divide, and certain bioactive compounds such as gold nanoparticles (AuNPs) may slow the shortening of telomeres by increasing telomerase activity. The objective of the present study is to assess the effect of AuNPs on telomerase activity and telomere length in human fibroblasts. Telomerase activity was measured using enzyme-linked immunosorbent assay (ELISA) in primary human lung fibroblasts (IMR90) and using quantitative PCR-based telomeric repeat amplification protocol (Q-TRAP) in primary human dermal fibroblasts, neonatal (HDFn). Telomere length was determined by Telomere Analysis Technology (TAT[®])assay in HDFn. In IMR90, all AuNP treatments showed significant increases in telomerase activity when compared to earlier passages. HDFn treated with AuNPs at 0 ppm, 0.05 ppm, 0.5 ppm, or 5 ppm did not show significant differences in telomerase activity compared to the control group. Significant differences in telomere length in HDFn were observed at 2 weeks of 0.05 and 0.5 ppm AuNPs under oxidative culture conditions as compared to the control group. The study showed preliminary evidence that AuNPs may increase telomerase activity and decelerate the shortening of telomeres in human fibroblasts, suggesting its potential anti-aging effects, which warrants further investigation.

RevDate: 2023-09-28

Hou J, Yun Y, Jeon B, et al (2023)

Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.

International journal of molecular sciences, 24(18): pii:ijms241814241.

Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.

RevDate: 2023-09-28

Bukic E, Milasin J, Toljic B, et al (2023)

Association between Combination Antiretroviral Therapy and Telomere Length in People Living with Human Immunodeficiency Virus.

Biology, 12(9): pii:biology12091210.

Long-term exposure to combination antiretroviral therapy (cART) may be associated with accelerated ageing. Telomere length is considered to be reliable aging biomarker. The aim of this study was to compare patients' relative telomere length (RTL) between and within different cART classes and to estimate the impact of certain HIV-related variables on RTL. The study was conducted in 176 HIV-infected male patients receiving cART, with ≤50 copies HIV RNA/mL plasma. RTL was determined from mononuclear cells by quantitative polymerase chain reaction. Standard statistical tests and unsupervised machine learning were performed. The mean RTL was 2.50 ± 1.87. There was no difference (p = 0.761) in RTL between therapeutic groups: two nucleoside reverse transcriptase inhibitors as the backbone treatment, combined with either integrase inhibitor, protease inhibitor, or non-nucleoside reverse transcriptase inhibitor (NNRTI). Machine learning results suggested duration of HIV infection, CD4+ T-cell count, and cART, including NNRTI, as potentially significant variables impacting RTL. Kendall's correlation test excluded duration of HIV infection (p = 0.220) and CD4+ T-cell count (p = 0.536) as significant. The Mann-Whitney test confirmed that cART containing NNRTI impacted RTL (p = 0.018). This was the first study to show that patients using efavirenz within cART had significantly shorter telomeres than patients using nevirapine.

RevDate: 2023-09-27

Anonymous (2023)

Correction to: Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

RevDate: 2023-09-27

Liu J, Zheng T, Chen D, et al (2023)

RBMX involves in telomere stability maintenance by regulating TERRA expression.

PLoS genetics, 19(9):e1010937.

Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from subtelomeric to telomeric region of chromosome ends. TERRA is prone to form R-loop structures at telomeres by invading into telomeric DNA. Excessive telomere R-loops result in telomere instability, so the TERRA level needs to be delicately modulated. However, the molecular mechanisms and factors controlling TERRA level are still largely unknown. In this study, we report that the RNA binding protein RBMX is a novel regulator of TERRA level and telomere integrity. The expression level of TERRA is significantly elevated in RBMX depleted cells, leading to enhanced telomere R-loop formation, replication stress, and telomere instability. We also found that RBMX binds to TERRA and the nuclear exosome targeting protein ZCCHC8 simultaneously, and that TERRA degradation slows down upon RBMX depletion, implying that RBMX promotes TERRA degradation by regulating its transportation to the nuclear exosome, which decays nuclear RNAs. Altogether, these findings uncover a new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and raising RBMX as a potential target of cancer therapy.

RevDate: 2023-09-28

Borghini A, Mercuri A, Campolo J, et al (2023)

Influence of Chromosome 9p21.3 rs1333049 Variant on Telomere Length and Their Interactive Impact on the Prognosis of Coronary Artery Disease.

Journal of cardiovascular development and disease, 10(9):.

BACKGROUND: Both telomere shortening and the chromosome 9p21.3 (Chr9p21) rs1333049 (G/C) variant are involved in coronary artery disease (CAD) risk, likely affecting mechanisms related to cell cycle arrest and vascular senescence. The aim of the study was to examine the link between Chr9p21 rs1333049 variant and leucocyte telomere length (LTL), as well as their interactive effect on the risk of major adverse cardiovascular events (MACEs).

METHODS: A cohort of 472 patients with angiographically proven and clinically stable CAD were included in the study. At baseline, the LTL, biochemical parameters, and genotype analysis of Chr9p21 rs1333049 variant were measured in all patients. The primary endpoint of this study was the occurrence of MACE defined as a composite of coronary-related death, nonfatal MI, and coronary revascularization.

RESULTS: On multivariable linear regression analysis, age (p = 0.02) and Chr9p21 rs1333049 variant (p = 0.002) were the only independent predictors of LTL levels. Carriers of the CC genotype of this SNP had shorter telomeres than GC carriers (p = 0.02) and GG carriers (p = 0.0005). After a follow-up with a mean period of 62 ± 19 months, 90 patients (19.1%) had MACE. Short LTL was an independent prognostic factor of MACE incidence (HR:2.2; 95% CI: 1.3-3.7; p = 0.005) after adjustment for potential confounders. There was a significant interaction (p = 0.01) between the LTL and rs1333049 variant, with patients with risk-allele C and short LTL having a higher risk (HR:5.8; 95% CI: 1.8-19.2; p = 0.004).

CONCLUSION: A strong relationship between LTL and Chr9p21 rs1333049 variant was identified, and they interactively affect the risk of poor prognosis in CAD patients.

RevDate: 2023-09-27

Torres-Montaner A (2023)

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis.

Current issues in molecular biology, 45(9):7582-7616 pii:cimb45090478.

Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage is an obligatory step preceding its stabilization. During tissue turnover, the telomeres of cells undergoing differentiation can be damaged as a consequence of defective DNA repair caused by endogenous or exogenous agents. This may result in the emergence of new mechanism of telomere maintenance which is the final outcome of DNA damage and the initial signal that triggers malignant transformation. Instead, transformation of stem cells is directly induced by primary derangement of telomere maintenance mechanisms. The newly modified telomere complex may promote survival of cancer stem cells, independently of telomere maintenance. An inherent resistance of stem cells to transformation may be linked to specific, robust mechanisms that help maintain telomere integrity.

RevDate: 2023-09-27

Romero-Haro AA, Figuerola J, C Alonso-Alvarez (2023)

Low Antioxidant Glutathione Levels Lead to Longer Telomeres: A Sex-Specific Link to Longevity?.

Integrative organismal biology (Oxford, England), 5(1):obad034.

Telomeres are repetitive DNA sequences at the end of chromosomes that protect them from degradation. They have been the focus of intense research because short telomeres would predict accelerated ageing and reduced longevity in vertebrates. Oxidative stress is considered a physiological driver of the telomere shortening and, consequently, short lifespan. Among molecules fighting against oxidative stress, glutathione is involved in many antioxidant pathways. Literature supports that oxidative stress may trigger a compensatory "hormetic" response increasing glutathione levels and telomere length. Here, we tested the link between total glutathione concentration and telomere length in captive birds (zebra finches; Taeniopygia guttata). Total glutathione levels were experimentally decreased during birds' growth using a specific inhibitor of glutathione synthesis (buthionine sulfoximine; BSO). We monitored the birds' reproductive performance in an outdoor aviary during the first month of life, and their longevity for almost 9 years. Among control individuals, erythrocyte glutathione levels during development positively predicted erythrocyte telomere length in adulthood. However, BSO-treated females, but not males, showed longer telomeres than control females in adulthood. This counterintuitive finding suggests that females mounted a compensatory response. Such compensation agrees with precedent findings in the same population where the BSO treatment increased growth and adult body mass in females but not males. BSO did not influence longevity or reproductive output in any sex. However, early glutathione levels and adult telomere length interactively predicted longevity only among control females. Those females with "naturally" low (non-manipulated) glutathione levels at the nestling age but capable of producing longer telomeres in adulthood seem to live longer. The results suggest that the capability to mount a hormetic response triggered by low early glutathione levels can improve fitness via telomere length. Overall, the results may indicate a sex-specific link between glutathione and telomere values. Telomerase activity and sexual steroids (estrogens) are good candidates to explain the sex-biased mechanism underlying the early-life impact of oxidative stress on adult telomere length.

RevDate: 2023-09-27

Shin YA, JH Kim (2023)

Effects of Cardiorespiratory Fitness on Cardiovascular Disease Risk Factors and Telomere Length by Age and Obesity.

Journal of obesity & metabolic syndrome, 32(3):259-268.

BACKGROUND: This study investigates differences in telomere length according to obesity, cardiovascular disease (CVD) risk factors, and fitness level in South Korean males.

METHODS: The subjects of this study were males in their 10s to 50s (n=249). We measured obesity indices, CVD risk factors, leukocyte telomere length (LTL), and cardiorespiratory fitness (CRF). Correlation and regression analyses were performed to analyze the data.

RESULTS: Measurement of participants' obesity indices, CVD risk factors, and maximum oxygen intake and analyzing their correlations with LTL revealed that LTL and CRF decreased with age and the levels and numbers of obesity indices and CVD risk factors increased. The LTL showed differences according to whether subjects exhibited obesity or dyslipidemia and by CRF level. When all the variables that influence the LTL were adjusted, the LTL became shorter as the age and low-density lipoprotein cholesterol (LDL-C) level increased, and it became longer as the maximum rate of oxygen utilization (VO2max) increased. When the age and CVD risk factors that influence the LTL were adjusted according to obesity and CRF for the obese group, the LTL became shorter as the age and LDL-C level increased (P<0.01), and it became longer as VO2max increased (P<0.01).

CONCLUSION: We found that obesity influenced the LTL by increasing the levels of CVD risk factors and decreasing CRF, whereas maintaining high CRF could alleviate the effects of obesity and CVD risk factors according to age while maintaining and influencing the elongation of LTL.

RevDate: 2023-09-26

Belyayev A, Kalendar R, Josefiová J, et al (2023)

Telomere sequence variability in genotypes from natural plant populations: unusual block-organized double-monomer terminal telomeric arrays.

BMC genomics, 24(1):572.

BACKGROUND: Telomeres are the nucleoprotein complexes that physically cap the ends of eukaryotic chromosomes. Most plants possess Arabidopsis-type telomere sequences (TSs). In addition to terminal TSs, more diverse interstitial TSs exists in plants. Although telomeres have been sufficiently studied, the actual diversity of TSs in land plants is underestimated.

RESULTS: We investigate genotypes from seven natural populations with contrasting environments of four Chenopodium species to reveal the variability in TSs by analyzing Oxford Nanopore reads. Fluorescent in situ hybridization was used to localize telomeric repeats on chromosomes. We identified a number of derivative monomers that arise in part of both terminal and interstitial telomeric arrays of a single genotype. The former presents a case of block-organized double-monomer telomers, where blocks of Arabidopsis-type TTTAGGG motifs were interspersed with blocks of derivative TTTAAAA motifs. The latter is an integral part of the satellitome with transformations specific to the inactive genome fraction.

CONCLUSIONS: We suggested two alternative models for the possible formation of derivative monomers from telomeric heptamer motifs of Arabidopsis-type. It was assumed that derivatization of TSs is a ubiquitous process in the plant genome but occurrence and frequencies of derivatives may be genotype-specific. We also propose that the formation of non-canonical arrays of TSs, especially at chromosomal termini, may be a source for genomic variability in nature.

RevDate: 2023-09-26

Li X, Duan X, Wang M, et al (2023)

MEG3 polymorphisms associated with leukocyte telomere length in workers exposed to polycyclic aromatic hydrocarbons.

Environmental science and pollution research international [Epub ahead of print].

Long non-coding RNA maternally expressed gene 3 (MEG3) has been revealed to be involved in telomere length (TL) maintenance and homeostasis. However, it is unknown whether single-nucleotide polymorphisms (SNPs) in MEG3 could regulate TL in populations exposed to polycyclic aromatic hydrocarbons (PAHs). This study aimed to explore the effect of MEG3 genetic polymorphisms on TL in PAH-exposed populations. This study recruited 544 coke oven workers and 238 controls using random cluster sampling. The concentrations of four urinary OH-PAHs were measured by employing high-performance liquid chromatography. TL was measured by a quantitative polymerase chain reaction assay. The MEG3 genetic polymorphisms were detected using a Sequenom MassARRAY matrix-assisted laser desorption/ionization-time of flight mass spectrometry platform. The concentrations of four urinary OH-PAHs in the exposure group were significantly higher than those in the control group (P < 0.001). TL in the exposure group (4.57 ± 0.84) was significantly lower than in the control (5.00 ± 0.75), and TL had a negative correlation with OH-PAHs. The generalized linear model found that PAH exposure [β(95% CI) = -0.409(-0.537, -0.282), P < 0.001] and the CT+TT genotype in MEG3 rs10132552 [β(95% CI) = -0.299(-0.582, -0.017), P = 0.038] were associated with the decreased TL. In conclusion, PAH exposure and the CT+TT genotype in MEG3 rs10132552 may be the risk factors for TL reduction.

RevDate: 2023-09-25

Kertes DA, Clendinen C, Duan K, et al (2023)

The Social Environment Matters for Telomere Length and Internalizing Problems During Adolescence.

Journal of youth and adolescence [Epub ahead of print].

Depression and anxiety symptoms are on the rise among adolescents. With increasing evidence that cellular aging may be associated with depressive and anxiety symptoms, there is an urgent need to identify the social environment context that may moderate this link. This study addresses this research gap by investigating the moderating role of the social environment on the relation between telomere length and emotional health among adolescents. Participants were 411 non-Hispanic (88.56%) Black (100%) adolescents (M = 14.23 years, SD = 1.85, female = 54%) in a major metropolitan city. Youth and parents reported on an array of social risk and protective factors, and youth provided DNA samples for telomere length measurement. Results demonstrated that the association of telomere length and anxiety symptoms was stronger among youth with higher perceived stress or lower school belongingness, and the association of telomere length with depressive symptoms was stronger under conditions of higher parent inter-partner psychological aggression. The results enhance our understanding of the complex associations between biological aging, the social environment, and mental health in adolescence.

RevDate: 2023-09-26
CmpDate: 2023-09-26

Nonaka K, Takubo K, Aida J, et al (2023)

Accelerated telomere shortening in adrenal zona reticularis in patients with prolonged critical illness.

Frontiers in endocrinology, 14:1244553.

BACKGROUND: The number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely dependent on cell divisions, and critically short telomeres lead to cellular dysfunction and aging. However, the association between PCI and telomere lengths in human adrenal cells is poorly understood. In this study, we investigated this association to assess whether the burden of PCI could accelerate the aging process in adrenal cells.

METHODS: Adrenocortical tissues from patients who died after PCI usually show a diffuse pattern of intracellular cholesterol ester depletion (i.e., lipid depletion). This study examined near-normal adrenal glands obtained from autopsied patients who died suddenly (control group) and lipid-depleted adrenal glands obtained from autopsied patients who died after PCI (PCI group). The control group included 7 men aged 80 to 94 years (mean age: 85.3 years) and 7 women aged 84 to 94 years (mean age: 87.7 years). The PCI group included 10 men aged 71 to 88 years (mean age: 78.8 years) and 8 women aged 77 to 95 years (mean age: 85.6 years). By using quantitative fluorescence in situ hybridization, relative telomere lengths (RTLs) were determined in the parenchymal cells of the three adrenocortical zones (zona glomerulosa, zona fasciculata, and zona reticularis [ZR]) and in the chromaffin cells of the medulla. The number of adrenal parenchymal cells was determined by immunohistochemistry and digital image analysis.

RESULTS: RTLs in ZR cells were significantly shorter in the PCI group than in the control group for both men and women (P = 0.0001 for men and P = 0.0012 for women). However, RTLs in the remaining three types of adrenal cells did not differ between the control and PCI groups for both men and women. The number of ZR cells was higher in the PCI group than in the control group for both men and women (P < 0.0001 for both men and women). The proportion of the number of ZR cells to the total number of adrenocortical parenchymal cells was also higher in the PCI group than in the control group (P < 0.0001 for both men and women). The Ki-67 proliferation index in ZR cells was higher in the PCI group than in the control group (P = 0.0039 for men and P = 0.0063 for women).

CONCLUSIONS: This study demonstrated ZR cell-specific telomere shortening in patients with adrenal lipid depletion who died after PCI. Our results suggest that the reactive proliferation of ZR cells accelerates the telomere shortening and aging process in ZR cells in these patients. The results of our study may contribute to the understanding of adrenal aging during PCI.

RevDate: 2023-09-26
CmpDate: 2023-09-26

Guo Y, Zhao H, Wang F, et al (2023)

Telomere length as a marker of changes in body composition and fractures-an analysis of data from the NHANES 2001-2002.

Frontiers in immunology, 14:1181544.

PURPOSE: There has been an association between changes in body composition, fracture incidence, and age in previous studies. Telomere length (TL) has been proposed as a biomarker of aging. However, the relationship between body composition, fractures, and TL has rarely been studied. Therefore, this study aimed to investigate the correlation between TL and body composition and fractures.Patients and methods: 20950 participants from the 2001-2002 National Health and Nutrition Examination Survey (NHANES) were included in the final analysis. In NHANES, body compositions were measured with DXA, and TL was determined with quantitative PCR. Correlation analysis of TL and body composition was conducted using multivariate weighted linear regression and logistic regression models.

RESULTS: The results showed that TL positively correlated with bone mineral density (BMD) and bone mineral content (BMC) in most body parts. However, BMD and BMC were negatively connected with TL in the upper limbs and skull. Fat content was negatively associated with TL, while muscle content was positively linked to TL. In addition, TL's trend analysis results were consistent with the regression model when transformed from a continuous to a classified variable. An increase in TL was associated with a higher incidence of wrist fractures, while a decrease in spine fractures. The above correlation also has a certain degree of sex specificity.

CONCLUSION: Our study indicate that TL is associated with body composition as well as fractures, but further research is needed to confirm these contrasting associations in the skull, upper limbs, and wrists.

RevDate: 2023-09-25
CmpDate: 2023-09-25

Moreno E, Martínez-Sanz J, Martín-Mateos R, et al (2023)

Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease.

BMC genomics, 24(1):567.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.

RevDate: 2023-09-22

Wood ML, Neumann R, Roy P, et al (2023)

Characterization of integrated Marek's disease virus genomes supports a model of integration by homology-directed recombination and telomere-loop-driven excision.

Journal of virology [Epub ahead of print].

Marek's disease virus (MDV) is a lymphotropic alphaherpesvirus that readily infects chickens and some other poultry, triggering complex disease phenotypes, including paralysis, immunosuppression, and lymphoma leading to death. MDV infection is partially controlled by extensive global vaccination programs but nevertheless, it imposes a significant financial burden on commercial poultry farming. Following infection, the MDV genome integrates into host telomeres, which is associated with the virus entering a latent state. The mechanism of integration remains poorly understood but it is contemporaneous with cellular transformation and lymphoma formation and therefore requires investigation. Here we have developed droplet digital PCR assays to quantify different regions of the MDV genome. We have also used long-range PCR and single telomere amplification to establish the organization and relative orientation of MDV genome regions in integrated MDV (iMDV). These analyses show that following integration, the MDV genome is oriented with the unique short region (US) internal to the unique long region (UL) and that an iMDV-associated telomere forms at the variable repeat array (mTMR) in a terminal a-like sequence. The data also reveal a very wide range of MDV copy numbers in cell lines, including unexpectedly, additional copies of specific MDV genome regions. IMPORTANCE Marek's disease virus (MDV) is a ubiquitous chicken pathogen that inflicts a large economic burden on the poultry industry, despite worldwide vaccination programs. MDV is only partially controlled by available vaccines, and the virus retains the ability to replicate and spread between vaccinated birds. Following an initial infection, MDV enters a latent state and integrates into host telomeres and this may be a prerequisite for malignant transformation, which is usually fatal. To understand the mechanism that underlies the dynamic relationship between integrated-latent and reactivated MDV, we have characterized integrated MDV (iMDV) genomes and their associated telomeres. This revealed a single orientation among iMDV genomes and the loss of some terminal sequences that is consistent with integration by homology-directed recombination and excision via a telomere-loop-mediated process.

RevDate: 2023-09-25
CmpDate: 2023-09-25

Dratwa M, Łacina P, Butrym A, et al (2023)

Telomere length and hTERT genetic variants as potential prognostic markers in multiple myeloma.

Scientific reports, 13(1):15792.

Telomere dysfunction is a notable event observed in many cancers contributing to their genomic instability. A major factor controlling telomere stability is the human telomerase reverse transcriptase catalytic subunit (hTERT). Telomere shortening has been observed in multiple myeloma (MM), a plasma cell malignancy with a complex and heterogeneous genetic background. In the present study, we aimed to analyse telomere length and hTERT genetic variants as potential markers of risk and survival in 251 MM patients. We found that telomere length was significantly shorter in MM patients than in healthy individuals, and patients with more advanced disease (stage III according to the International Staging System) had shorter telomeres than patients with less advanced disease. MM patients with hTERT allele rs2736100 T were characterized with significantly shorter progression-free survival (PFS). Moreover, allele rs2736100 T was also found to be less common in patients with disease progression in response to treatment. hTERT rs2853690 T was associated with higher haemoglobin blood levels and lower C-reactive protein. In conclusion, our results suggest that telomere length and hTERT genetic variability may affect MM development and can be potential prognostic markers in this disease.

RevDate: 2023-09-22

Ochi S, Roy B, Prall K, et al (2023)

Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals.

Molecular psychiatry [Epub ahead of print].

Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.

RevDate: 2023-09-21

Lima SM, Ren X, Mu L, et al (2023)

Food Insecurity, Telomere Length and the Potential Modifying Effects of Social Support in NHANES.

Public health nutrition pii:S1368980023002008 [Epub ahead of print].

OBJECTIVE: Telomere length (TL) is a posited pathway through which chronic stress results in biological dysregulation and subsequent adverse health outcomes. Food insecurity is associated with shorter TL. Social support, which is defined by the size and function of an individual's social network, is associated with better health outcomes. The present study assesses whether social support modifies the relationship between food security and TL.

DESIGN: Cross-sectional study design. Linear regression was used to assess the association between social support and TL, stratified by social support level. A multiplicative interacted model was used to formally test modification.

SETTING: Data come from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2001-2002 waves.

PARTICIPANTS: Adults aged 60 years and older who have measurements for TL.

RESULTS: Our sample comprised 2,674 participants, and 63.5% of the total sample had low social support, with 13.3% being food insecure. In fully adjusted models, food insecurity was negatively though modestly associated (P=0.13) with TL. Associations between food insecurity and TL were significantly modified by social support (interaction P=0.026), whereby food insecurity had a stronger effect among individuals with high social support (coefficient = -0.099 (95% CI: -0.161, -0.038)) compared to low social support (coefficient = -0.001, (95% CI: -0.033, 0.032)).

CONCLUSION: Food insecurity is modestly associated with shorter TL. Contrary to our hypothesis, food insecurity had more deleterious effects on TL among participants with high social support than low social support. Results may indicate that the food insecure population is a higher needs population, and increased social support reflects these needs rather than providing protective effects.

RevDate: 2023-09-21

Gellert-Kristensen H, Bojesen SE, Tybjærg-Hansen A, et al (2023)

Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from the general population.

Hepatology (Baltimore, Md.) pii:01515467-990000000-00574 [Epub ahead of print].

BACKGROUND AIMS: Inherited short telomeres are associated with risk of liver disease, whereas longer telomeres predispose to cancer. The association between telomere length and risk of hepatocellular carcinoma and cholangiocarcinoma remains unknown.

APPROACH RESULTS: We measured leukocyte telomere length using multiplex PCR in 63,272 individuals from the Danish general population. Telomere length and plasma alanine transaminase concentration were not associated (β = 4 ×10⁻⁶, p-value = 0.06) in a linear regression model, without any signs of a non-linear relationship. We tested the association between telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma using Cox regression. During a median follow-up of 11 years, 241, 76, and 112 individuals developed cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma, respectively. Telomere length and risk of cirrhosis were inversely and linearly associated (p-value = 0.004, p for nonlinearity = 0.27). Individuals with telomeres in the shortest vs. longest quartile had a 2.25-fold higher risk of cirrhosis. Telomere length and risk of hepatocellular carcinoma were nonlinearly associated (p-value = 0.009, p-value for nonlinearity = 0.01). This relationship resembled an inverted J-shape, with the highest risk observed in individuals with short telomeres. Individuals with telomeres in the shortest vs. longest quartile had a 2.29-fold higher risk of hepatocellular carcinoma. Telomere length was inversely and linearly associated with the risk of cholangiocarcinoma. Individuals with telomeres in the shortest vs. longest quartile had a 1.86-fold higher risk of cholangiocarcinoma.

CONCLUSION: Shorter telomere length is associated with a higher risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma.

RevDate: 2023-09-22
CmpDate: 2023-09-22

Hao Y, Lv M, Peng J, et al (2023)

Alteration of relative telomere length and telomerase reverse transcriptase expression in the granulosa cells of women during aging and assessment of in vitro fertilization outcomes.

Molecular medicine reports, 28(5):.

Telomere attrition plays a critical role in the reproductive aging process in humans. Telomere length (TL) is typically regulated by telomerase, the main component of which is telomerase reverse transcriptase (TERT). The aim of the present study was to investigate the changes of relative TL (RTL) and TERT expression in granulosa cells (GCs) during aging and its association with reproduction. Clinical data on the frozen‑thawed embryo transfer cycles of older (>35 year old) and younger (≤35 year old) women from a single center over a 3‑year period were retrospectively analyzed. Preimplantation genetic testing for chromosome aneuploidies in older women during the same period was also analyzed. Following the analysis of the data, several biological characteristics of senescent GCs were explored. In addition, a total of 160 women who were undergoing their first fresh cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection were included in the study. GCs were collected from all participants. The changes of RTL and TERT expression in GCs during aging were investigated using quantitative PCR and western blotting. The associations of RTL and TERT with IVF outcomes were also assessed. The clinical data demonstrated that the pregnancy and live birth rates of women aged >35 years were ~20% lower than those of women aged ≤35 years, and the number of embryos with aneuploidy was 7‑fold of that without euploidy in the older age group. An aging‑induced change in follicle stimulating hormone receptor expression was observed. A shorter TL and increased TERT expression were detected in the older women. A significant inverse correlation between the expression levels of TERT and oocyte yield was identified. However, no association of RTL and TERT with blastocyst formation rate and the probability of clinical pregnancy was detected. It may be concluded that RTL and TERT alterations in GCs are potential determinants of ovarian aging. TERT expression in GCs appears to be a potential biomarker for the prediction of ovarian response, which provides a novel strategy for the assessment of female fertility.

RevDate: 2023-09-21

Frontiers Editorial Office (2023)

Retraction: Leukocyte telomere length and obesity in children and adolescents: a systematic review and meta-analysis.

Frontiers in genetics, 14:1285214 pii:1285214.

[This retracts the article DOI: 10.3389/fgene.2022.861101.].

RevDate: 2023-09-20

Zhang J, Zhang F, Porter KI, et al (2023)

Telomere dysfunction in Tert knockout mice delays Braf[V600E] -induced melanoma development.

International journal of cancer [Epub ahead of print].

Telomerase activation is a crucial step in melanomagenesis, often occurring because of ultraviolet radiation (UVR)-induced mutations at the telomerase gene (TERT) promoter and rendering TERT transcription in response to the activated Raf-MAP kinase pathway by BRAF[V600E] mutation. Due to the excessively long telomeres in mice, this process does not occur during melanomagenesis in mouse models. To investigate the impact of telomere dysfunction on melanomagenesis, Braf[V600E] was induced in generations 1 and 4 (G1 and G4) of Tert[-/-] mice. Our findings revealed that, regardless of UVR exposure, melanoma development was delayed in G4 mice, which had shorter telomeres compared to G1 and wild-type C57BL/6J (G0) mice. Moreover, many G4 tumors displayed an accumulation of excessive DNA damage, as evidenced by increased γH2A.X staining. Tumors from UVR-exposed mice exhibited elevated p53 protein expression. Cultured tumor cells isolated from G4 mice displayed abundant chromosomal fusions and rearrangements, indicative of telomere dysfunction in these cells. Additionally, tumor cells derived from UVB-exposed mice exhibited constitutively elevated expression of mutant p53 proteins, suggesting that p53 was a target of UVB-induced mutagenesis. Taken together, our findings suggest that telomere dysfunction hampers melanomagenesis, and targeting telomere crisis-mediated genomic instability may hold promise for the prevention and treatment of melanoma.

RevDate: 2023-09-19

Hassler EM, Almer G, Reishofer G, et al (2023)

A sex-specific association of leukocyte telomere length with thigh muscle mass.

Clinical chemistry and laboratory medicine [Epub ahead of print].

OBJECTIVES: Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored.

METHODS: We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour.

RESULTS: In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females.

CONCLUSIONS: In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.

RevDate: 2023-09-19

Liang J, Cui J, Cheng J, et al (2023)

SIRT6 Knockdown in Buffalo Fetal Fibroblasts Exacerbates Premature Senescence Caused by DNA and Telomere Damage.

Cellular reprogramming [Epub ahead of print].

As a gene with antiaging functions, sirtuin6 (SIRT6) belonging to the sirtuin family plays a vital role in DNA repair, telomerase function, and cellular senescence, as well as maintains epigenomic stability and promotes longevity. However, its role in cell senescence in large animals, such as buffaloes, remains unknown. Fibroblasts are commonly used for somatic reprogramming, and their physiological characteristics affect the efficiency of this process. We aimed to elucidate the role of SIRT6 in cellular senescence and proliferation and analyze its effect on the biological function of buffalo fibroblasts to help improve the efficiency of buffalo somatic cell reprogramming. The expression of SIRT6 and related DNA damage was measured in buffalo fibroblasts obtained at different developmental stages (in the fetus and at 3 and 10 years of age), and the effect of SIRT6 knockdown on the senescence of buffalo fetal fibroblast was investigated. An inverse relationship was observed between SIRT6 expression and senescence in buffalo fibroblasts obtained from animals of various ages. This was accompanied by decreased cell growth, viability, and increased DNA damage. Short hairpin RNA-mediated SIRT6 knockdown accelerated the senescence of buffalo fetal fibroblasts. It blocked the cell cycle during in vitro cell culture, which further enhanced DNA damage, particularly with respect to the telomeres. Collectively, our findings suggest that SIRT6 expression was closely associated with buffalo senescence in fibroblasts. These findings serve as a foundation to better understand the cellular functions of SIRT6 and also aid in selecting donor cells for buffalo somatic cell reprogramming.

RevDate: 2023-09-18

Wong JY, Shu XO, Hu W, et al (2023)

Associations between longer leukocyte telomere length and increased lung cancer risk among never smokers in urban China.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:729118 [Epub ahead of print].

BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically-predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology.

METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's and Men's Health Studies (SWHS: 798 cases and 792 controls; SMHS: 161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. Additionally, we conducted Mendelian Randomization (MR) using MR-PRESSO.

RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (p-trendLTL=4x10-6; p-trendgTL=3x10-4). Similarly among never-smoking men, longer measured LTL was associated with over triple the risk compared to those with the shortest (OR=3.48, 95%CI: 1.85, 6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL=1.19 (95%CI: 1.03, 1.37; p=0.03).

CONCLUSIONS: Longer pre-diagnostic leukocyte telomere length is associated with increased lung cancer risk among never smokers.

IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.

RevDate: 2023-09-19
CmpDate: 2023-09-19

Bhat GR, Jamwal RS, Sethi I, et al (2023)

Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India.

BMC cancer, 23(1):874.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk.

METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR.

RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004).

CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

RevDate: 2023-09-19
CmpDate: 2023-09-18

Liu X, Arshad R, Wang X, et al (2023)

The phased telomere-to-telomere reference genome of Musa acuminata, a main contributor to banana cultivars.

Scientific data, 10(1):631.

Musa acuminata is a main wild contributor to banana cultivars. Here, we reported a haplotype-resolved and telomere-to-telomere reference genome of M. acuminata by incorporating PacBio HiFi reads, Nanopore ultra-long reads, and Hi-C data. The genome size of the two haploid assemblies was estimated to be 469.83 Mb and 470.21 Mb, respectively. Multiple assessments confirmed the contiguity (contig N50: 16.53 Mb and 18.58 Mb; LAI: 20.18 and 19.48), completeness (BUSCOs: 98.57% and 98.57%), and correctness (QV: 45.97 and 46.12) of the genome. The repetitive sequences accounted for about half of the genome size. In total, 40,889 and 38,269 protein-coding genes were annotated in the two haploid assemblies, respectively, of which 9.56% and 3.37% were newly predicted. Genome comparison identified a large reciprocal translocation involving 3 Mb and 10 Mb from chromosomes 01 and 04 within M. acuminata. This reference genome of M. acuminata provides a valuable resource for further understanding of subgenome evolution of Musa species, and precise genetic improvement of banana.

RevDate: 2023-09-18

Tichy ED, Lee JH, Li G, et al (2023)

Impacts of radiation exposure, hindlimb unloading, and recovery on murine skeletal muscle cell telomere length.

NPJ microgravity, 9(1):76.

Astronauts are exposed to harsh conditions, including cosmic radiation and microgravity. Spaceflight elongates human telomeres in peripheral blood, which shorten upon return to Earth and approach baseline levels during postflight recovery. Astronauts also encounter muscle atrophy, losing up to 20% loss of muscle mass on spaceflights. Telomere length changes in muscle cells of astronauts remain unexplored. This study investigates telomere alterations in grounded mice experiencing radiation exposure and muscle atrophy, via a hindlimb unloading spaceflight mimicking model. We find telomere lengthening is present in muscle stem cells and in myofiber nuclei, but not in muscle-resident endothelial cells. We further assessed telomere length in the model following hindlimb unloading recovery. We find that telomere length failed to return to baseline values. Our results suggest a role for telomeres in muscle acclimatization, which is relevant for the well-being of astronauts in space, and upon their return to Earth.

RevDate: 2023-09-15

Manzato C, Larini L, Pegorar CO, et al (2023)

TERRA expression is regulated by the telomere-binding proteins POT-1 and POT-2 in Caenorhabditis elegans.

Nucleic acids research pii:7275007 [Epub ahead of print].

Several aspects of telomere biology are regulated by the telomeric repeat-containing RNA TERRA. While TERRA expression is conserved through evolution, species-specific mechanisms regulate its biogenesis and function. Here we report on the expression of TERRA in Caenorhabditis elegans. We show that C. elegans TERRA is regulated by the telomere-binding proteins POT-1 and POT-2 which repress TERRA in a telomere-specific manner. C. elegans TERRA transcripts are heterogeneous in length and form discrete nuclear foci, as detected by RNA FISH, in both postmitotic and germline cells; a fraction of TERRA foci localizes to telomeres. Interestingly, in germ cells, TERRA is expressed in all stages of meiotic prophase I, and it increases during pachytene, a stage in meiosis when homologous recombination is ongoing. We used the MS2-GFP system to study the spatiotemporal dynamics of single-telomere TERRA molecules. Single particle tracking revealed different types of motilities, suggesting complex dynamics of TERRA transcripts. Finally, we unveiled distinctive features of C. elegans TERRA, which is regulated by telomere shortening in a telomere-specific manner, and it is upregulated in the telomerase-deficient trt-1; pot-2 double mutant prior to activation of the alternative lengthening mechanism ALT. Interestingly, in these worms TERRA displays distinct dynamics with a higher fraction of fast-moving particles.

RevDate: 2023-09-14

Jalan-Sakrikar N, Anwar A, Yaqoob U, et al (2023)

Telomere dysfunction promotes cholangiocyte senescence and biliary fibrosis in Primary Sclerosing Cholangitis.

JCI insight pii:170320 [Epub ahead of print].

Cellular senescence and biliary fibrosis are prototypical features of obliterative cholangiopathies, such as Primary Sclerosing Cholangitis (PSC). Telomere dysfunction can lead to senescence either through telomere erosion or damaged telomeres. Our goal was to investigate a mechanistic relationship between telomere damage and biliary fibrosis in PSC. Telomere attrition was observed in the bile ducts of PSC patients along with a reduction in telomerase reverse transcriptase (TERT) expression compared to normal livers. Similarly, liver tissue from mice models of biliary fibrosis showed telomere attrition with increased damage at telomeres measured as telomere-associated foci (TAF). Cellular models of senescence induction increased the TAFs in cholangiocytes. This coincided with decreased TERT expression and increased senescence, which was rescued by modulating TERT levels. Epigenetic analysis revealed increased acquisition of repressive histone methylation at the TERT promoter which correlated with decreased TERT transcription. Cholangiocyte-selective deletion of TERT in mice exacerbated fibrosis whereas androgen therapy towards telomerase rescued liver fibrosis and liver function in genetic mouse model of PSC. Our results demonstrate a mechanistic role for telomere dysfunction in cellular senescence and fibrosis that characterize PSC. This suggests that PSC may be, in part, a telomere biology disorder, and identifies TERT as a potential therapeutic target.

RevDate: 2023-09-16

Cao Z, Hou Y, C Xu (2023)

Leucocyte telomere length, brain volume and risk of dementia: a prospective cohort study.

General psychiatry, 36(4):e101120.

BACKGROUND: The evidence regarding the association between leucocyte telomere length (LTL) and brain health is sparse and inconclusive.

AIMS: To investigate the associations of LTL with brain structure and the risk of dementia based on a large-scale prospective study.

METHODS: LTL in the peripheral blood was measured by the quantitative polymerase chain reaction (qPCR) assay from 439 961 individuals in the UK Biobank recruited between 2006 and 2010 and followed up until 2020. Electronic health records were used to record the incidence of dementia, including Alzheimer's disease (AD) and vascular dementia (VD). The brain structure, including total and regional brain volume, of 38 740 participants was then assessed by magnetic resonance imaging (MRI).

RESULTS: During a median follow-up of 11.6 years, a total of 5 820 (1.3%) dementia cases were documented. The restricted cubic spline model showed significant overall associations between LTL and the risk of dementia and AD (p for overall <0.05). The multivariable adjusted hazard ratios (HRs) for the lowest LTL tertile compared with the highest LTL tertile were 1.14 (95% confidence interval (CI): 1.06 to 1.21) for dementia, 1.28 (95% CI: 1.12 to 1.46) for AD and 1.18 (95% CI: 0.98 to 1.42) for VD. Furthermore, we found that shorter LTL was associated with smaller total brain volume (β=-0.012 8, p=0.003), white matter volume (β=-0.022 4, p<0.001), hippocampus volume (β=-0.017 2, p<0.001), thalamus volume (β=-0.023 9, p<0.001) and accumbens (β=-0.015 5, p=0.001).

CONCLUSIONS: Shorter LTL is associated with total and regional brain structure and a higher risk of incident dementia and AD, implying the potential of telomere length as a predictive biomarker of brain health.

RevDate: 2023-09-14

Houminer-Klepar N, Bord S, Epel E, et al (2023)

Working status of first-time postpartum mothers and telomere length - a one-year prospective study.

Journal of occupational and environmental medicine pii:00043764-990000000-00404 [Epub ahead of print].

OBJECTIVE: Transitioning to motherhood can create work family conflicts affecting mothers' health. Although employment is generally associated with longer telomeres, this may diminish during the early years of child-rearing. This study aimed to assess the impact of work re-entry on TL among first-time mothers.

METHODS: In this one-year prospective study, a total of 103 first time postpartum mothers participated from two medical institutions in Northern Israel, they completed validated questionnaires, reported their current working status and provided dried blood spots measuring telomere length (TL).

RESULTS: We found that working status significantly predicted change in TL and was negatively correlated with change in TL over time (β = - 0.245, 95% CI -0.169, -0.018, p = 0.016).

CONCLUSIONS: Identifying ideal timing of work re-entry is recommended for first-time postpartum mother's optimal health and TL.

RevDate: 2023-09-14
CmpDate: 2023-09-14

Rahman ST, Waterhouse M, Pham H, et al (2023)

Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

The journal of nutrition, health & aging, 27(8):609-616.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio).

Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation.

RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration.

CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.

RevDate: 2023-09-14

Huang HR, Liu X, Arshad R, et al (2023)

Telomere-to-telomere haplotype-resolved reference genome reveals subgenome divergence and disease resistance in triploid Cavendish banana.

Horticulture research, 10(9):uhad153.

Banana is one of the most important crops of the world. Cavendish-type bananas, which have a monospecific Musa acuminata origin (AAA), account for around half of the global banana production, thereby are of great significance for human societies. However, until now, the high-quality haplotype-resolved reference genome was still undecoded for banana cultivars. Here, we reported the telomere-to-telomere (T2T) and haplotype-resolved reference genome of 'Baxijiao' (Cavendish) consisting of three haploid assemblies. The sizes of the three haploid assemblies were estimated to be 477.16 Mb, 477.18 Mb, and 469.57 Mb, respectively. Although with monospecific origins, the three haploid assemblies showed great differences with low levels of sequence collinearity. Several large reciprocal translocations were identified among chromosomes 1, 4, and 7. An expansion of gene families that might affect fruit quality and aroma was detected, such as those belonging to sucrose/disaccharide/oligosaccharide catabolic processes, sucrose metabolic process, starch metabolic process, and aromatic compound biosynthetic process. Besides, an expansion of gene families related to anther and pollen development was observed, which could be associated with parthenocarpy and sterility of the Cavendish cultivar. Finally, much fewer resistance genes were identified in 'Baxijiao' than in M. acuminata, particularly in the gene clusters in chromosomes 3 and 10, providing potential targets to explore for molecular analysis of disease resistance in banana. This T2T haplotype-resolved reference genome will thus be a valuable genetic resource for biological studies, molecular breeding, and genetic improvement of banana.

RevDate: 2023-09-11

Han D, Zhu Y, Choudhry AA, et al (2023)

Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank.

Lung cancer (Amsterdam, Netherlands), 184:107358 pii:S0169-5002(23)00896-6 [Epub ahead of print].

OBJECTIVES: Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies.

METHODS: This prospective cohort study included data from 425,146 participants 37-73 years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer.

RESULTS: An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03-1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09-1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18-1.43]), female sex (HR 1.16 [95% CI 1.06-1.26]), non-smokers (HR 1.45 [95% CI 1.23-1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03-1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24-1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13-3.56]) in never smokers.

CONCLUSIONS: Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.

RevDate: 2023-09-13

Yu W, Mei Y, Lu Z, et al (2023)

The causal relationship between genetically determined telomere length and meningiomas risk.

Frontiers in neurology, 14:1178404.

BACKGROUND: Studies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors.

METHODS: We used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR).

RESULTS: In the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10[-5]], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected.

CONCLUSION: In brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations.

RevDate: 2023-09-12

Anonymous (2023)

"Interstitial lung abnormalities are associated with decreased mean telomere length." R.K. Putman, G.T. Axelsson, S.Y. Ash, et al. Eur Respir J 2022; 60: 2101814.

The European respiratory journal, 62(3): pii:62/3/2151814.

RevDate: 2023-09-11

Martinez S, JD Jones (2023)

A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.

Pharmacology, biochemistry, and behavior, 231:173631 pii:S0091-3057(23)00118-1 [Epub ahead of print].

BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry.

METHODS: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL.

RESULTS: The multiple linear regression model fit the data well, R[2] = 0.265, F(7,49) = 2.53, p < .026. Chronological age (β = -0.36, p = .017), neuroticism (β = 0.46, p = .044), and conscientiousness (β = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF[10] = 5.77, R[2] = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]).

CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.

RevDate: 2023-09-09

Sullivan DI, Bello FM, Silva AG, et al (2023)

Intact mitochondrial function in the setting of telomere-induced senescence.

Aging cell [Epub ahead of print].

Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.

RevDate: 2023-09-09

Kreilmeier-Berger T, Aupperle-Lellbach H, Reifinger M, et al (2023)

Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma.

Cancers, 15(17): pii:cancers15174214.

Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1-14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value.

RevDate: 2023-09-08

Benitez-Roig V, Martínez-Carpio PA, Trelles MA, et al (2023)

Clinical and laboratory results in vaginal wall restoration using a fractional-pixel-CO2 laser: histological findings and changes in the Ki67 protein and telomere length.

Lasers in medical science, 38(1):206.

Thermal deposition of laser energy in the vaginal epithelium in genitourinary syndrome of menopause (GSM) results in clinical and biological effects, but many cellular and molecular changes indicating cell proliferation or senescence inhibition are unknown. The aim of this study is to evaluate the clinical efficacy of the fractional-pixel-CO2 laser in the possible improvement of GMS signs and symptoms that can be correlated with histological changes or with cellular or molecular indicators of restoration. A detailed prospective study was designed to assess 17 women diagnosed with GSM who were treated intravaginally with two laser sessions. Seven non-treated women diagnosed with GSM were used as controls. Three validated outcome questionnaires for assessment of quality of sexual life and urinary incontinence were performed. Vaginal biopsies were collected before the first laser treatment and 4 months following the second session. Histological status, elastin, collagen, and hyaluronic acid content of the biopsies were also evaluated. Cell proliferation was assessed by Ki67 staining. Telomere length (TL) was measured by qPCR. The results show an improvement of the clinical symptoms of GSM (p < 0.05), vaginal epithelium recovery and enhancement of collagen (p < 0.05), elastic fibers (p < 0.005), and hyaluronic acid (p < 0.0005) content in the lamina propria after fractional-pixel-CO2 laser treatment. The laser treatment induced a significant rise on the TL of vaginal epithelial cells (VECs), and a positive correlation was found between the improvements of the collagen and hyaluronic acid content and TL changes (r = 0.82, p < 0.05; r = 0.38, p < 0.05). The percentage of proliferative Ki67-positive VECs was increased in patients whose vaginal TL lengthened after laser treatment (p < 0.05). In conclusion, the results indicate that laser treatment may induce restoration of the vaginal epithelium which is associated to increased TL and proliferation in the VECs. Performing a TL assay could be a suitable tool to evaluate the efficacy of vaginal laser treatment.

RevDate: 2023-09-09

Yin F, Zhou Y, Xie D, et al (2023)

Effects of nanomaterial exposure on telomere dysfunction, hallmarks of mammalian and zebrafish cell senescence, and zebrafish mortality.

Ageing research reviews, 91:102062 pii:S1568-1637(23)00221-0 [Epub ahead of print].

Environmental and occupational exposure to hazardous substances accelerates biological aging. However, the toxic effects of nanomaterials on telomere and cellular senescence (major hallmarks of the biological aging) remained controversial. This study was to synthesize all published evidence to explore the effects of nanomaterial exposure on the telomere change, cellular senescence and mortality of model animals. Thirty-five studies were included by searching electronic databases (PubMed, Embase and Web of Science). The pooled analysis by Stata 15.0 software showed that compared with the control, nanomaterial exposure could significantly shorten the telomere length [measured as kbp: standardized mean difference (SMD) = -1.88; 95% confidence interval (CI) = -3.13 - - 0.64; % of control: SMD = -1.26; 95%CI = -2.11- - 0.42; < 3 kbp %: SMD = 5.76; 95%CI = 2.92 - 8.60), increase the telomerase activity (SMD = -1.00; 95%CI = -1.74 to -0.26), senescence-associated β-galactosidase levels in cells (SMD = 8.20; 95%CI = 6.05 - 10.34) and zebrafish embryos (SMD = 7.32; 95%CI = 4.70 - 9.94) as well as the mortality of zebrafish (SMD = 3.83; 95%CI = 2.94 - 4.72)]. The expression levels of telomerase TERT, shelterin components (TRF1, TRF2 and POT1) and senescence biomarkers (p21, p16) were respectively identified to be decreased or increased in subgroup analyses. In conclusion, this meta-analysis demonstrates that nanomaterial exposure is associated with telomere attrition, cell senescence and organismal death.

RevDate: 2023-09-06

Fan G, Liu Q, Bi J, et al (2023)

Association between female-specific reproductive factors and leukocyte telomere length.

Human reproduction (Oxford, England) pii:7260908 [Epub ahead of print].

STUDY QUESTION: What are the associations between female-specific reproductive factors and leukocyte telomere length (LTL)?

SUMMARY ANSWER: Early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of oral contraceptives (OCs) and hormone replacement therapy (HRT) were associated with shorter LTL.

WHAT IS KNOWN ALREADY: Reproductive factors have been associated with age-related diseases, but their associations with cellular aging, as indicated by LTL, are unclear.

STUDY DESIGN, SIZE, DURATION: This population-based study included 224 965 women aged 40-69 years from the UK Biobank between 2006 and 2010.

Women aged 40-69 were included. Female-specific reproductive factors, including age at menarche, age at natural menopause, reproductive lifespan, number of live births, age at first live birth, history of stillbirth, history of miscarriage, and use of OCs and HRT were self-reported. LTL was measured using a validated polymerase chain reaction method. Multiple linear regression and restricted cubic spline models were applied to explore the association between each reproductive factor and LTL.

After adjustment for potential confounders, early menarche (<12 years; percent change, per unit change in LTL Z score: -1.29%, 95% CI: -2.32%, -0.26%), early menopause (<45 years; percent change: -7.18%, 95% CI: -8.87%, -5.45%), short reproductive lifespan (<30 years; percent change: -6.10%, 95% CI: -8.14%, -4.01%), multiparity (percent change: -3.38%, 95% CI: -4.38%, -2.37%), early age at first live birth (<20 years; percent change: -4.46%, 95% CI: -6.00%, -2.90%), and use of OCs (percent change: -1.10%, 95% CI: -2.18%, -0.02%) and HRT (percent change: -3.72%, 95% CI: -4.63%, -2.80%) were all significantly associated with shorter LTL. However, no significant association was found for history of miscarriage and stillbirth. We observed nonlinear relationships of age at menarche, age at natural menopause, reproductive lifespan, and age at first live birth with LTL (Pnonlinear < 0.05).

Considering that the participants were predominantly of European ethnicity, the findings may not be generalizable to women of other ethnic backgrounds.

Our findings suggest that early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of OCs and HRT were associated with shorter LTL, which has been linked to various chronic diseases. The accelerated shortening of telomeres may potentially contribute to the development of chronic diseases related to reproductive factors.

This study was funded by the National Natural Science Foundation of China (82003479, 82073660), Hubei Provincial Natural Science Foundation of China (2023AFB663), and the China Postdoctoral Science Foundation (2019M662646, 2020T130220). The authors have no competing interests to disclose.


RevDate: 2023-09-04

Ferrer A, Lasho T, Fernandez JA, et al (2023)

Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants.

Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.

RevDate: 2023-09-05
CmpDate: 2023-09-05

Han X, Yan Z, Fan K, et al (2023)

The combined signatures of telomere and immune cell landscape provide a prognostic and therapeutic biomarker in glioma.

Frontiers in immunology, 14:1220100.

BACKGROUND: Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma.

METHODS: This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways.

RESULTS: The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001).

CONCLUSION: Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.

RevDate: 2023-09-03

Zhou HH, Jin B, Liao Y, et al (2023)

Associations of Various Physical Activities With Mortality and Life Expectancy Are Mediated by Telomere Length.

Journal of the American Medical Directors Association pii:S1525-8610(23)00710-7 [Epub ahead of print].

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality.

DESIGN: Prospective cohort study.

SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed.

METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy.

RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001).

CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

RevDate: 2023-09-02

Casagrande S, Loveland JL, Oefele M, et al (2023)

Dietary nucleotides can prevent glucocorticoid-induced telomere attrition in a fast-growing wild vertebrate.

Molecular ecology [Epub ahead of print].

Telomeres are chromosome protectors that shorten during eukaryotic cell replication and in stressful conditions. Developing individuals are susceptible to telomere erosion when their growth is fast and resources are limited. This is critical because the rate of telomere attrition in early life is linked to health and life span of adults. The metabolic telomere attrition hypothesis (MeTA) suggests that telomere dynamics can respond to biochemical signals conveying information about the organism's energetic state. Among these signals are glucocorticoids, hormones that promote catabolic processes, potentially impairing costly telomere maintenance, and nucleotides, which activate anabolic pathways through the cellular enzyme target of rapamycin (TOR), thus preventing telomere attrition. During the energetically demanding growth phase, the regulation of telomeres in response to two contrasting signals - one promoting telomere maintenance and the other attrition - provides an ideal experimental setting to test the MeTA. We studied nestlings of a rapidly developing free-living passerine, the great tit (Parus major), that either received glucocorticoids (Cort-chicks), nucleotides (Nuc-chicks) or a combination of both (NucCort-chicks), comparing these with controls (Cnt-chicks). As expected, Cort-chicks showed telomere attrition, while NucCort- and Nuc-chicks did not. NucCort-chicks was the only group showing increased expression of a proxy for TOR activation (the gene TELO2), of mitochondrial enzymes linked to ATP production (cytochrome oxidase and ATP-synthase) and a higher efficiency in aerobically producing ATP. NucCort-chicks had also a higher expression of telomere maintenance genes (shelterin protein TERF2 and telomerase TERT) and of enzymatic antioxidant genes (glutathione peroxidase and superoxide dismutase). The findings show that nucleotide availability is crucial for preventing telomere erosion during fast growth in stressful environments.

RevDate: 2023-08-31

Roisné-Hamelin F, S Marcand (2023)

All roads lead to MRN regulation at telomeres: different paths to one solution.

Nature structural & molecular biology [Epub ahead of print].

RevDate: 2023-08-31

Myler LR, Toia B, Vaughan CK, et al (2023)

DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres.

Nature structural & molecular biology [Epub ahead of print].

Telomeres replicated by leading-strand synthesis lack the 3' overhang required for telomere protection. Surprisingly, resection of these blunt telomeres is initiated by the telomere-specific 5' exonuclease Apollo rather than the Mre11-Rad50-Nbs1 (MRN) complex, the nuclease that acts at DNA breaks. Without Apollo, leading-end telomeres undergo fusion, which, as demonstrated here, is mediated by alternative end joining. Here, we show that DNA-PK and TRF2 coordinate the repression of MRN at blunt mouse telomeres. DNA-PK represses an MRN-dependent long-range resection, while the endonuclease activity of MRN-CtIP, which could cleave DNA-PK off of blunt telomere ends, is inhibited in vitro and in vivo by the iDDR of TRF2. AlphaFold-Multimer predicts a conserved association of the iDDR with Rad50, potentially interfering with CtIP binding and MRN endonuclease activation. We propose that repression of MRN-mediated resection is a conserved aspect of telomere maintenance and represents an ancient feature of DNA-PK and the iDDR.

RevDate: 2023-08-31

Liu M, Lan Y, Zhang H, et al (2023)

Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study.

Melanoma research pii:00008390-990000000-00095 [Epub ahead of print].

The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.

RevDate: 2023-08-30

Greenland JR, Guo R, Lee S, et al (2023)

Short Airway Telomeres are Associated with Primary Graft Dysfunction and Chronic Lung Allograft Dysfunction.

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation pii:S1053-2498(23)02003-X [Epub ahead of print].

Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 - 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (P = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16 - 3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.

RevDate: 2023-08-30

Li H, R Durbin (2023)

Genome assembly in the telomere-to-telomere era.


De novo assembly is the process of reconstructing the genome sequence of an organism from sequencing reads. Genome sequences are essential to biology, and assembly has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best but technological advances in long-read sequencing now enable near complete chromosome-level assembly, also known as telomere-to-telomere assembly, for many organisms. Here we review recent progress on assembly algorithms and protocols. We focus on how to derive near telomere-to-telomere assemblies and discuss potential future developments.

RevDate: 2023-08-29

Häussler S, Ghaffari MH, Seibt K, et al (2023)

Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with L-carnitine under systemic inflammation.

Journal of dairy science pii:S0022-0302(23)00569-6 [Epub ahead of print].

The current study was conducted to examine the effect of L-carnitine supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). Besides comparing the responses in cows with or without L-carnitine, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an L-carnitine supplemented group (CAR; 25 g L-carnitine/cow/d; d 42 ante partum to d 126 postpartum (pp), n = 27). On d 111 pp, each cow was injected intravenously with LPS (Escherichia coli O111: B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary L-carnitine supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of L-carnitine. Dietary L-carnitine supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary L-carnitine than the outer mitochondrial membrane translocase (TOM complex).

RevDate: 2023-08-27

Wang L, Zhang M, Li M, et al (2023)

A telomere-to-telomere gap-free assembly of soybean genome.

Molecular plant pii:S1674-2052(23)00247-2 [Epub ahead of print].

RevDate: 2023-08-29
CmpDate: 2023-08-28

Igoshin AV, Yudin NS, Romashov GA, et al (2023)

A Multibreed Genome-Wide Association Study for Cattle Leukocyte Telomere Length.

Genes, 14(8):.

Telomeres are terminal DNA regions of chromosomes that prevent chromosomal fusion and degradation during cell division. In cattle, leukocyte telomere length (LTL) is associated with longevity, productive lifespan, and disease susceptibility. However, the genetic basis of LTL in this species is less studied than in humans. In this study, we utilized the whole-genome resequencing data of 239 animals from 17 cattle breeds for computational leukocyte telomere length estimation and subsequent genome-wide association study of LTL. As a result, we identified 42 significant SNPs, of which eight were found in seven genes (EXOC6B, PTPRD, RPS6KC1, NSL1, AGBL1, ENSBTAG00000052188, and GPC1) when using covariates for two major breed groups (Turano-Mongolian and European). Association analysis with covariates for breed effect detected 63 SNPs, including 13 in five genes (EXOC6B, PTPRD, RPS6KC1, ENSBTAG00000040318, and NELL1). The PTPRD gene, demonstrating the top signal in analysis with breed effect, was previously associated with leukocyte telomere length in cattle and likely is involved in the mechanism of alternative lengthening of telomeres. The single nucleotide variants found could be tested for marker-assisted selection to improve telomere-length-associated traits.

RevDate: 2023-08-24

Ha SJ, Kwag E, Kim S, et al (2023)

Effect of Traditional Korean Medicine Oncotherapy on the Survival, Quality of Life, and Telomere Length: A Prospective Cohort Study.

Integrative cancer therapies, 22:15347354231154267.

A 4-year prospective cohort study on patients with lung, gastric, hepatic, colorectal, breast, uterine, and ovarian cancer was conducted at the East-West Cancer Center (EWCC) of Daejeon Korean Medicine Hospital in Daejeon, Korea. We divided patients into 2 groups based on how long they had been receiving TKM oncotherapy and compared event-free survival (EFS), telomere length change, and quality of life (QoL). The study collected data on 83 patients from October 2016 to June 2020 and discovered no statistical differences in EFS based on the duration of TKM oncotherapy. In the analysis of changes in QoL outcomes, there were no statistically significant group differences between the groups. After controlling for covariates that could affect telomere length, the long-term TKM oncotherapy group had a higher daily telomere attrition rate. The study of the relationship between telomere length and prognostic factors discovered that patients with advanced N stage at the time of diagnosis and who had previously received radiotherapy had shorter telomere length. When examining associations between SNP genotype and percentile score of telomere length, this study was able to confirm an association between telomere length and rs4387287. This study is significant because it is the first to assess the effects of TKM oncotherapy and investigate telomere length-related factors. To assess the effects of TKM oncotherapy on cancer patients' survival and QoL, a longer-term observational study with a larger sample size is required.

RevDate: 2023-08-23

Dupoué A, Mello DF, Trevisan R, et al (2023)

Intertidal limits shape covariation between metabolic plasticity, oxidative stress and telomere dynamics in Pacific oyster (Crassostrea gigas).

Marine environmental research, 191:106149 pii:S0141-1136(23)00277-5 [Epub ahead of print].

In intertidal zones, species such as sessile shellfish exhibit extended phenotypic plasticity to face rapid environmental changes, but whether frequent exposure to intertidal limits of the distribution range impose physiological costs for the animal remains elusive. Here, we explored how phenotypic plasticity varied along foreshore range at multiple organization levels, from molecular to cellular and whole organism acclimatization, in the Pacific oyster (Crassostrea gigas). We exposed 7-month-old individuals for up to 16 months to three foreshore levels covering the vertical range for this species, representing 20, 50 and 80% of the time spent submerged monthly. Individuals at the upper range limit produced energy more efficiently, as seen by steeper metabolic reactive norms and unaltered ATP levels despite reduced mitochondrial density. By spending most of their time emerged, oysters mounted an antioxidant shielding concomitant with lower levels of pro-oxidant proteins and postponed age-related telomere attrition. Instead, individuals exposed at the lower limit range near subtidal conditions showed lower energy efficiencies, greater oxidative stress and shorter telomere length. These results unraveled the extended acclimatization strategies and the physiological costs of living too fast in subtidal conditions for an intertidal species.

RevDate: 2023-08-23

Frydrychová RČ, Konopová B, Peska V, et al (2023)

Telomeres and telomerase: active but complex players in life-history decisions.

Biogerontology [Epub ahead of print].

Studies on human telomeres have established that telomeres exert a significant influence on lifespan and health of organisms. However, recent research has indicated that the original idea that telomeres affect lifespan in a universal and central manner across all eukaryotic species is an oversimplification. Indeed, findings from a variety of animal species revealed that the role of telomere biology in aging is more subtle and intricate than previously recognized. Here, we show how telomere biology varies depending on the taxon. We also show how telomere biology corresponds to basic life history traits and affects the life table of a species and investments in growth, body size, reproduction, and lifespan; telomeres are hypothesized to shape evolutionary perspectives for species in an active but complex manner. Our evaluation is based on telomere biology data from many examples from throughout the animal kingdom that vary according to the degree of organismal complexity and life history strategies.

RevDate: 2023-08-24
CmpDate: 2023-08-24

Liu C, Ding K, Abdul M, et al (2023)

The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis.

BMC anesthesiology, 23(1):284.

BACKGROUND: Cognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases.

METHODS: For this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score ≤ -1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL.

RESULTS: Overall, 20.4% [40/196; 95% confidence interval (CI), 14.7-26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01-54.84; P < 0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29-46.24; P < 0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722-0.859; P < 0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%.

CONCLUSIONS: In summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.

RevDate: 2023-08-22

Eastwood JR, Dupoué A, Verhulst S, et al (2023)

Cool, dry nights and short heatwaves during growth result in longer telomeres in temperate songbird nestlings.

Molecular ecology [Epub ahead of print].

Exposure to rising sublethal temperatures can affect development and somatic condition, and thereby Darwinian fitness. In the context of climate warming, these changes could have implications for population viability, but they can be subtle and consequently difficult to quantify. Using telomere length (TL) as a known biomarker of somatic condition in early life, we investigated the impact of pre-hatching and nestling climate on six cohorts of wild nestling superb fairy wrens (Malurus cyaneus) in temperate south-eastern Australia. Models incorporating only climate information from the nestling phase were best supported compared to those including the (pre-)laying to incubation phase (previously shown to affect mass) or both phases combined. This implies that nestling TL is most sensitive to ambient climate in the nestling phase. The top model showed a negative relationship between early-life TL and nestling mean daily minimum temperature when rainfall was low which gradually became positive with increasing rainfall. In addition, there was a positive relationship between TL and the frequency of hot days (daily maximum temperature ≥35°C), although these temperatures were rare and short-term. Including other pre-hatching and nestling period, climate variables (e.g., mean daily maximum temperature and mean diurnal temperature variability) did not improve the prediction of nestling TL. Overall, our results suggest that cooler nights when conditions are dry and short-term temperature spikes above 35°C during development are conducive for somatic maintenance. While these findings indicate a potential pathway for climate warming to impact wildlife fitness, they emphasize the need to elucidate the mechanisms underlying these complex associations.

RevDate: 2023-08-21

Lyčka M, Bubeník M, Závodník M, et al (2023)

TeloBase: a community-curated database of telomere sequences across the tree of life.

Nucleic acids research pii:7246534 [Epub ahead of print].

Discoveries over the recent decade have demonstrated the unexpected diversity of telomere DNA motifs in nature. However, currently available resources, 'Telomerase database' and 'Plant rDNA database', contain just fragments of all relevant literature published over decades of telomere research as they have a different primary focus and limited updates. To fill this gap, we gathered data about telomere DNA sequences from a thorough literature screen as well as by analysing publicly available NGS data, and we created TeloBase (http://cfb.ceitec.muni.cz/telobase/) as a comprehensive database of information about telomere motif diversity. TeloBase is supplemented by internal taxonomy utilizing popular on-line taxonomic resources that enables in-house data filtration and graphical visualisation of telomere DNA evolutionary dynamics in the form of heat tree plots. TeloBase avoids overreliance on administrators for future data updates by having a simple form and community-curation system for application and approval, respectively, of new telomere sequences by users, which should ensure timeliness of the database and topicality. To demonstrate TeloBase utility, we examined telomere motif diversity in species from the fungal genus Aspergillus, and discovered (TTTATTAGGG)n sequence as a putative telomere motif in the plant family Chrysobalanaceae. This was bioinformatically confirmed by analysing template regions of identified telomerase RNAs.

RevDate: 2023-08-23

Gorsi HS, Gallardo-Rios M, S Savaşan (2023)

Short telomere length in autoimmune neutropenia of childhood: A mere coincidence or an association?.

EJHaem, 4(3):827-828.

RevDate: 2023-08-22
CmpDate: 2023-08-22

Han X, Wu T, CY Liu (2023)

Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes.

Frontiers in endocrinology, 14:1225600.

BACKGROUND: Numerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear.

METHODS: Mendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings.

RESULTS: After Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714-0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births.

CONCLUSION: Our MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.

RevDate: 2023-08-20

Mo W, Shu Y, Liu B, et al (2023)

Single-molecule targeted accessibility and methylation sequencing of centromeres, telomeres and rDNAs in Arabidopsis.

Nature plants [Epub ahead of print].

The short read-length of next-generation sequencing makes it challenging to characterize highly repetitive regions (HRRs) such as centromeres, telomeres and ribosomal DNAs. Based on recent strategies that combined long-read sequencing and exogenous enzymatic labelling of open chromatin, we developed single-molecule targeted accessibility and methylation sequencing (STAM-seq) in plants by further integrating nanopore adaptive sampling to investigate the HRRs in wild-type Arabidopsis and DNA methylation mutants that are defective in CG- or non-CG methylation. We found that CEN180 repeats show higher chromatin accessibility and lower DNA methylation on their forward strand, individual rDNA units show a negative correlation between their DNA methylation and accessibility, and both accessibility and CHH methylation levels are lower at telomere compared to adjacent subtelomeric region. Moreover, DNA methylation-deficient mutants showed increased chromatin accessibility at HRRs, consistent with the role of DNA methylation in maintaining heterochromatic status in plants. STAM-seq can be applied to study accessibility and methylation of repetitive sequences across diverse plant species.

RevDate: 2023-08-20

Stylianakis E, Chan JPK, Law PP, et al (2023)

Mouse HP1γ regulates TRF1 expression and telomere stability.

Life sciences pii:S0024-3205(23)00665-3 [Epub ahead of print].

AIMS: Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance.

MAIN METHODS: We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP).

KEY FINDINGS: Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X.

SIGNIFICANCE: Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

RevDate: 2023-08-20

Zhang D, Chen X, Huang K, et al (2023)

Urinary essential and toxic metal mixtures, and type 2 diabetes mellitus: Telomere shortening as an intermediary factor?.

Journal of hazardous materials, 459:132329 pii:S0304-3894(23)01612-6 [Epub ahead of print].

The joint effect of metal mixtures on telomere function and type 2 diabetes mellitus (T2DM) is unclear. This large-scale cross-sectional study sought to assess the role of telomere length (TL) in the relationship between urinary essential and toxic metal mixtures, and T2DM in 7410 Chinese adults ≥ 60 years of age. Essential (Cr, Cu, Zn, Se) and non-essential metals (V, Al, Sb, Sn, Cd, Pb) in urine samples were quantified, while leukocyte TL was measured from blood samples. Restricted cubic splines regression showed nonlinear relationships between single metal and T2DM, and between TL and T2DM. Bayesian kernel machine regression and quantile-based g-computation showed that the overall status of urinary metals was positively associated with risk of developing T2DM, which was mainly explained by exposure to Pb, Cd, and Sb, excessive Se intake, and high excretion of Zn. Mediation analyses showed that shortened TL mediated 27.9% of the overall positive effect of metal exposure on T2DM, and this mediation was mainly explained by toxic metal exposure and excessive Se intake. Tobacco smoke exposure, extensive cooking at home, and black tea consumption were found to be important contributors of toxic metal exposures. Further studies are needed to explore the recommended Zn dosage for T2DM patients at different stages, which may ameliorate pancreatic senescence and glycemic progression.

RevDate: 2023-08-19

Zhang Y, Zhu Y, Ye M, et al (2023)

Telomere length and its association with systemic lupus erythematosus in an Asian population: A Mendelian randomization study.

Lupus [Epub ahead of print].

OBJECTIVES: To investigate whether shorter telomere length is a causal risk factor for systemic lupus erythematosus (SLE) in the Asian population.

METHODS: We applied the two-sample Mendelian randomization (MR) method to the pooled statistics from a genome-wide association study (GWAS) of 6,707 SLE cases and 16,047 controls. We selected nine single-nucleotide polymorphisms (SNPs) with genome-wide significance as instrumental variables for telomere length. The main analysis was carried out by the random-effects inverse-variance weighted (IVW) method. Horizontal pleiotropy was evaluated by the intercept of MR-Egger regression.

RESULTS: A potentially causal relationship between longer genetically predicted telomere length and increased risk of systemic lupus erythematosus (OR = 1.72, 95%CI: 1.21, 2.46, p = 0.01) was observed. The MR-Egger regression demonstrated an intercept proximal to zero (intercept = 0.017, p = 0.69), which does not provide evidence of the presence of horizontal pleiotropy.

CONCLUSIONS: Our findings provided evidence supporting a potential causal relationship between longer telomere length and increased risk of systemic lupus erythematosus.

RevDate: 2023-08-18

He Y, Chu Y, Guo S, et al (2023)

T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.

Genomics, proteomics & bioinformatics pii:S1672-0229(23)00100-6 [Epub ahead of print].

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere version-T2T-CHM13-reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. To provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we have assembled the genome of a male Han Chinese individual, T2T-YAO, which includes telomere-to-telomere assemblies of all the 22+X+M and 22+Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼330 Mb exclusive sequences, ∼3100 unique genes, and tens of thousands of nucleotide and structural variations as compared to CHM13, highlighting the necessity of population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

RevDate: 2023-08-18

Rinne GR, Carroll JE, Guardino CM, et al (2023)

Parental preconception posttraumatic stress symptoms and maternal prenatal inflammation prospectively predict shorter telomere length in children.

Psychosomatic medicine pii:00006842-990000000-00153 [Epub ahead of print].

OBJECTIVE: Parental trauma exposure and trauma-related distress can increase risk for adverse health outcomes in offspring, but the pathways implicated in intergenerational transmission are not fully explicated. Accelerated biological aging may be one mechanism underlying less favorable health in trauma-exposed individuals and their offspring. This study examines associations of preconception maternal and paternal posttraumatic stress disorder (PTSD) symptoms with child telomere length, and maternal prenatal C-reactive protein (CRP) as a biological mechanism.

METHODS: Mothers (n = 127) and a subset of the fathers (n = 84) reported on PTSD symptoms before conception. Mothers provided blood spots in the second and third trimester that were assayed for CRP. At age 4, children provided buccal cells for measurement of telomere length. Models adjusted for parental age, socioeconomic status, maternal pre-pregnancy BMI, child biological sex, and child age.

RESULTS: Mothers' PTSD symptoms were significantly associated with shorter child telomere length (β = -0.22, SE = 0.10, p = .023). Fathers' PTSD symptoms were also inversely associated with child telomere length (β = -0.21, SE = 0.11), though nonsignificant (p = .065). There was no significant indirect effect of mothers' PTSD symptoms on child telomere length through CRP in pregnancy, but higher second trimester CRP was significantly associated with shorter child telomere length (β = -0.35, SE = 0.18, p = .048).

CONCLUSIONS: Maternal symptoms of PTSD prior to conception and second trimester inflammation were associated with shorter telomere length in offspring in early childhood, independent of covariates. Findings indicate intergenerational transmission of parental trauma may occur in part through accelerated biological aging processes and provide further evidence that prenatal pro-inflammatory processes program child telomere length.Open Science Framework Pre-registration:https://osf.io/7c2d5/?view_only=cd0fb81f48db4b8f9c59fc8bb7b0ef97.

RevDate: 2023-08-18

Luo X, Ruan Z, L Liu (2023)

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study.

Epilepsia open [Epub ahead of print].

OBJECTIVE: Observational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis.

METHODS: We performed a bidirectional two-sample MR analysis using pooled statistics from genome-wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse-variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.

RESULTS: Our analysis found no evidence of a causal relationship between epilepsy and TL (all P-values > 0.05). The sensitivity analysis confirms the robustness of these results.

SIGNIFICANCE: In summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.

RevDate: 2023-08-18

Huang X (2023)

A Complete Telomere-to-Telomere Assembly Provides New Reference Genome for Rice.

Molecular plant pii:S1674-2052(23)00223-X [Epub ahead of print].

RevDate: 2023-08-17

Zhang D, Adegunsoye A, Oldham JM, et al (2023)

Telomere Length and Immunosuppression in Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Disease.

The European respiratory journal pii:13993003.00441-2023 [Epub ahead of print].

Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).A retrospective, multi-centre cohort analysis was performed in fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and connective tissue disease ILD patients from five centres. LTL was measured by qPCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on two-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality HR 4.97, 95% CI 2.26-10.92, p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77, p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (Discovery p-interaction=0.013; Replication p-interaction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for connective tissue disease ILD.Similar to IPF, fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

RevDate: 2023-08-17

Naudé PJW, Stein DJ, Lin J, et al (2023)

Investigating the association of prenatal psychological adversities with mother and child telomere length and neurodevelopment.

Journal of affective disorders pii:S0165-0327(23)01054-6 [Epub ahead of print].

BACKGROUND: Exposure to prenatal maternal psychological adversities can negatively affect the offspring's developing brain. Shortened telomere length (TL) has been implicated as a mechanism for the transgenerational effects of maternal psychological adversities on offspring. This study aimed to determine associations between prenatal psychological stressors and distress with maternal and early life TL, and associations between maternal, newborn and child TL with neurodevelopmental outcomes at 2 years of age.

METHODS: Follow-up TL was measured in a subgroup of African mothers (n = 138) and their newborns (n = 142) and children (n = 96) at 2-years in the Drakenstein Child Health Study. Prenatal symptoms of depression, distress, intimate partner violence, posttraumatic stress-disorder and childhood trauma were measured at 27 weeks gestation. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. TLs were measured in whole bloods from mothers and their children at 2-years, and cord bloods in newborns.

RESULTS: Maternal prenatal stressors and distress were not significantly associated with TL in mothers or their children at birth or at 2-years. Furthermore, maternal psychological measures were not associated with early-life attrition of TL. Longer TL in children at 2-years was associated (p = 0.04) with higher motor functioning.

LIMITATIONS: Limited numbers of participants and single time-point psychological measures.

CONCLUSIONS: This study is the first to provide information on the association of early life TL with prenatal psychological adversities and neurodevelopmental outcomes in a population of low-income African mothers and their children.

RevDate: 2023-08-17

Lu ZH, Sun B, Wang YX, et al (2023)

Ozone exposure associates with sperm quality indicators: Sperm telomere length as a potential mediating factor.

Journal of hazardous materials, 459:132292 pii:S0304-3894(23)01575-3 [Epub ahead of print].

Evidence linking O3 exposure and human semen quality is limited and conflicting and the mechanism underlying the association remains unclear. Therefore, we investigated the associations between ambient O3 exposure and sperm quality parameters and explored the mediating role of sperm mitochondrial DNA copy number (mtDNAcn) and sperm telomere length (STL) among 1068 potential sperm donors who provided 5002 repeated semen samples over approximately 90 days. We found that every 10 μg/m[3] increase in O3 exposure was associated with a decrease in STL, sperm concentration, total count, total motile sperm number, and semen volume. However, O3 exposure was associated with increased total motility and progressive motility. The association for sperm quality parameters was stronger when exposure was measured at spermatogenesis stages I and II. For STL, the strongest association was observed when exposure was measured at spermatogenesis stage II. Additionally, we found that approximately 9% and 8% of the association between O3 exposure and sperm concentration and count was mediated by STL, respectively. In summary, our findings suggest that O3 pollution may affect sperm telomere length, eventually leading to reduced semen quality.

RevDate: 2023-08-17

Vellingiri B, Balasubramani K, Iyer M, et al (2023)

Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?.

Advanced biology [Epub ahead of print].

Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.

RevDate: 2023-08-17

Chen H, Liang W, Zheng W, et al (2023)

A novel telomere-related gene prognostic signature for survival and drug treatment efficiency prediction in lung adenocarcinoma.

Aging, 15: pii:204877 [Epub ahead of print].

OBJECTIVE: Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency.

METHODS: A total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups.

RESULTS: A total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy.

CONCLUSION: This study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy.

RevDate: 2023-08-17

Zhu S, Yang M, Wang T, et al (2023)

Causal relationships between telomere length and liver disease: a Mendelian randomization study.

Frontiers in genetics, 14:1164024.

Background: Leukocyte telomere length and hepatic disorders have been linked in various research studies, although their causative association has not been clarified. This study investigated the causal relationship between the length of telomeres on peripheral blood leukocytes and certain liver disorders. Methods: Mendelian randomization (MR) analysis was used to examine the relationship between leukocyte telomere length and risk of liver disease using the publicly accessible worldwide gene-wide association study (GWAS) database. The weighted mode, weighted median, and inverse variance weighted (IVW) methods were employed as supplements to the IVW approach, which is the main analytical method. Results: Leukocytes with longer telomeres may have a lower risk of developing cirrhosis [OR = 0.645 (0.524, 0.795), p = 3.977E-05] and a higher chance of developing benign liver tumors [OR = 3.087 (1.721, 5.539), p = 1.567E-04]. There was no direct link between telomere length and fatty liver, hepatic fibrosis, or liver cancer. Our findings in the replication analysis agreed with those of the previous studies. Conclusion: Further research is needed to examine the mechanisms underlying the probable causal association between the length of leukocyte telomeres and cirrhosis and benign liver cancer.

RevDate: 2023-08-16

He Q, CJ Lim (2023)

Models for human telomere C-strand fill-in by CST-Polα-primase.

Trends in biochemical sciences pii:S0968-0004(23)00174-3 [Epub ahead of print].

Telomere maintenance is essential for the genome integrity of eukaryotes, and this function is underpinned by the two-step telomeric DNA synthesis process: telomere G-overhang extension by telomerase and complementary strand fill-in by DNA polymerase alpha-primase (polα-primase). Compared to the telomerase step, the telomere C-strand fill-in mechanism is less understood. Recent studies have provided new insights into how telomeric single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) and polα-primase coordinate to synthesize the telomeric C-strand for telomere overhang fill-in. Cryogenic electron microscopy (cryo-EM) structures of CST-polα-primase complexes have provided additional insights into how they assemble at telomeric templates and de novo synthesize the telomere C-strand. In this review, we discuss how these latest findings coalesce with existing understanding to develop a human telomere C-strand fill-in mechanism model.

RevDate: 2023-08-14

Brown RL, Epel EE, Lin J, et al (2023)

Associations between klotho and telomere biology in high stress caregivers.

Aging, 15: pii:204961 [Epub ahead of print].

Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.

RevDate: 2023-08-14

Lee J, Lee J, Sohn EJ, et al (2023)

Extrachromosomal Telomeres Derived from Excessive Strand Displacements.

bioRxiv : the preprint server for biology pii:2023.07.31.551186.

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication (BIR), evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), unique to ALT cells, are considered potential precursors of C-circles, their generation process remains undefined. Here, we introduce a highly sensitive method to detect single stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single stranded DNAs are near 500 bp in size. Both C-rich ssDNAs and C-circles are abundant in cytoplasmic fraction which supports the idea that C-rich ssDNAs may indeed precede C-circles. We also found that C-rich ssDNAs originate during Okazaki fragment processing in lagging strands. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha)-complex mediated priming of the C-strand synthesis and subsequent excessive strand displacement of C-rich strand through DNA Polymerase delta and BLM helicase. Our work proposes a new model for the generation of C-rich ssDNAs and C-circles that are indicative of the presence of ALT pathway.

RevDate: 2023-08-14
CmpDate: 2023-08-14

Yamaguchi I, Ikawa K, Takimiya N, et al (2023)

Tetraphenylethene Derivatives Bearing Alkylammonium Substituents: Synthesis, Chemical Properties, and Application as BSA, Telomere DNA, and Hydroxyl Radical Sensors.

Molecules (Basel, Switzerland), 28(15):.

Tetraphenylethene derivatives (TPEs) are used as luminescence probes for the detection of metal ions and biomolecules. These sensors function by monitoring the increase in the photoluminescence (PL) intensity of the TPEs resulting from aggregation-induced emission (AIE) upon interaction with the analytes. The AIE behavior of the sensors was investigated by measuring their PL. In this study, PL, PL lifetime, and confocal laser scanning microscopy measurements were carried out as part of our in-depth investigation of AIE behavior of TPEs for the detection of biomolecules and radical species. We used 1,1,2,2-tetrakis(4-((trimethylammonium)alkoxy)phenyl)tetraphenylethene tetrabromide (TPE-C(m)N[+]Me3Br[-], m = 2, 4, and 6, where m denotes the number of methylene groups in the alkyl chain) and TPE-C(m)N[+]Me3TCNQ[-•] (TCNQ[-•] is the 7,7',8,8'-tetracyanoquinodimethane anion radical) as luminescent probes for the detection of bovine serum albumin (BSA), DNA, and the hydroxyl radical ([•]OH) generated from Fenton's reagent. The sensing performance of TPE-C(m)N[+]Me3Br[-] for BSA and DNA was found to depend on the length of the alkyl chains (m). UV-vis and PL measurements revealed that the responses of TPE-C(m)N[+]Me3Br[-] and TPE-C(4)N[+]TCNQ[-•] to Fenton's reagent depended on the solvent. The electrochemical properties of the TPE derivatives prepared in this study were additionally investigated via cyclic voltammetry.

RevDate: 2023-08-14
CmpDate: 2023-08-14

Li XH, Sun MH, Jiang WJ, et al (2023)

ZSCAN4 Regulates Zygotic Genome Activation and Telomere Elongation in Porcine Parthenogenetic Embryos.

International journal of molecular sciences, 24(15):.

Zinc finger and SCAN domain-containing 4 (ZSCAN4), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of ZSCAN4 in porcine parthenogenetic embryos remains unclear. To investigate the function of ZSCAN4 and the underlying mechanism in porcine embryo development, ZSCAN4 was knocked down via dsRNA injection in the one-cell stage. ZSCAN4 was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the ZSCAN4 knockdown group than in the control group. Notably, depletion of ZSCAN4 induced the protein expression of DNMT1 and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following ZSCAN4 knockdown. Furthermore, ZSCAN4 knockdown led to DNA damage and shortened telomere compared with the control. Additionally, DNMT1-dsRNA was injected to reduce DNA hypermethylation in ZSCAN4 knockdown embryos. DNMT1 knockdown rescued telomere shortening and developmental defects caused by ZSCAN4 knockdown. In conclusion, ZSCAN4 is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating DNMT1 expression in porcine ZGA.

RevDate: 2023-08-11

Ye Q, Apsley AT, Etzel L, et al (2023)

Telomere length and chronological age across the human lifespan: a systematic review and meta-analysis of 414 study samples including 743,019 individuals.

Ageing research reviews pii:S1568-1637(23)00190-3 [Epub ahead of print].

Telomere attrition is a proposed hallmark of aging. To evaluate the association of telomere length (TL) with chronological age across the human lifespan, we conducted a systematic review and meta-analysis of 414 study samples comprising 743,019 individuals aged 0 to 112 years. We examined both cross-sectional and longitudinal data, and evaluated the impact of various biological and methodological factors including sex, health status, tissue types, DNA extraction procedures, and TL measurement methods. The pooled corrected correlation between TL and age from cross-sectional samples was -0.19 (95%CI: -0.22 to -0.15), which weakened with increased chronological age (β=0.003, p<0.001). Z-score change rates of TL across the lifespan showed a gradual decrease in shortening rate until around age 50 and remained at a relatively stable rate towards the elderly period. A greater attrition rate was observed in longitudinal than cross-sectional evaluations. For TL measured in base pairs, the median change rate of TL was -23 bp/year in cross-sectional samples and -38 bp/year in longitudinal samples. Methodological factors including TL measurement methods and tissue types impacted the TL-age correlation, while sex or disease status did not. This meta-analysis revealed the non-linear shortening trend of TL across the human lifespan and provides a reference value for future studies. Results also highlight the importance of methodological considerations when using TL as an aging biomarker.

RevDate: 2023-08-11

Nose D, Shiga Y, Takahashi RU, et al (2023)

Association Between Telomere G-Tail Length and Coronary Artery Disease or Statin Treatment in Patients With Cardiovascular Risks - A Cross-Sectional Study.

Circulation reports, 5(8):338-347.

Background: The utility of telomere G-tail length to predict coronary artery disease (CAD) remains controversial. CAD results from coronary artery narrowing due to cholesterol and lipid accumulation, augmented by inflammatory cells and other factors. This study explored the significance of telomere G-tail length in suspected CAD patients. Methods and Results: In all, 95 patients with suspected CAD or ≥1 cardiac risk factor underwent coronary computed tomography angiography (CCTA). We measured leukocyte telomere length and G-tail length using a hybrid protection method, and diagnosed the presence of CAD using CCTA. Associations between G-tail length and the presence of CAD, the number of stenosed coronary arteries, and brachial-ankle pulse wave velocity (baPWV) were analyzed. No significant difference was observed in G-tail length when comparing groups with or without CAD or statin treatment. However, in the non-statin group, G-tail length was significantly shorter in patients with 3-vessel disease compared with 1-vessel disease. Dividing the group using a baPWV of 1,300 cm/s, telomere G-tail length was significantly shorter in the high-risk (baPWV ≥1,300 cm/s) group. Conclusions: The clinical utility of telomere G-tail length as a CAD risk indicator seems limited. There was a trend for longer telomere G-tail length in the statin-treated group. Moreover, telomere G-tail length was reduced in patients at high-risk of cardiovascular events, aligning with the trend of a shortening in telomere G-tail length with CAD severity.

RevDate: 2023-08-10

Takasugi T, Gu P, Liang F, et al (2023)

Pot1b -/- tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation.

Nucleic acids research pii:7240375 [Epub ahead of print].

Malignant cancers must activate telomere maintenance mechanisms to achieve replicative immortality. Mutations in the human Protection of Telomeres 1 (POT1) gene are frequently detected in cancers with abnormally long telomeres, suggesting that the loss of POT1 function disrupts the regulation of telomere length homeostasis to promote telomere elongation. However, our understanding of the mechanisms leading to elongated telomeres remains incomplete. The mouse genome encodes two POT1 proteins, POT1a and POT1b possessing separation of hPOT1 functions. We performed serial transplantation of Pot1b-/- sarcomas to better understand the role of POT1b in regulating telomere length maintenance. While early-generation Pot1b-/- sarcomas initially possessed shortened telomeres, late-generation Pot1b-/- cells display markedly hyper-elongated telomeres that were recognized as damaged DNA by the Replication Protein A (RPA) complex. The RPA-ATR-dependent DNA damage response at telomeres promotes telomerase recruitment to facilitate telomere hyper-elongation. POT1b, but not POT1a, was able to unfold G-quadruplex present in hyper-elongated telomeres to repress the DNA damage response. Our findings demonstrate that the repression of the RPA-ATR DDR is conserved between POT1b and human POT1, suggesting that similar mechanisms may underly the phenotypes observed in human cancers harboring human POT1 mutations.

RevDate: 2023-08-11

Teng Y, Huang DQ, Li RX, et al (2023)

Association Between Telomere Length and Risk of Lung Cancer in an Asian Population: A Mendelian Randomization Study.

World journal of oncology, 14(4):277-284.

BACKGROUND: Several traditional observational studies and Mendelian randomization (MR) studies have indicated an association between leukocyte telomere length (LTL) and the risk of lung cancer in the European population. However, the results in the Asian population are still unclear. The objective was to reveal the genetic causal association between LTL and the risk of lung cancer in the Asian population.

METHODS: We conducted a two-sample MR analysis using summary statistics. Instrumental variables (IVs) were obtained from the genome-wide association studies (GWAS) of LTL (n = 23,096) and lung cancer (n = 212,453) of Asian ancestry. We applied the random-effects inverse-variance weighted (IVW) model as the main method. As well, several other models were performed as complementary methods to assess the impact of potential MR assumption violations, including MR-Egger regression, weighted median, and weighted mode models.

RESULTS: We included eight single-nucleotide polymorphisms (SNPs) as IVs for LTL and found that LTL was significantly associated with the risk of lung cancer in the IVW model (odds ratio (OR): 1.60; 95% confidence interval (CI): 1.31 - 1.97; P = 5.96 × 10[-6]), which was in line with the results in the weighted median and weighted mode models. However, the relationship was not statistically significant in the MR-Egger regression model (OR: 1.44; 95% CI: 0.92 - 2.26; P = 0.160). Sensitivity analyses indicated the robustness of the results.

CONCLUSIONS: This two-sample MR study confirmed that longer telomere length significantly increased the risk of lung cancer in the Asian population, which was in accord with findings in the Western population.

RevDate: 2023-05-31
CmpDate: 2023-05-29

Hill C, Duffy S, Kettyle LM, et al (2023)

Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.

Genes, 14(5):.

Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10[-6]). Telomere length was also significantly reduced (p = 6.6 × 10[-5]) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10[-8]) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.

RevDate: 2023-05-02

Fattahi M, Maghsudlu M, M Hasan Sheikhha (2023)

Is sperm telomere length altered in teratozoospermia specimens? A case-control study.

International journal of reproductive biomedicine, 21(3):229-236.

BACKGROUND: Male factor infertility is a multifactorial defect, and many of its etiologies are unknown. Teratozoospermia is determined by the existence of over 85% morphologically abnormal spermatozoa in semen which are almost incompetent in fertilization function. One of the most novel issues in genetic alterations studies is the variation of sperm telomere lengths (STL) and its collaboration with male infertility. The present study has been focused on STL alterations in teratozoospermia.

OBJECTIVE: Investigation of differences in telomere length of teratozoospermia specimens and sperms with normal parameters.

MATERIALS AND METHODS: In this case-control study, 60 men referred to Arak Fertility Clinic, Markazi province, Iran from November 2017 to February 2018 were categorized into teratozoospermia and normozoospermic groups. Sperm genomic DNA extraction was conducted, and STL were evaluated using quantitative polymerase chain reaction.

RESULTS: Statistical evaluation of relative telomere length was calculated by the ratio of telomere to single-copy gene for teratozoospermia and normal specimens. Results significantly demonstrated that relative telomere length in teratozoospermia samples is nearly 3 times shorter than in normal samples (p > 0.001).

CONCLUSION: Our results represent the reduction of telomeres length in teratozoospermia and suggest that this alteration might be one of the factors contributing to the sperm fertility potential of this kind of specimen. However, defining relevant molecular processes requires further detailed investigations.

RevDate: 2023-07-19
CmpDate: 2023-05-29

Ngo K, Gittens TH, Gonzalez DI, et al (2023)

A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.

Genetics, 224(2):.

Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition (dnTA) on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker's yeast, Saccharomyces cerevisiae, that act as hotspots of dnTA [termed Sites of Repair-associated Telomere Addition (SiRTAs)], but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.

RevDate: 2023-05-12
CmpDate: 2023-05-12

Saradadevi GP, Fultz D, Ramgopal MK, et al (2023)

Structural variation among assembled genomes facilitates development of rapid and low-cost NOR-linked markers and NOR-telomere junction mapping in Arabidopsis.

Plant cell reports, 42(6):1059-1069.

Genome-wide structural variants we identified and new NOR-linked markers we developed would be useful for future genome-wide association studies (GWAS), and for new gene/trait mapping purposes. Bioinformatic alignment of the assembled genomes of Col-0 and Sha ecotypes of Arabidopsis thaliana revealed ~ 13,000 genome-wide structural variants involving simple insertions or deletions and repeat contractions or expansions. Using some of these structural variants, we developed new, rapid, and low-cost PCR-based molecular markers that are genetically linked to the nucleolus organizer regions (NORs). A. thaliana has two NORs, one each on chromosome 2 (NOR2) and chromosome 4 (NOR4). Both NORs are ~ 4 Mb each, and hundreds of 45S ribosomal RNA (rRNA) genes are tandemly arrayed at these loci. Using previously characterized recombinant inbred lines (RILs) derived from Sha x Col-0 crosses, we validated the utility of the newly developed NOR-linked markers in genetically mapping rRNA genes and the associated telomeres to either NOR2 or NOR4. Lastly, we sequenced Sha genome using Oxford Nanopore Technology (ONT) and used the data to obtain sequences of NOR-telomere junctions, and with the help of RILs, we mapped them as new genetic markers to their respective NORs (NOR2-TEL2N and NOR4-TEL4N). The structural variants obtained from this study would serve as valuable data for genome-wide association studies (GWAS), and to rapidly design more genome-wide genetic (molecular) markers for new gene/trait mapping purposes.

RevDate: 2023-05-09
CmpDate: 2023-04-24

Flor-Alemany M, Acosta-Manzano P, Migueles JH, et al (2023)

Influence of an exercise intervention plus an optimal Mediterranean diet adherence during pregnancy on the telomere length of the placenta. The GESTAFIT project.

Placenta, 136:42-45.

We aimed to investigate whether the effects of exercise on placental relative telomere length (RTL) after delivery are modulated by the Mediterranean diet [MD] adherence in 65 pregnant women (control n = 34, exercise n = 31). No differences were found in placental RTL between the exercise and the control groups (p = 0.557). The interaction-term between exercise and MD adherence with placental RTL was significant (p = 0.001). Specifically, women in the exercise group showed longer placental RTL after birth compared to controls (referent group), only for those women with a high MD adherence (mean difference = 0.467, p=0.010). A concurrent-exercise training plus an optimal MD adherence during pregnancy might prevent the placental RTL shortening.

RevDate: 2023-04-11

González-Amor M, Dorado B, V Andrés (2023)

Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.

Frontiers in cell and developmental biology, 11:1128594.

Population aging and age-related cardiovascular disease (CVD) are becoming increasingly prevalent worldwide, generating a huge medical and socioeconomic burden. The complex regulation of aging and CVD and the interaction between these processes are crucially dependent on cellular stress responses. Interferon-stimulated gene-15 (ISG15) encodes a ubiquitin-like protein expressed in many vertebrate cell types that can be found both free and conjugated to lysine residues of target proteins via a post-translational process termed ISGylation. Deconjugation of ISG15 (deISGylation) is catalyzed by the ubiquitin-specific peptidase 18 (USP18). The ISG15 pathway has mostly been studied in the context of viral and bacterial infections and in cancer. This minireview summarizes current knowledge on the role of ISG15 in age-related telomere shortening, genomic instability, and DNA damage accumulation, as well as in hypertension, diabetes, and obesity, major CVD risk factors prevalent in the elderly population.

RevDate: 2023-07-26
CmpDate: 2023-07-26

Rose AM, Goncalves T, Cunniffe S, et al (2023)

Induction of the alternative lengthening of telomeres pathway by trapping of proteins on DNA.

Nucleic acids research, 51(13):6509-6527.

Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this is achieved through the alternative lengthening of telomeres (ALT) pathway. Whilst loss of ATRX is a near universal feature of ALT-cancers, it is insufficient in isolation. As such, other cellular events must be necessary - but the exact nature of the secondary events has remained elusive. Here, we report that trapping of proteins (such as TOP1, TOP2A and PARP1) on DNA leads to ALT induction in cells lacking ATRX. We demonstrate that protein-trapping chemotherapeutic agents, such as etoposide, camptothecin and talazoparib, induce ALT markers specifically in ATRX-null cells. Further, we show that treatment with G4-stabilising drugs cause an increase in trapped TOP2A levels which leads to ALT induction in ATRX-null cells. This process is MUS81-endonuclease and break-induced replication dependent, suggesting that protein trapping leads to replication fork stalling, with these forks being aberrantly processed in the absence of ATRX. Finally, we show ALT-positive cells harbour a higher load of genome-wide trapped proteins, such as TOP1, and knockdown of TOP1 reduced ALT activity. Taken together, these findings suggest that protein trapping is a fundamental driving force behind ALT-biology in ATRX-deficient malignancies.

RevDate: 2023-03-28
CmpDate: 2023-03-24

D'Aronco G, Ferraro P, Sassano V, et al (2023)

SAMHD1 restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase-positive cells.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37(4):e22883.

SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain-containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular dNTP pools, which support genome integrity. In SAMHD1 deficient fibroblasts isolated from Aicardi-Goutières Syndrome (AGS) patients, all four DNA precursors are increased and markedly imbalanced with the largest effect on dGTP, a key player in the modulation of telomerase processivity. Here, we present data showing that SAMHD1, by restricting the dGTP pool, contributes to telomere maintenance in hTERT-immortalized human fibroblasts from AGS patients as well as in telomerase positive cancer cell lines. Only in cells expressing telomerase, the lack of SAMHD1 causes excessive lengthening of telomeres and telomere fragility, whereas primary fibroblasts lacking both SAMHD1 and telomerase enter normally into senescence. Telomere lengthening observed in SAMHD1 deficient but telomerase proficient cells is a gradual process, in accordance with the intrinsic property of telomerase of adding only a few tens of nucleotides for each cycle. Therefore, only a prolonged exposure to high dGTP content causes telomere over-elongation. hTERT-immortalized AGS fibroblasts display also high fragility of chromosome ends, a marker of telomere replication stress. These results not only demonstrate the functional importance of dGTP cellular level but also reveal the critical role played by SAMHD1 in restraining telomerase processivity and safeguarding telomere stability.

RevDate: 2023-03-27
CmpDate: 2023-03-22

Liu S, Nong W, Ji L, et al (2023)

The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases.

Experimental gerontology, 174:112132.

Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.

RevDate: 2023-02-27

Levy MA, Tian J, Gandelman M, et al (2023)

A Multivitamin Mixture Protects against Oxidative Stress-Mediated Telomere Shortening.

Journal of dietary supplements [Epub ahead of print].

Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. Telomeres shorten with each cell division; hence telomere length is associated with aging and longevity. Numerous lifestyle factors have been identified that impact the rate of telomere shortening; high vitamin consumption has been associated with longer telomere length, whereas oxidative stress is associated with telomere shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins and a blend of polyphenolic compounds, could reduce telomere shortening consequent to an oxidative stress (10 uM H2O2 for 8 weeks) in a primary fibroblast cell culture model. Under conditions of oxidative stress, the median and 20[th] percentile telomere length were significantly greater (p < 0.05), and the percentage of critically short telomeres (<3000 bp) was significantly less (p < 0.05) in cells treated with the multivitamin mixture at 4, 15 and 60 ug/ml compared to control (0 ug/ml). Median and 20[th] percentile telomere shortening rate was also reduced under the same conditions (p < 0.05). Taken together, these findings demonstrate that the multivitamin mixture protects against oxidative stress-mediated telomere shortening in cell culture, findings which may have implications in human health.

RevDate: 2023-05-23
CmpDate: 2023-05-23

Pepke ML, Ringsby TH, DTA Eisenberg (2023)

The evolution of early-life telomere length, pace-of-life and telomere-chromosome length dynamics in birds.

Molecular ecology, 32(11):2898-2912.

Telomeres, the short DNA sequences that protect chromosome ends, are an ancient molecular structure, which is highly conserved across most eukaryotes. Species differ in their telomere lengths, but the causes of this variation are not well understood. Here, we demonstrate that mean early-life telomere length is an evolutionary labile trait across 57 bird species (representing 35 families in 12 orders) with the greatest trait diversity found among passerines. Among these species, telomeres are significantly shorter in fast-lived than in slow-lived species, suggesting that telomere length may have evolved to mediate trade-offs between physiological requirements underlying the diversity of pace-of-life strategies in birds. This association was attenuated when excluding studies that may include interstitial telomeres in the estimation of mean telomere length. Curiously, within some species, larger individual chromosome size predicts longer telomere lengths on that chromosome, leading to the hypothesis that telomere length also covaries with chromosome length across species. We show that longer mean chromosome length or genome size tends to be associated with longer mean early-life telomere length (measured across all chromosomes) within a phylogenetic framework constituting up to 31 bird species. These associations were strengthened when excluding highly influential outliers. However, sensitivity analyses suggested that they were susceptible to sample size effects and not robust to the exclusion of studies that may include interstitial telomeres. Combined, our analyses generalize patterns previously found within a few species and provide potential adaptive explanations for the 10-fold variation in telomere lengths observed among birds.


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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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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