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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 17 Sep 2021 at 01:36 Created: 


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

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Citations The Papers (from PubMed®)


RevDate: 2021-09-15

García García C, Shin C, I Baik (2021)

Association between body temperature and leukocyte telomere length in middle-aged and older adults.

Epidemiology and health pii:epih.e2021063 [Epub ahead of print].

Objectives: Data on the association between body temperature (BT) and leukocyte telomere length (LTL), which has been widely used as a biomarker of cellular senescence in recent epidemiological studies, are limited. Aims: The present study aimed to explore the association between a normal BT range (35.0 to 37.5℃) and LTL in a 6-year longitudinal observation among 2004 male and female adults aged 50 or older.

Methods: BT was obtained by measuring a tympanic temperature and relative LTL was assayed using real-time polymerase chain reaction. Robust regression analysis was used to evaluate the association for baseline and follow-up values of LTL and their differences.

Results: A significant inverse association was found between baseline BT and LTL: regression coefficient estimate was -0.03 [95% confidence interval: -0.07, -0.001] (p<0.05). Such an association was stronger in participants with a body mass index >25 kg/m2 and in males (p<0.01). However, BT was not associated with the follow-up LTL and 6-year longitudinal differences in LTL.

Conclusion: These findings suggest that having a higher BT within a range between 35 and 37.5 ℃ (95 and 99 ℉) may be detrimental for obese persons in terms of biological aging.

RevDate: 2021-09-15

Roake CM, Juntilla M, Agarwal-Hashmi R, et al (2021)

Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita.

Human pathology (New York), 25:.

Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.

RevDate: 2021-09-15

Melicher D, Illés A, Littvay L, et al (2021)

Positive association and future perspectives of mitochondrial DNA copy number and telomere length - a pilot twin study.

Archives of medical science : AMS, 17(5):1191-1199 pii:99503.

Introduction: Recent experimental and population studies have highlighted the existence of telomere-mitochondria interplay. Besides studies revealing the molecular mechanisms underlying the associations of telomere defects and mitochondrial functions, investigations of mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in healthy and disease phenotypes have likewise begun, with the aim of gaining more insights about their relationship in humans.

Material and methods: A total of 142 asymptomatic adult twins, comprising 96 monozygotic (MZ) and 46 dizygotic (DZ) twins (mean age: 50.54 ±15.43 years), members of the Hungarian Twin Registry, were included in the analysis. Applying the qPCR standard curve method, we investigated the relationship of mtDNA copy number, telomere length and clinical data, besides assessing co-twin similarities of MZ and DZ twins for their mtDNAcn and TL measures.

Results: We found that twins were similar in their intraclass correlation coefficients irrespective of zygosity, suggesting a possibly more important role of common (shared) environmental factors compared to non-shared (unique) environmental and to a smaller degree also individual genetic influences. We confirmed a significant positive association between mtDNAcn and TL (r = 0.28, p < 0.01) in age- and sex-corrected analysis. Following bivariate estimates and correction with significant predictors, the independent positive associations were further verified.

Conclusions: Our results extend the until now modest number of studies investigating mtDNAcn and TL simultaneously in humans. In addition, we are the first to examine the relationship between mtDNAcn and telomere length in MZ and DZ twin subjects.

RevDate: 2021-09-13

Ravindran S, Froy H, Underwood SL, et al (2021)

The association between female reproductive performance and leukocyte telomere length in wild Soay sheep.

Molecular ecology [Epub ahead of print].

Telomere length (TL), typically measured across a sample of blood cells, has emerged as an exciting potential marker of physiological state and of the costs of investment in growth and reproduction within evolutionary ecology. While there is mounting evidence from studies of wild vertebrates that short TL predicts raised subsequent mortality risk, the relationship between reproductive investment and TL is less clear cut, and previous studies report both negative and positive associations. In this study, we examined the relationship between TL and different aspects of maternal reproductive performance in a free-living population of Soay sheep. We find evidence for shorter TL in females that bred, and thus paid any costs of gestation, compared to females that did not breed. However, we found no evidence for any association between TL and litter size. Furthermore, females that invested in gestation and lactation actually had longer TL than females who only invested in gestation because their offspring died shortly after birth. We used multivariate models to decompose these associations into among- and within-individual effects, and discovered that within-individual effects were driving both the negative association between TL and gestation, and the positive association between TL and lactation. This suggests that telomere dynamics may reflect recent physiologically costly investment or variation in physiological condition, depending on the aspect of reproduction being investigated. Our results highlight the physiological complexity of vertebrate reproduction, and the need to better understand how and why different aspects of physiological variation underpinning life histories impact blood cell TL.

RevDate: 2021-09-11

Dhillon VS, Deo P, Chua A, et al (2021)

Sleep duration, Health Promotion Index (HPI), sRAGE and ApoE-ε4 genotype are associated with telomere length (TL) in healthy elderly Australians.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6368769 [Epub ahead of print].

Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular ageing. We examined the relationship between TL and sleep duration, Health Promotion Index (HPI), and tested whether the presence of ApoE-ε4 allele impacts both sleep and TL. The present study was carried out in 174 healthy elderly subjects (21% male; mean age 53.79 years) from South Australia. Lymphocyte telomere length (TL) was measured by real-time qPCR and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = - 0.199; p = 0.008) and BMI (r = - 0.121; p = 0.11), and was significantly shorter in participants who slept for <7 hours (p = 0.001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = 0.009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = 0.01) compared to non-carriers. Plasma sRAGE level was significantly (p = 0.001) lower in individuals who sleep <7 hours and ApoE-ϵ4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal elderly people and that carriage of APOE-ε4 genotype may influence the extent of these effects.

RevDate: 2021-09-10

Shin HK, Park JH, Yu JH, et al (2021)

Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease.

Scientific reports, 11(1):18004.

Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p < 0.001) with age, regardless of NAFLD status. Therefore, telomere length was corrected for age. Age-adjusted telomere length than decreased gradually with an increasing severity of fibrosis in patients with NAFLD (p < 0.028). In multivariate analysis, age-adjusted telomere length (odds ratio [OR] 0.59; 95% CI 0.37-0.92; p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80-0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.

RevDate: 2021-09-08

Lin A, Mertens AN, Arnold BF, et al (2021)

Telomere length is associated with growth in children in rural Bangladesh.

eLife, 10: pii:60389 [Epub ahead of print].

Background: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.

Methods: We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders.

Results: In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score (95% CI 0.05, 0.42; FDR-corrected p-value = 0.01)). TL was not associated with other outcomes.

Conclusions: Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first two years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories.

Funding: Funded by the Bill and Melinda Gates Foundation.

RevDate: 2021-09-08

Belser C, Baurens FC, Noel B, et al (2021)

Telomere-to-telomere gapless chromosomes of banana using nanopore sequencing.

Communications biology, 4(1):1047.

Long-read technologies hold the promise to obtain more complete genome assemblies and to make them easier. Coupled with long-range technologies, they can reveal the architecture of complex regions, like centromeres or rDNA clusters. These technologies also make it possible to know the complete organization of chromosomes, which remained complicated before even when using genetic maps. However, generating a gapless and telomere-to-telomere assembly is still not trivial, and requires a combination of several technologies and the choice of suitable software. Here, we report a chromosome-scale assembly of a banana genome (Musa acuminata) generated using Oxford Nanopore long-reads. We generated a genome coverage of 177X from a single PromethION flowcell with near 17X with reads longer than 75 kbp. From the 11 chromosomes, 5 were entirely reconstructed in a single contig from telomere to telomere, revealing for the first time the content of complex regions like centromeres or clusters of paralogous genes.

RevDate: 2021-09-08

Shi S, Zhou Y, Lu Y, et al (2021)

Ccq1-Raf2 interaction mediates CLRC recruitment to establish heterochromatin at telomeres.

Life science alliance, 4(11): pii:4/11/e202101106.

Telomeres, highly ordered DNA-protein complexes at eukaryotic linear chromosome ends, are specialized heterochromatin loci conserved among eukaryotes. In Schizosaccharomyces pombe, the shelterin complex is important for subtelomeric heterochromatin establishment. Despite shelterin has been demonstrated to mediate the recruitment of the Snf2/histone deacetylase-containing repressor complex (SHREC) and the Clr4 methyltransferase complex (CLRC) to telomeres, the mechanism involved in telomeric heterochromatin assembly remains elusive due to the multiple functions of the shelterin complex. Here, we found that CLRC plays a dominant role in heterochromatin establishment at telomeres. In addition, we identified a series of amino acids in the shelterin subunit Ccq1 that are important for the specific interaction between Ccq1 and the CLRC subunit Raf2. Finally, we demonstrated that the Ccq1-Raf2 interaction is essential for the recruitment of CLRC to telomeres, that contributes to histone H3 lysine 9 methylation, nucleosome stability and the shelterin-chromatin association, promoting a positive feedback mechanism for the nucleation and spreading of heterochromatin at subtelomeres. Together, our findings provide a mechanistic understanding of subtelomeric heterochromatin assembly by shelterin-dependent CLRC recruitment to chromosomal ends.

RevDate: 2021-09-07

Rolles B, Gorgulho J, Tometten M, et al (2021)

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.

Frontiers in oncology, 11:729207.

Background: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.

Methods: Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.

Results: ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.

Conclusion: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.

RevDate: 2021-09-07

Yang L, Wang B, Jiao X, et al (2021)

TAZ maintains telomere length in TNBC cells by mediating Rad51C expression.

Breast cancer research : BCR, 23(1):89.

BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells.

METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism.

RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication.

CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.

RevDate: 2021-09-06

Dogan F, NR Forsyth (2021)

Epigenetic features in regulation of telomeres and telomerase in stem cells.

Emerging topics in life sciences pii:229723 [Epub ahead of print].

The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.

RevDate: 2021-09-06

Hu K, Ghandi M, FW Huang (2021)

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines.

eLife, 10: pii:66198 [Epub ahead of print].

In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

RevDate: 2021-09-06

Peng X, Huang J, Xia S, et al (2021)

Association of leukocyte telomere length with metabolic syndrome in type 2 diabetes mellitus.

Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 26:43 pii:JRMS-26-43.

Background: Leukocyte telomere length (LTL) has been revealed to be associated with aging-related diseases such as metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM). We aimed to investigate the correlation of LTL with MetS and its components in T2DM patients in this cross-sectional study.

Materials and Methods: A total of 344 T2DM patients were enrolled into this study. LTL was measured by Southern blot-based terminal restriction fragment length analysis. MetS was clinically defined by 2007 Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults.

Results: Of 344 T2DM patients, 53% had MetS. T2DM patients with MetS had significantly longer LTL than those without MetS (6451.95 ± 51.10 base pairs vs. 6076.13 ± 55.13 base pairs, P < 0.001), especially when T2DM patients had poor glycemic control (hemoglobin A1c ≥7%). Meanwhile, the trend of longer LTL was associated with the increased components of MetS in T2DM patient. Finally, LTL had a significant association with MetS (odds ratio [OR]: 2.096, 95% confidence interval [CI] 1.337-3.285, P = 0.001), low levels of high-density lipoprotein-cholesterol (HDL-C) (OR: 2.412, 95% CI 1.350-4.308, P = 0.003) in T2DM patients.

Conclusion: T2DM patients with MetS had a significantly longer LTL than those without MetS. The longer LTL was especially evident in T2DM patients with poor glycemic control. Longer LTL was positively associated with MetS, particularly low levels of HDL-C in T2DM patients.

RevDate: 2021-09-05

Darvishi FZ, M Saadat (2021)

Morphine treatment is associated with diminished telomere length together with down-regulated TERT and TERF2 mRNA levels.

Drug and alcohol dependence, 227:108982 pii:S0376-8716(21)00477-4 [Epub ahead of print].

BACKGROUND: Drug dependence promotes accelerated aging and higher mortality compare with the general population. Telomere length is a biomarker of determination of cellular aging. Telomere attrition has been reported in heroin dependent patients. To investigate whether telomere length is affected by morphine or not, the expressions of hTERT and TERF2 in morphine treated human SH-SY5Y cells were determined and compared with untreated cells.

METHODS: The SH-SY5Y cells were treated with 1 and 5 μM concentrations of morphine for different exposure times (1d, 2d, 3d, 7d and 60 days). The mRNA levels of hTERT and TERF2 were determined using quantitative real-time RCR. The relative telomere length was measured as the ratio of telomere/36B4.

RESULTS: The hTERT and TERF2 mRNA levels were down regulated in morphine treated cells as a function of exposure duration. These alterations were reversible if morphine was removed from the culture medium. No reduction in the relative expression of hTERT and TERF2 in the cells exposed to N-acetyl cysteine (NAC) plus morphine was observed. In the SH-SY5Y cells treated by 5 μM morphine for 60 consecutive days, the hTERT and TERF2 mRNA levels and relative telomere lengths remarkably decreased.

CONCLUSIONS: Reversible alteration of mRNA levels by removing morphine from culture medium, and effect of NAC in co-treatment of morphine plus NAC, emphasize the role of reactive oxygen species in down-regulation of the expression of hTERT and TERF2 by morphine. Telomere attrition in morphine treated cells is a consequence of down-regulation of the expression of hTERT and TERF2.

RevDate: 2021-09-03

Atema E, van Noordwijk AJ, S Verhulst (2021)

Telomere dynamics in relation to experimentally increased locomotion costs and fitness in great tits.

Molecular ecology [Epub ahead of print].

Evidence that telomere length (TL) and dynamics can be interpreted as proxy for 'life stress' experienced by individuals stems largely from correlational studies. We tested for effects of an experimental increase of workload on telomere dynamics by equipping male great tits (Parus major) with a 0.9 gram backpack for a full year. In addition, we analysed associations between natural life-history variation, TL and TL dynamics. Carrying 5% extra weight for a year did not significantly accelerate telomere attrition. This agrees with our earlier finding that this experiment did not affect survival or future reproduction. Apparently, great tit males were able to compensate behaviourally or physiologically for the increase in locomotion costs we imposed. We found no cross-sectional association between reproductive success and TL, but individuals with higher reproductive success (number of recruits) lost fewer telomere base pairs in the subsequent year. We used the TRF method to measure TL, which method yields a TL distribution for each sample, and the association between reproductive success and telomere loss was more pronounced in the higher percentiles of the telomere distribution, in agreement with the higher impact of ageing on longer telomeres within individuals. Individuals with longer telomeres and less telomere shortening were more likely to survive to the next breeding season, but these patterns did not reach statistical significance. Whether successful individuals are characterized by losing fewer or more base pairs from their telomeres varies between species, and we discuss aspects of ecology and social organisation that may explain this variation.

RevDate: 2021-09-03

Saunders CN, Kinnersley B, Culliford R, et al (2021)

Relationship between genetically determined telomere length and glioma risk.

Neuro-oncology pii:6363706 [Epub ahead of print].

BACKGROUND: Telomere maintenance is increasingly recognised as being fundamental to glioma oncogenesis with longer leucocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma we conducted several complementary analyses, using GWAS data on LTL (78,592 individuals) and glioma (12,488 cases and 18,169 controls).

METHODS: We performed both classical and Summary Mendelian Randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations we analysed gene expression and DNA methylation data.

RESULTS: Genetically increased LTL was significantly associated with increased glioma risk, IVW-RE ORSD 4.79 (95% CI: 2.11-10.85, P = 1.76 × 10 -4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10 -5), 5p15.33 (TERT; PSMR = 9.80 × 10 -27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10 -5) and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10 -4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10 -2), 6p21.3 (PSMR = 9.76 × 10 -3), 6p22.2 (PSMR = 5.45 × 10 -3), 7q31.33 (PSMR = 6.52 × 10 -3) and 11q22.3 (PSMR = 8.89 × 10 -4) as risk factors for glioma risk. Whilst complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1 and ATM-NPAT1 was implicated in the aetiology of glioma.

CONCLUSIONS: These observations extend the role of telomere-related genes in the development of glioma.

RevDate: 2021-09-03

Purdue-Smithe AC, Kim K, Andriessen VC, et al (2021)

Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.

Human reproduction (Oxford, England) pii:6363634 [Epub ahead of print].

STUDY QUESTION: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses?

SUMMARY ANSWER: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth.

WHAT IS KNOWN ALREADY: As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case-control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking.

STUDY DESIGN, SIZE, DURATION: Participants included 1228 women aged 18-40 years with a history of 1-2 prior pregnancy losses who were recruited at four university medical centers (2006-2012).

Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models.

After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62).

Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35 years, limiting our ability to evaluate associations among older women. Participants had a history of 1-2 prior pregnancy losses; therefore, our findings may not be widely generalizable.

Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception.

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose.

TRIAL REGISTRATION NUMBER: The trial was registered with, number NCT00467363.

RevDate: 2021-09-01

Pennarun G, Picotto J, Etourneaud L, et al (2021)

Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells.

Nucleic acids research pii:6362072 [Epub ahead of print].

Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.

RevDate: 2021-09-01

Abbasalizad-Farhangi M (2021)

Central obesity accelerates leukocyte telomere length (LTL) shortening in apparently healthy adults: A systematic review and meta-analysis.

Critical reviews in food science and nutrition [Epub ahead of print].

Shorter telomere length is associated with numerous comorbidities; central obesity might trigger leukocyte telomere shortening; in the current meta-analysis we evaluated the association of central obesity with leukocyte telomere length among adults. A systematic search from Scopus, PubMed, Embase and Proquest electronic databases up to May 2021 was done. The final screening, provided five articles to be included in final meta-analysis. Those in the highest category of telomere length had 3.72 cm lower waist circumference (WC) compared with those in the lowest category (WMD=-3.718; CI=-7.180, -0.257 P = 0.035; I2 = 95.4%). Also, those in the highest LTL category had 0.02 lower waist to hip ratio (WHR) compared with those in the lowest category, although this association was not significant (WMD: -0.02; CI=-0.04, 0.01; P = 0.19; I2= 90.7%). In quality assessment of included studies, all of the studies had moderate or high quality score and there was no study with poor quality. Higher leukocyte telomere length was accompanied with lower WC among adults. This association was not significant for difference in WHR. Because of the high heterogeneity values and also because of the observational design of included studies, the inference of causality of these associations needs further investigations.Supplemental data for this article is available online at .

RevDate: 2021-08-30

Hailu EM, Lewis TT, Needham BL, et al (2021)

Longitudinal Associations Between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6324315 [Epub ahead of print].

BACKGROUND: We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in leukocyte telomere length (LTL).

METHODS: Data are from the Multi-Ethnic Study of Atherosclerosis (N = 1064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, ≥2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract-defined neighborhoods. 10-year change in LTL was defined as regression to the mean-corrected 10-year difference in the ratio of telomeric DNA to a single-copy gene (T/S).

RESULTS: In linear mixed-effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(χ 2) = .01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in ≥2 domains was associated with faster LTL attrition over 10 years, compared to reporting no discrimination (β = -0.03; 95% confidence interval: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion.

CONCLUSIONS: Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.

RevDate: 2021-08-29

Kärkkäinen T, Briga M, Laaksonen T, et al (2021)

Within-individual repeatability in telomere length: a meta-analysis in non-mammalian vertebrates.

Molecular ecology [Epub ahead of print].

Telomere length is increasingly used as a biomarker of long-term somatic state and future survival prospects. While most studies have overlooked this aspect, biological interpretations based on a given telomere length will benefit from considering the level of within-individual repeatability of telomere length through time. Therefore, we conducted a meta-analysis on 74 longitudinal studies in non-mammalian vertebrates, with the aim to establish the current pattern of within-individual repeatability in telomere length and to identify the methodological (e.g. qPCR/TRF) and biological factors (e.g. age class, phylogeny) that may affect it. While the median within-individual repeatability of telomere length was moderate to high (R = 0.55; 95% CI: 0.05-0.95; N = 82), marked heterogeneity between studies was evident. Measurement method affected the repeatability estimate strongly, with TRF-based studies exhibiting high repeatability (R = 0.80; 95% CI: 0.34-0.96; N = 25), while repeatability of qPCR-based studies was markedly lower and more variable (R = 0.46; 95% CI: 0.04-0.82; N = 57). While phylogeny explained some variance in repeatability, phylogenetic signal was not significant (λ = 0.32; 95% CI: 0.00-0.83). None of the biological factors investigated here significantly explained variation in the repeatability of telomere length, being potentially obscured by methodological differences. Our meta-analysis highlights the high variability in within-individual repeatability estimates between studies and the need to put more effort into separating technical and biological explanations. This is important to better understand to what extent biological factors can affect the repeatability of telomere length and thus the interpretation of telomere length data.

RevDate: 2021-08-29

Bolzán AD (2021)

Mutagen-induced telomere instability in human cells.

Mutation research, 868-869:503387.

Telomere instability is one of the main sources of genome instability and may result from chromosome end loss (due to chromosome breakage at one or both ends) or, more frequently, telomere dysfunction. Dysfunctional telomeres arise when they lose their end-capping function or become critically short, which causes chromosomal termini to behave like a DNA double-strand break. Telomere instability may occur at the chromosomal or at the molecular level, giving rise, respectively, to telomere-related chromosomal aberrations or the loss or modification of any of the components of the telomere (telomere DNA, telomere-associated proteins, or telomere RNA). Since telomeres play a fundamental role in maintaining genome stability, the study of telomere instability in cells exposed to mutagens is of great importance to understand the telomere-driven genomic instability present in those cells. In the present review, we will focus on the current knowledge about telomere instability induced by physical, chemical, and biological mutagens in human cells.

RevDate: 2021-08-29

Bull C, Mayrhofer G, M Fenech (2021)

Exposure to hypomethylating 5-aza-2'-deoxycytidine (decitabine) causes rapid, severe DNA damage, telomere elongation and mitotic dysfunction in human WIL2-NS cells.

Mutation research, 868-869:503385.

BACKGROUND: 5-aza-2'-deoxycytidine (5azadC, decitabine) is a DNA hypomethylating agent used in the treatment of myelodysplastic syndromes. Due to cytotoxic side effects dose optimization is essential. The aim of this study was to define and quantify the effects of 5azadC on biomarkers of chromosomal stability, and telomere length, in human lymphoblastoid cell line, WIL2-NS, at clinically relevant dosages.

METHODS: Human WIL2-NS cells were maintained in complete medium containing 0, 0.2 or 1.0 μM 5azadC for four days, and analysed daily for telomere length (flow cytometry), chromosomal stability (cytokinesis-block micronucleus cytome (CBMN-cyt) assay), and global methylation (%5me-C).

RESULTS: DNA methylation decreased significantly in 1.0 μM 5azadC, relative to control (p < 0.0001). Exposure to 1.0 μM 5azadC resulted in 1.7-fold increase in telomere length (p < 0.0001), in parallel with rapid increase in biomarkers of DNA damage; (micronuclei (MN, 6-fold increase), nucleoplasmic bridges (NPB, a 12-fold increase), and nuclear buds (NBud, a 13-fold increase) (all p < 0.0001). Fused nuclei (FUS), indicative of mitotic dysfunction, showed a 5- and 13-fold increase in the 0.2 μM and 1.0 μM conditions, respectively (p = 0.001) after 4 days.

CONCLUSIONS: These data show that (i) clinically relevant concentrations of 5azadC are highly genotoxic; (ii) hypomethylation was associated with increased TL and DNA damage; and (iii) longer TL was associated with chromosomal instability. These findings suggest that lower doses of 5azdC may be effective as a hypomethylating agent, while potentially reducing DNA damage and risk for secondary disease.

RevDate: 2021-08-29

Clarity C, Trowbridge J, Gerona R, et al (2021)

Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.

Environmental health : a global access science source, 20(1):97.

BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA.

METHODS: We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length.

RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (- 0.14(- 0.28, - 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding.

CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

RevDate: 2021-08-28

Li B, Y Zhao (2021)

Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities.

Pathogens (Basel, Switzerland), 10(8): pii:pathogens10080967.

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1's nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.

RevDate: 2021-08-27

Gleason JL, Thoma ME, Zukerman Willinger N, et al (2021)

Endometriosis and Uterine Fibroids and Their Associations with Elevated C-Reactive Protein and Leukocyte Telomere Length Among a Representative Sample of U.S. Women: Data from the National Health and Nutrition Examination Survey, 1999-2002.

Journal of women's health (2002) [Epub ahead of print].

Background: Recent studies have suggested a link between reproductive health and later-life chronic conditions, yet the mechanism remains unclear. One proposed mechanism is through chronic inflammation. The objective of this study was to examine the association between endometriosis and uterine fibroids and biomarkers of inflammation and cellular aging. Materials and Methods: We used data from the National Health and Nutrition Examination Survey (N = 2342; 1999-2002). Adjusted logistic and linear regression were used to examine the association between these two reproductive conditions and elevated C-reactive protein (CRP; >3.0 mg/L) and leukocyte telomere length (T/S ratio), respectively. Given that a greater length of time spent with a condition may represent persistence of an inflammatory process, we further examined the association between time since disease diagnosis on telomere length among the subset of women with diagnosed endometriosis and fibroids. Results: Women with endometriosis had greater odds of having elevated CRP than those without endometriosis (OR = 1.60; 95% CI: 1.05 to 2.45). Women with endometriosis had a shorter telomere length than women without endometriosis (-3.4, 95% CI: -7.3 to -0.3 in age-adjusted models and -2.9, 95% CI: -8.8 to 3.5 in fully adjusted models). Telomeres were 1% (95% CI: -1.2 to -0.6) shorter for every elapsed year since endometriosis diagnosis. No substantive patterns emerged between uterine fibroids and CRP or telomere length. Conclusions: Women with endometriosis (or a longer duration of time spent with endometriosis) had higher inflammatory markers and shorter mean telomere length. These results provide further insights into potential mechanisms linking endometriosis to chronic disease and later-life health.

RevDate: 2021-08-27

Friesen CR, Wapstra E, M Olsson (2021)

Of telomeres and temperature: measuring thermal effects on telomeres in ectothermic animals.

Molecular ecology [Epub ahead of print].

Ectotherms are classic models for understanding life-history tradeoffs, including the reproduction-somatic maintenance tradeoffs that may be reflected in telomere length and their dynamics. Importantly, life-history traits of ectotherms are tightly linked to their thermal environment, with diverse or synergistic mechanistic explanations underpinning the variation. Telomere dynamics potentially provide a mechanistic link that can be used to monitor thermal effects on individuals in response to climatic perturbations. Growth rate, age and developmental stage are all affected by temperature, which interacts with telomere dynamics in complex and intriguing ways. The physiological processes underpinning telomere dynamics can be visualized and understood using thermal performance curves (TPC). TPCs reflect the evolutionary history and the thermal environment during an individual's ontogeny. Telomere maintenance should be enhanced at or near the thermal performance optimum of a species, population and individual. The thermal sensitivity of telomere dynamics should reflect the interacting TPCs of the processes underlying them. The key processes directly underpinning telomere dynamics are mitochondrial function (reactive oxygen production), antioxidant activity, telomerase activity and telomere endcap protein status. We argue that identifying TPCs for these processes will significantly help design robust, repeatable experiments and field studies of telomere dynamics in ectotherms. Conceptually, TPCs are a valuable framework to predict and interpret taxon- and population-specific telomere dynamics across thermal regimes. The literature of thermal effects on telomeres in ectotherms is sparse and mostly limited to vertebrates, but our conclusions and recommendations are relevant across ectothermic animals.

RevDate: 2021-08-27

Anonymous (2021)

Retraction statement: Wang Z, Li J, Liu J, Wang L, Lu Y, Liu J-P. Molecular insight into the selective binding between human telomere G-quadruplex, a negatively charged stabilizer. Clin Exp Pharmacol Physiol. 2020;47:892-902.

Clinical and experimental pharmacology & physiology, 48(9):1300.

RevDate: 2021-08-27

Womersley JS, Spies G, Tromp G, et al (2021)

Longitudinal telomere length profile does not reflect HIV and childhood trauma impacts on cognitive function in South African women.

Journal of neurovirology [Epub ahead of print].

HIV-associated neurocognitive disorders (HAND) present a challenge in South Africa where the burden of HIV infection is the highest. Identification of biological correlates of HAND is required to improve diagnosis and inform interventions. Telomeres maintain genomic integrity and their shortening is a marker of biological aging sensitive to environmental influences. This study examined relative telomere length (rTL) as a predictor of cognitive function in the context of HIV and childhood trauma (CT), a risk factor for HAND. Two hundred and eighty-six women completed a neurocognitive assessment battery and the Childhood Trauma Questionnaire-Short Form (CTQ). Quantitative polymerase chain reaction for amplification of telomeric repeats and the reference gene human beta-globin was used to calculate rTL. Neurocognitive and rTL assessments were repeated at 1 year in 110 participants. Cross-sectional and longitudinal data were assessed using linear and mixed models, respectively. Participants with HIV (n = 135 in cross-sectional and n = 62 in longitudinal study groups) reported more severe CT and had shorter baseline rTL compared to seronegative controls. Participants without HIV had a greater 1-year decline in rTL. Global cognitive and attention/working memory scores declined in participants with HIV. Our data indicate that baseline rTL in the context of CT and HIV did not predict decline in cognitive scores. HIV-associated pathophysiological processes driving cognitive decline may also engage mechanisms that protect against telomere shortening. The results highlight the importance of examining biological correlates in longitudinal studies.

RevDate: 2021-08-27

Salehian S, Semple T, R Pabary (2021)

Childhood interstitial lung disease: short lessons from telomeres.

Thorax pii:thoraxjnl-2021-217479 [Epub ahead of print].

RevDate: 2021-08-27

Paltoglou G, Raftopoulou C, Nicolaides NC, et al (2021)

A Comprehensive, Multidisciplinary, Personalized, Lifestyle Intervention Program Is Associated with Increased Leukocyte Telomere Length in Children and Adolescents with Overweight and Obesity.

Nutrients, 13(8): pii:nu13082682.

Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females; 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.

RevDate: 2021-08-27

Ruiz-Narváez EA, Baylin A, Azofeifa J, et al (2021)

Diet and Leukocyte Telomere Length in a Population with Extended Longevity: The Costa Rican Longevity and Healthy Aging Study (CRELES).

Nutrients, 13(8): pii:nu13082585.

Elderly Costa Ricans have lower mortality rates compared to their counterparts from developed countries. Reasons for this survival advantage are not completely known. In the present study, we aimed to identify dietary factors associated with leukocyte telomere length (LTL), a marker of biologic aging, in the elderly population of Costa Rica. We conducted prospective analysis in 909 participants aged 60+ years from the Costa Rican Longevity and Healthy Aging Study (CRELES). We used a food frequency questionnaire to assess usual diet. We calculated dietary patterns using Principal Component Analysis (PCA). We used generalized linear models to examine the association of dietary patterns and food groups with leukocyte telomere length. We found two major dietary patterns explaining 9.15% and 7.18% of the total variation of food intake, respectively. The first dietary pattern, which represents a traditional Costa Rican rice and beans pattern, was more frequent in rural parts of the country and was positively associated with baseline LTL: β (95% CI) = 42.0 base-pairs (bp) (9.9 bp, 74.1 bp) per one-unit increase of the traditional dietary pattern. In analysis of individual food groups, intake of grains was positively associated with baseline LTL: β (95% CI) = 43.6 bp (13.9 bp, 73.3 bp) per one-serving/day increase of consumption of grains. Our results suggest that dietary factors, in particular a traditional food pattern, are associated with telomere length and may contribute to the extended longevity of elderly Costa Ricans.

RevDate: 2021-08-27

Pavanello S, Campisi M, Grassi A, et al (2021)

Longer Leukocytes Telomere Length Predicts a Significant Survival Advantage in the Elderly TRELONG Cohort, with Short Physical Performance Battery Score and Years of Education as Main Determinants for Telomere Elongation.

Journal of clinical medicine, 10(16): pii:jcm10163700.

Leukocyte telomere length (LTL) represents a key integrating component of the cumulative effects of environmental, lifestyle, and genetic factors. A question, however, remains on whether LTL can be considered predictive for a longer and healthier life. Within the elderly prospective TRELONG cohort (n = 612), we aimed to investigate LTL as a predictor of longevity and identify the main determinants of LTL among many different factors (physiological and lifestyle characteristics, physical performance and frailty measures, chronic diseases, biochemical measurements and apolipoprotein E genotyping). We found an ever-increasing relationship between LTL quartiles and survival. Hazard ratio analysis showed that for each unit increase in LTL and Short Physical Performance Battery (SPPB) scores, the mortality risk was reduced by 22.41% and 8.78%, respectively. Conversely, male gender, Charlson Comorbidity Index, and age threatened survival, with mortality risk growing by 74.99%, 16.57% and 8.5%, respectively. Determinants of LTL elongation were SPPB scores (OR = 1.1542; p = 0.0066) and years of education (OR = 1.0958; p = 0.0065), while male gender (OR = 0.4388; p = 0.0143) and increased Disease Count Index (OR = 0.6912; p = 0.0066) were determinants of LTL attrition. Longer LTL predicts a significant survival advantage in elderly people. By identifying determinants of LTL elongation, we provided additional knowledge that could offer a potential translation into prevention strategies.

RevDate: 2021-08-27

Kordowitzki P (2021)

Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors.

Cells, 10(8): pii:cells10081866.

Research from the past decades provided strong evidence that in humans the pool of oocytes starts to decline already before the birth of a female individual, and from menarche to menopause the oocyte is exposed to different environmental stimuli. Since more and more women of the 21st century in developed countries wish to postpone the first pregnancy to their thirties, higher rates of miscarriage and chromosomal non-disjunction might occur. In oocytes of advanced maternal age, meaning above 35 years of age, characteristics such as chromosomal instabilities/abnormalities, spindle defects, decreased mitochondrial function and telomere shortening become more prevalent than in younger counterparts. Telomere attrition belongs to the so-called "hallmarks of aging" which are also relevant for the female germ-line cells. In oocytes, telomeres shorten with advancing maternal age due to the effects of reactive oxygen species and not upon replicative senescence, similar to how it is common in dividing cells.

RevDate: 2021-08-27

Carugno M, Borroni E, Fedrizzi L, et al (2021)

Long- and Short-Term Exposures to PM10 Can Shorten Telomere Length in Individuals Affected by Overweight and Obesity.

Life (Basel, Switzerland), 11(8): pii:life11080808.

Reduced telomere length (TL) has been associated with increased risk of age-related diseases, most likely through oxidative stress and inflammation, which have also been claimed as mechanisms underlying health effects of air pollution exposure. We aimed to verify whether exposure to particulate matter with diameter ≤10 µm (PM10) affects TL. We recruited 1792 participants with overweight/obesity in Milan (Italy) in 2010-2015 who completed a structured questionnaire on sociodemographic data, gave a blood sample for TL measurement by real-time PCR, and were assigned air pollution and meteorological data of their residential address. In multivariate mixed-effects linear models (with a random intercept on PCR plate), we observed a -0.51% change in TL (95% confidence interval (CI): -0.98; -0.05)) per 10 µg/m3 increase in PM10 at the day of recruitment. A similar decreasing trend in TL was observed up to two weeks before withdrawal, with percentage changes as low as -1.53% (average exposure of the 12 days before recruitment). Mean annual exposure to PM10 was associated with -2.57% TL reduction (95%CI: -5.06; -0.08). By showing consistent associations between short- and long-term PM10 exposures and reduced TL, our findings shed light on the potential mechanisms responsible for the excess of age-related diseases associated with air pollution exposure.

RevDate: 2021-08-27

Akter J, T Kamijo (2021)

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?.

Biomolecules, 11(8): pii:biom11081112.

Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.

RevDate: 2021-08-26

Remot F, Ronget V, Froy H, et al (2021)

Decline in telomere length with increasing age across non-human vertebrates: a meta-analysis.

Molecular ecology [Epub ahead of print].

The prediction that telomere length (TL) shortens with increasing age is a major element in considering the role of telomeres as a key player in evolution. While telomere attrition is found in humans both in vitro and in vivo, the increasing number of studies reporting diverse age-specific patterns of TL challenges the hypothesis of a universal decline of TL with increasing age. Here we performed a meta-analysis to estimate the relationship between TL and age across 175 estimates encompassing 98 species of vertebrates. We found that, on average, TL does decline with increasing age during adulthood. However, this decline was weak and variable across vertebrate classes, and we also found evidence for a publication bias that might weaken our current evidence of decreasing TL with increasing age. We found no evidence for a faster decline in TL with increasing age when considering the juvenile stage (from birth to age at first reproduction) compared to the adult stage. Heterogeneity in TL ageing rates was explained by the method used to measure telomeres: detectable TL declines with increasing age were found only among studies using TRF with in-gel hybridisation and qFISH methods, but not in studies using qPCR and Southern blot-based TRF methods. While we confirmed that TL declines with increasing age in most adult vertebrates, our results identify an influence of telomere measurement methodology, which highlights the need to examine more thoroughly the effect of the method of measurement on TL estimates.

RevDate: 2021-08-26

Anonymous (2019)

RAD51AP1 Promotes Maintenance of Telomere Length in ALT+ Cancer Cells.

Cancer discovery, 9(10):1339.

Cancer cells using alternative lengthening of telomeres (ALT) require RAD51AP for telomere maintenance.

RevDate: 2021-08-26

Glousker G, J Lingner (2021)

Challenging endings: How telomeres prevent fragility.

BioEssays : news and reviews in molecular, cellular and developmental biology [Epub ahead of print].

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so-called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions.

RevDate: 2021-08-26

Metcalfe NB, M Olsson (2021)

How telomere dynamics are influenced by the balance between mitochondrial efficiency, ROS production and DNA damage.

Molecular ecology [Epub ahead of print].

It is well known that oxidative stress is a major cause of DNA damage and telomere attrition. Most endogenous Reactive Oxygen Species (ROS) are produced in the mitochondria, producing a link between mitochondrial function, DNA integrity and telomere dynamics. In this review we will describe how ROS production, rates of damage to telomeric DNA and DNA repair are dynamic processes. The rate of ROS production depends on mitochondrial features such as the level of inner membrane uncoupling and the proportion of time that ATP is actively being produced. However, the efficiency of ATP production (the ATP/O ratio) is positively related to the rate of ROS production, so leading to a trade-off between the body's energy requirements and its need to prevent oxidative stress. Telomeric DNA is especially vulnerable to oxidative damage due to features such as its high guanine content; while repair to damaged telomere regions is possible through a range of mechanisms, these can result in more rapid telomere shortening. There is increasing evidence that mitochondrial efficiency varies over time and with environmental context, as do rates of DNA repair. We argue that telomere dynamics can only be understood by appreciating that the optimal solution to the trade-off between energetic efficiency and telomere protection will differ between individuals and will change over time, depending on resource availability, energetic demands and life history strategy.

RevDate: 2021-08-26

Rahnama M, Wang B, Dostart J, et al (2021)

Telomere Roles in Fungal Genome Evolution and Adaptation.

Frontiers in genetics, 12:676751.

Telomeres form the ends of linear chromosomes and usually comprise protein complexes that bind to simple repeated sequence motifs that are added to the 3' ends of DNA by the telomerase reverse transcriptase (TERT). One of the primary functions attributed to telomeres is to solve the "end-replication problem" which, if left unaddressed, would cause gradual, inexorable attrition of sequences from the chromosome ends and, eventually, loss of viability. Telomere-binding proteins also protect the chromosome from 5' to 3' exonuclease action, and disguise the chromosome ends from the double-strand break repair machinery whose illegitimate action potentially generates catastrophic chromosome aberrations. Telomeres are of special interest in the blast fungus, Pyricularia, because the adjacent regions are enriched in genes controlling interactions with host plants, and the chromosome ends show enhanced polymorphism and genetic instability. Previously, we showed that telomere instability in some P. oryzae strains is caused by novel retrotransposons (MoTeRs) that insert in telomere repeats, generating interstitial telomere sequences that drive frequent, break-induced rearrangements. Here, we sought to gain further insight on telomeric involvement in shaping Pyricularia genome architecture by characterizing sequence polymorphisms at chromosome ends, and surrounding internalized MoTeR loci (relics) and interstitial telomere repeats. This provided evidence that telomere dynamics have played historical, and likely ongoing, roles in shaping the Pyricularia genome. We further demonstrate that even telomeres lacking MoTeR insertions are poorly preserved, such that the telomere-adjacent sequences exhibit frequent presence/absence polymorphism, as well as exchanges with the genome interior. Using TERT knockout experiments, we characterized chromosomal responses to failed telomere maintenance which suggested that much of the MoTeR relic-/interstitial telomere-associated polymorphism could be driven by compromised telomere function. Finally, we describe three possible examples of a phenomenon known as "Adaptive Telomere Failure," where spontaneous losses of telomere maintenance drive rapid accumulation of sequence polymorphism with possible adaptive advantages. Together, our data suggest that telomere maintenance is frequently compromised in Pyricularia but the chromosome alterations resulting from telomere failure are not as catastrophic as prior research would predict, and may, in fact, be potent drivers of adaptive polymorphism.

RevDate: 2021-08-25

Kotah JM, Hoeijmakers L, Nutma E, et al (2021)

Early-life stress does not alter spatial memory performance, hippocampal neurogenesis, neuroinflammation, or telomere length in 20-month-old male mice.

Neurobiology of stress, 15:100379 pii:S2352-2895(21)00087-4.

Early-life stress (ES) increases the risk for psychopathology and cognitive decline later in life. Because the neurobiological substrates affected by ES (i.e., cognition, neuroplasticity, and neuroinflammation) are also altered in aging, we set out to investigate if and how ES in the first week of life affects these domains at an advanced age, and how ES modulates the aging trajectory per se. We subjected C57BL/6j mice to an established ES mouse model from postnatal days 2-9. Mice underwent behavioral testing at 19 months of age and were sacrificed at 20 months to investigate their physiology, hippocampal neuroplasticity, neuroinflammation, and telomere length. ES mice, as a group, did not perform differently from controls in the open field or Morris water maze (MWM). Hippocampal neurogenesis and synaptic marker gene expression were not different in ES mice at this age. While we find aging-associated alterations to neuroinflammatory gene expression and telomere length, these were unaffected by ES. When integrating the current data with those from our previously reported 4- and 10-month-old cohorts, we conclude that ES leads to a 'premature' shift in the aging trajectory, consisting of early changes that do not further worsen at the advanced age of 20 months. This could be explained e.g. by a 'floor' effect in ES-induced impairments, and/or age-induced impairments in control mice. Future studies should help understand how exactly ES affects the overall aging trajectory.

RevDate: 2021-08-24

Niu Z, Wen X, Buka SL, et al (2021)

Associations of telomere length at birth with predicted atherosclerotic lesions and cardiovascular disease risk factors in midlife: A 40-year longitudinal study.

Atherosclerosis, 333:67-74 pii:S0021-9150(21)01274-0 [Epub ahead of print].

BACKGROUND AND AIMS: Adult telomere length (TL) is substantially determined by birth TL, but associations of birth TL with cardiovascular disease (CVD) are unknown.

METHODS: We included 144 adult offspring born in 1959-1966 from the Collaborative Perinatal Project, a US birth cohort. Birth TL was measured from banked cord blood with quantitative polymerase chain reaction. Atherosclerotic lesions were predicted by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) score that was based on blood pressure, lipids, hemoglobin A1c, and body weight at the midlife follow-up in 2003-2008 (average age: 42 years). Information on midlife CVD risk factors including the age at first diagnoses of hypertension, hypercholesterolemia, and diabetes was also collected. We used linear and logistic regression models to analyze associations of birth TL with the continuous PDAY score and categorical CVD risk factors, respectively, adjusting for prenatal confounders.

RESULTS: At midlife follow-up, 31.2% and 18.7% of participants had ever been diagnosed with hypercholesterolemia and hypertension, respectively, and 8.3% met the criteria for metabolic syndrome. Short birth TL (Quartile 1, Q1) was associated with a higher PDAY score (adjusted β: 1.78, 95% CI: 0.31, 3.25), increased odds of hypercholesterolemia (adjusted odds ratio [OR]: 3.23, 95% CI: 1.28, 8.18) and the presence of any cardiometabolic abnormalities (adjusted OR: 2.54, 95% CI: 1.00, 6.48) as compared to longer birth TL (Q2-Q4) after adjusting for prenatal confounders.

CONCLUSIONS: People born with short TL may be at increased risk of predicted midlife atherosclerotic lesions and hypercholesterolemia. Future studies with larger sample sizes and CVD morbidities are warranted to replicate our findings.

RevDate: 2021-08-23

Sellami M, Bragazzi N, Prince MS, et al (2021)

Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.

Frontiers in genetics, 12:652497.

Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5'-TTAGGG n -3' tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

RevDate: 2021-08-19

Koneru B, Farooqi A, Nguyen TH, et al (2021)

ALT neuroblastoma chemoresistance due to telomere dysfunction-induced ATM activation is reversible with ATM inhibitor AZD0156.

Science translational medicine, 13(607):.

Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, P < 0.05; in vivo mouse event-free survival (EFS), P < 0.0001] vs. telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifested constitutive ataxia-telangiectasia mutated (ATM) activation due to spontaneous telomere dysfunction which was not observed in telomerase-positive neuroblastoma cells. We demonstrated that induction of telomere dysfunction resulted in ATM activation that, in turn, conferred resistance to temozolomide + SN-38 (4.2-fold change in IC50, P < 0.001). ATM knockdown (shRNA) or inhibition using a clinical-stage small-molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell lines in vitro (P < 0.001) and in four ALT xenografts in vivo (EFS, P < 0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. Ataxia telangiectasia and Rad3 related (ATR) inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cells. Thus, ALT neuroblastoma chemotherapy resistance occurs via ATM activation and is reversible with ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing for neuroblastoma.

RevDate: 2021-08-18

Jeon HJ, Kang M, Kim JS, et al (2021)

TCTP overexpression reverses age-associated telomere attrition by upregulating telomerase activity in mouse oocytes.

Journal of cellular physiology [Epub ahead of print].

A prolonged time span between ovulation and fertilization can cause postovulatory aging of oocytes, which impairs oocyte quality and subsequent embryo development. Telomere attrition has long been considered as the primary hallmark of aging or the cause of age-associated diseases. However, the status of telomere and its regulation during postovulatory oocyte aging are poorly understood. Here we found that oocytes experience telomere shortening during postovulatory aging, although they have the capacity to maintain telomere length. However, translationally controlled tumor protein (TCTP) overexpression could reverse age-associated telomere shortening by upregulating telomerase activity in mouse oocytes. Telomere length in mature oocytes gradually decreased with postovulatory aging, which was associated with a marked reduction in TRF1 expression, decreased telomerase activity, and decreased homologous combination (HR)-based alternative lengthening of telomeres (ALT) with a concomitant increase in oxidative stress. Surprisingly, however, overexpression of TCTP led to a remarkable increase in telomere length during postovulatory aging. Notably, neither TRF1 nor BRCA1 level was altered by TCTP overexpression. Moreover, TCTP-mediated telomere lengthening was not blocked by HR inhibition. In striking contrast, telomerase activity, as well as TERT and TERC levels, increased after TCTP overexpression. Importantly, unlike the chromosome-wide distribution of endogenous TCTP, overexpressed TCTP was ectopically localized at telomeres, implying that TCTP overexpression is required to increase telomerase activity. Collectively, our results demonstrate that TCTP prevents telomere attrition during postovulatory aging by upregulating telomerase activity in mouse oocytes.

RevDate: 2021-08-18

Geronimus AT, Bound J, Mitchell C, et al (2021)

Coming up short: Comparing venous blood, dried blood spots & saliva samples for measuring telomere length in health equity research.

PloS one, 16(8):e0255237 pii:PONE-D-21-03127.

BACKGROUND: Telomere length (TL) in peripheral blood mononuclear cells (PBMC) from fresh venous blood is increasingly used to estimate molecular impacts of accumulated social adversity on population health. Sometimes, TL extracted from saliva or dried blood spots (DBS) are substituted as less invasive and more scalable specimen collection methods; yet, are they interchangeable with fresh blood? Studies find TL is correlated across tissues, but have not addressed the critical question for social epidemiological applications: Do different specimen types show the same association between TL and social constructs?

METHODS: We integrate expertise in social epidemiology, molecular biology, and the statistical impact of measurement error on parameter estimates. Recruiting a diverse sample of 132 Metro-Detroit women, we measure TL for each woman from fresh blood PBMC, DBS, and saliva. Using regression methods, we estimate associations between social characteristics and TL, comparing estimates across specimen types for each woman.

RESULTS: Associations between TL and social characteristics vary by specimen type collected from the same woman, sometimes qualitatively altering estimates of the magnitude or direction of a theorized relationship. Being Black is associated with shorter TL in PBMC, but longer TL in saliva or DBS. Education is positively associated with TL in fresh blood, but negatively associated with TL using DBS.

CONCLUSION: Findings raise concerns about the use of TL measures derived from different tissues in social epidemiological research. Investigators need to consider the possibility that associations between social variables and TL may be systematically related to specimen type, rather than be valid indicators of socially-patterned biopsychosocial processes.

RevDate: 2021-08-18

Teixeira MZ (2021)

Telomere length: biological marker of cellular vitality, aging, and health-disease process.

Revista da Associacao Medica Brasileira (1992), 67(2):173-177.

The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.

RevDate: 2021-08-17

Singh M, Merwat SK, Fair JH, et al (2021)

Liver transplant recipient with respiratory failure due to pulmonary fibrosis related to telomere disease requiring lung transplantation.

Respiratory medicine case reports, 33:101443 pii:S2213-0071(21)00105-2.

Short telomere syndrome (STS) is characterized as multiorgan dysfunction presenting with unexplained cytopenias, cryptogenic cirrhosis and pulmonary fibrosis. We present a liver transplant recipient that gradually developed hypoxic respiratory failure attributed to idiopathic pulmonary fibrosis associated telomere disease that culminated in a successful single lung transplantation.

RevDate: 2021-08-16

Planas-Cerezales L, Arias-Salgado EG, Berastegui C, et al (2021)

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction.

Frontiers in medicine, 8:695919.

Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.

RevDate: 2021-08-16

Adibkia K, Ehsani A, Jodaei A, et al (2021)

Silver nanoparticles induce the cardiomyogenic differentiation of bone marrow derived mesenchymal stem cells via telomere length extension.

Beilstein journal of nanotechnology, 12:786-797.

Finding new strategies for the treatment of heart failures using stem cells has attracted a lot of attention. Meanwhile, nanotechnology-based approaches to regenerative medicine hypothesize a possible combination of stem cells and nanotechnology in the treatment of diseases. This study aims to investigate the in vitro effect of silver nanoparticles (Ag-NPs) on the cardiomyogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) through detection of cardiac markers. For this purpose, MSCs were isolated from bone marrow resident and differentiated to the cardiac cells using a dedicated medium with Ag-NPs. Also, the cardiomyogenic differentiation of BM-MSCs was confirmed using immunocytochemistry. Then, real-time PCR and western blotting assay were used for measuring absolute telomere length (TL) measurement, and gene and protein assessment of the cells, respectively. It was found that 2.5 µg/mL Ag-NPs caused elongation of the telomeres and altered VEGF, C-TnI, VWF, SMA, GATA-4, TERT, and cyclin D protein and gene expression in the cardiomyogenically differentiated BM-MSCs. Also, there was a significant increase in the protein and gene expression of Wnt3 and β-catenin as main components of pathways. We concluded that Ag-NPs could change the in vitro expression of cardiac markers of BM-MSCs via the Wnt3/β-catenin signaling pathway.

RevDate: 2021-08-16

Zhang Y, Xu Z, Yang Y, et al (2021)

Association Between Weight Change and Leukocyte Telomere Length in U.S. Adults.

Frontiers in endocrinology, 12:650988.

Objective: To investigate the association of dynamic weight change in adulthood with leukocyte telomere length among U.S. adults.

Methods: This study included 3,886 subjects aged 36-75 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 cycle. Survey-weighted multivariable linear regression with adjustments for potential confounders was utilized.

Results: 3,386 individuals were finally included. People with stable obesity had a 0.130 kbp (95% CI: 0.061-0.198, P=1.97E-04) shorter leukocyte telomere length than those with stable normal weight (reference group) during the 10-year period, corresponding to approximately 8.7 years of aging. Weight gain from non-obesity to obesity shortened the leukocyte telomere length by 0.094 kbp (95% CI: 0.012-0.177, P=0.026), while normal weight to overweight or remaining overweight shortened the leukocyte telomere length by 0.074 kbp (95% CI: 0.014-0.134, P=0.016). The leukocyte telomere length has 0.003 kbp attrition on average for every 1 kg increase in weight from a mean age of 41 years to 51 years. Further stratified analysis showed that the associations generally varied across sex and race/ethnicity.

Conclusions: This study found that weight changes during a 10-year period was associated with leukocyte telomere length and supports the theory that weight gain promotes aging across adulthood.

RevDate: 2021-08-14

Page RL, Han G, Akinlotan M, et al (2021)

Telomere Length and Preterm Birth in Pregnant Mexican-Origin Women.

Maternal and child health journal [Epub ahead of print].

OBJECTIVES: Despite the obstacles of limited education and employment opportunities-and the stress associated with immigration and pregnancy-Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB.

METHODS: This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36 weeks gestation. PTB data was collected from the participant's medical record after delivery.

RESULTS: TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p = 0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL.

CONCLUSIONS FOR PRACTICE: This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.

RevDate: 2021-08-14

Shan W, Kubová M, Mandáková T, et al (2021)

Nuclear organization in crucifer genomes: nucleolus-associated telomere clustering is not a universal interphase configuration in Brassicaceae.

The Plant journal : for cell and molecular biology [Epub ahead of print].

Arabidopsis thaliana (arabidopsis) has become a major plant research model where interphase nuclear organization exhibits unique features, including nucleolus-associated telomere clustering. The chromocenter (CC)-loop model, or rosette-like configuration, describes intranuclear chromatin organization in arabidopsis as megabase-long loops anchored in, and emanating from, peripherally positioned chromocenters, and those containing telomeres associate with the nucleolus. To investigate whether the CC-loop organization is universal across the mustard family (crucifers), the nuclear distributions of centromeres, telomeres and nucleoli were analyzed by fluorescence in situ hybridization in seven diploid species (2n = 10 - 16) representing major crucifer clades with an up to 26-fold variation in genome size (160 Mb - 4 260 Mb). Nucleolus-associated telomere clustering was confirmed in arabidopsis (157 Mb) and was newly identified as the major nuclear phenotype in other species with a small genome (215 - 381 Mb). In large-genome species (2 611 - 4 264 Mb), centromeres and telomeres adopted either a Rabl-like configuration or dispersed distribution in the nuclear interior; telomeres only rarely associated with the nucleolus. In Arabis cypria (381 Mb) and Bunias orientalis (2 611 Mb), tissue-specific patterns deviating from the major nuclear phenotypes were observed in anther and stem tissues, respectively. The rosette-like configuration, including nucleolus-associated telomere clustering in small-genome species from different infrafamiliar clades, suggests that genomic properties rather than phylogenetic position, determine the interphase nuclear organization. Our data suggest that nuclear genome size, average chromosome size and degree of longitudinal chromosome compartmentalization affect interphase chromosome organization in crucifer genomes.

RevDate: 2021-08-13

Degradi L, Tava V, Kunova A, et al (2021)

Telomere to telomere genome assembly of Fusarium musae F31, causal agent of crown rot disease of banana.

Molecular plant-microbe interactions : MPMI [Epub ahead of print].

Fusarium musae van Hove causes crown rot of banana and it is also associated to clinical fusariosis. A chromosome-level genome assembly of Fusarium musae F31 obtained combining Nanopore long reads and Illumina paired end reads resulted in 12 chromosomes plus one contig with overall N50 of 4.36 Mb, and is presented together with its mitochondrial genome (58072 bp). F31 genome includes telomeric regions for 11 of the 12 chromosomes representing the most complete genome available in the Fusarium fujikuroi species complex. The high-quality assembly of the F31 genome will be a valuable resource for studying the pathogenic interactions occurring between F. musae and banana. Moreover, it represents an important resource for understanding the genome evolution in the Fusarium fujikuroi species complex.

RevDate: 2021-08-13

Schroder JD, de Araújo JB, de Oliveira T, et al (2021)

Telomeres: the role of shortening and senescence in major depressive disorder and its therapeutic implications.

Reviews in the neurosciences pii:revneuro-2021-0070 [Epub ahead of print].

Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

RevDate: 2021-08-13

Power ML, Foley NM, Jones G, et al (2021)

Taking flight: an ecological, evolutionary and genomic perspective on bat telomeres.

Molecular ecology [Epub ahead of print].

Over 20% of all living mammals are bats (order Chiroptera). Bats possess extraordinary adaptations including powered flight, laryngeal echolocation and a unique immune system that enables them to tolerate a diversity of viral infections without presenting clinical disease symptoms. They occupy multiple trophic niches and environments globally. Significant physiological and ecological diversity occurs across the order. Bats also exhibit extreme longevity given their body size with many species showing few signs of ageing. The molecular basis of this extended longevity has recently attracted attention. Telomere maintenance potentially underpins bats' extended healthspan, although functional studies are still required to validate the causative mechanisms. In this review, we detail the current knowledge on bat telomeres, telomerase expression, and how these relate to ecology, longevity and life-history strategies. Patterns of telomere shortening and telomerase expression vary across species, and comparative genomic analyses suggest that alternative telomere maintenance mechanisms evolved in the longest lived bats. We discuss the unique challenges faced when working with populations of wild bats and highlight ways to advance the field including expanding long-term monitoring across species that display contrasting life-histories and occupy different environmental niches. We further review how new high quality, chromosome-level genome assemblies can enable us to uncover the molecular mechanisms governing telomere dynamics and how phylogenomic analyses can reveal the adaptive significance of telomere maintenance and variation in bats.

RevDate: 2021-08-13

Sonnenberg ASM, Sedaghat-Telgerd N, Lavrijssen B, et al (2021)

Author Correction: Telomere-to-telomere assembled and centromere annotated genomes of the two main subspecies of the button mushroom Agaricus bisporus reveal especially polymorphic chromosome ends.

Scientific reports, 11(1):16734 pii:10.1038/s41598-021-96123-y.

RevDate: 2021-08-12

Anonymous (2021)

Erratum to: Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men.

RevDate: 2021-08-10

Salmón P, Millet C, Selman C, et al (2021)

Growth acceleration results in faster telomere shortening later in life.

Proceedings. Biological sciences, 288(1956):20211118.

There is a wealth of evidence for a lifespan penalty when environmental conditions influence an individual's growth trajectory, such that growth rate is accelerated to attain a target size within a limited time period. Given this empirically demonstrated relationship between accelerated growth and lifespan, and the links between lifespan and telomere dynamics, increased telomere loss could underpin this growth-lifespan trade. We experimentally modified the growth trajectory of nestling zebra finches (Taeniopygia guttata), inducing a group of nestlings to accelerate their growth between 7 and 15 days of age, the main phase of body growth. We then sequentially measured their telomere length in red blood cells at various time points from 7 days to full adulthood (120 days). Accelerated growth between 7 and 15 days was not associated with a detectable increase in telomere shortening during this period compared with controls. However, only in the treatment group induced to show growth acceleration was the rate of growth during the experimental period positively related to the amount of telomere shortening between 15 and 120 days. Our findings provide evidence of a long-term influence of growth rate on later-life telomere shortening, but only when individuals have accelerated growth in response to environmental circumstances.

RevDate: 2021-08-09

Miner AE, JS Graves (2021)

What telomeres teach us about MS.

Multiple sclerosis and related disorders, 54:103084 pii:S2211-0348(21)00351-5 [Epub ahead of print].

While the precise mechanisms driving progressive forms of MS are not fully understood, patient age has clear impact on disease phenotype. The very young with MS have high relapse rates and virtually no progressive disease, whereas older patients tend to experience more rapid disability accumulation with few relapses. Defining a patient's biological age may offer more precision in determining the role of aging processes in MS phenotype and pathophysiology than just working with an individual's birthdate. The most well recognized measurement of an individual's "biological clock" is telomere length (TL). While TL may differ across tissue types in an individual, most cells TL correlate well with leukocyte TL (LTL), which is the most common biomarker used for aging. LTL has been associated with risk for aging related diseases and most recently with higher levels of disability and brain atrophy in people living with MS. LTL explains 15% of the overall association of chronological age with MS disability level. While LTL may be used just as a biomarker of overall somatic aging processes, triggering of the DNA damage response by telomere attrition leads to senescence pathways that are likely highly relevant to a chronic autoimmune disease. Considering reproductive aging factors, particularly ovarian aging in women, which correlates with LTL and oocyte telomere length, may complement measurements of somatic aging in understanding MS progression. The key to stopping non-relapse related progression in MS might lie in targeting pathways related to biological aging effects on the immune and nervous systems.

RevDate: 2021-08-09

Amirzadegan M, Sadeghi N, Tavalaee M, et al (2021)

Analysis of leukocyte and sperm telomere length in oligozoospermic men.

Andrologia [Epub ahead of print].

Telomere length is considered one of the most relevant biological markers of genomic stability since it protects DNA from impairment and also ensures chromosome alignment during DNA replication. The negative impact of telomere shortening on sperm quality has been suggested as an important indicator of male infertility. Therefore, we aimed to assess leucocyte and sperm telomere length (LTL&STL), as well as sperm parameters, DNA damage and protamine deficiency in men with oligozoospermia as compared to fertile men. Our results demonstrated a significant reduction in sperm parameters (concentration, motility, morphology), LTL & STL and a significant increase in sperm DNA damage and protamine deficiency in oligozoospermic men compared with fertile individuals. These outcomes revealed that low sperm concentration in men is possibly a sign of impaired meiotic and/or meiotic division during the spermatogenesis process. It is not only associated with proper chromatin packaging but also with telomere length as a key player in the process of mitosis and meiosis, assisting in chromosomal alignment, pairing, synapsis and crossing over during spermatogenesis.

RevDate: 2021-08-09

Ferensztajn-Rochowiak E, Kurczewska E, Rubiś B, et al (2021)

Decreased leukocyte telomere length in male patients with chronic bipolar disorder: lack of effect of long-term lithium-treatment.

Acta neuropsychiatrica pii:S092427082100020X [Epub ahead of print].

OBJECTIVES: Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the telomere length between patients with bipolar disorder and control subjects. The effect of long-term lithium treatment was also assessed.

METHODS: The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. Telomere length was assessed by the quantitative polymerase chain reaction (qPCR).

RESULTS: In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients.

CONCLUSION: The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.

RevDate: 2021-08-09

Campisi M, Liviero F, Maestrelli P, et al (2021)

DNA Methylation-Based Age Prediction and Telomere Length Reveal an Accelerated Aging in Induced Sputum Cells Compared to Blood Leukocytes: A Pilot Study in COPD Patients.

Frontiers in medicine, 8:690312.

Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (-4.5 ± 5.02 vs. -10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge (r = 0.927245; p = 0.0026) and AgeAcc (r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV1% enhancement (p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy (p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.

RevDate: 2021-08-08

Anonymous (2020)

A Phosphoswitch in Shelterin Component TRF2 Mediates Telomere Dynamics.

Cancer discovery, 10(1):OF8.

Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

RevDate: 2021-08-07

Sun J, Liu W, Guo Y, et al (2021)

Characterization of tree shrew telomeres and telomerase.

Journal of genetics and genomics = Yi chuan xue bao pii:S1673-8527(21)00173-9 [Epub ahead of print].

The use of tree shrews as experimental animals for biomedical research is a new practice. Several recent studies suggest that tree shrews are suitable for studying cancers, including breast cancer, glioblastoma, lung cancer, and hepatocellular carcinoma. However, the telomeres and the telomerase of tree shrews have not been studied to date. Here, we characterize telomeres and telomerase in tree shrews. The telomere length of tree shrews is approximately 23 kb, which is longer than that of primates and shorter than that of mice, and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization analyses. Tree shrew spleen, bone marrow, testis, ovary, and uterus show high telomerase activities, which are increased in breast tumor tissues by telomeric repeat amplification protocol assays. The telomere length becomes shorter, and telomerase activity decreases with age. The tree shrew TERT and TERC are more highly similar to primates than to rodents. These findings lay a solid foundation for using tree shrews to study aging and cancers.

RevDate: 2021-08-07

Ghilain C, Gilson E, MJ Giraud-Panis (2021)

Multifunctionality of the Telomere-Capping Shelterin Complex Explained by Variations in Its Protein Composition.

Cells, 10(7): pii:cells10071753.

Protecting telomere from the DNA damage response is essential to avoid the entry into cellular senescence and organismal aging. The progressive telomere DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. In several organisms, including mammals, telomeres are protected by a protein complex named Shelterin that counteract at various levels the DNA damage response at chromosome ends through the specific function of each of its subunits. The changes in Shelterin structure and function during development and aging is thus an intense area of research. Here, we review our knowledge on the existence of several Shelterin subcomplexes and the functional independence between them. This leads us to discuss the possibility that the multifunctionality of the Shelterin complex is determined by the formation of different subcomplexes whose composition may change during aging.

RevDate: 2021-08-07

Li Y, Sundquist K, Wang X, et al (2021)

Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women: A Prospective Swedish Population-Based Study.

Cancers, 13(15): pii:cancers13153842.

Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.

RevDate: 2021-08-07

Zheng X, Wezel F, Azoitei A, et al (2021)

Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma.

Cancers, 13(15): pii:cancers13153774.

BACKGROUND: Telomeres are protein-DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC).

METHODS: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated.

RESULTS: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041).

CONCLUSION: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.

RevDate: 2021-08-08

Hsiao CB, Bedi H, Gomez R, et al (2021)

Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV.

Vaccines, 9(7):.

The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP's who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction.

RevDate: 2021-08-08

Kaali S, Jack D, Opoku-Mensah J, et al (2021)

Prenatal Household Air Pollution Exposure, Cord Blood Mononuclear Cell Telomere Length and Age Four Blood Pressure: Evidence from a Ghanaian Pregnancy Cohort.

Toxics, 9(7):.

Associations between prenatal household air pollution exposure (HAP), newborn telomere length and early childhood blood pressure are unknown. Methods: Pregnant women were randomized to liquefied petroleum gas (LPG) stove, improved biomass stove or control (traditional, open fire cook stove). HAP was measured by personal carbon monoxide (CO) (n = 97) and fine particulate matter (PM2.5) (n = 60). At birth, cord blood mononuclear cells (CBMCs) were collected for telomere length (TL) analyses. At child age four years, we measured resting blood pressure (BP) (n = 97). We employed multivariable linear regression to determine associations between prenatal HAP and cookstove arm and assessed CBMC relative to TL separately. We then examined associations between CBMC TL and resting BP. Results: Higher prenatal PM2.5 exposure was associated with reduced TL (β = -4.9% (95% CI -8.6, -0.4), p = 0.03, per 10 ug/m3 increase in PM2.5). Infants born to mothers randomized to the LPG cookstove had longer TL (β = 55.3% (95% CI 16.2, 109.6), p < 0.01)) compared with control. In all children, shorter TL was associated with higher systolic BP (SBP) (β = 0.35 mmHg (95% CI 0.001, 0.71), p = 0.05, per 10% decrease in TL). Increased prenatal HAP exposure is associated with shorter TL at birth. Shorter TL at birth is associated with higher age four BP, suggesting that TL at birth may be a biomarker of HAP-associated disease risk.

RevDate: 2021-08-06

Guillén R, Otero F, Mosquera A, et al (2021)

Association of accelerated dynamics of telomere sequence loss in peripheral blood leukocytes with incident knee osteoarthritis in Osteoarthritis Initiative cohort.

Scientific reports, 11(1):15914.

Osteoarthritis (OA) is a chronic degenerative joint disease, being the main cause of laboral inability. Decreased telomere size in peripheral blood leukocytes (PBL) has been correlated with age-related pathologies, like knee OA. In a dynamic approach, telomere-qPCR was performed to evaluate the relative percentage of PBL telomere loss after a 6-year follow-up, in 281 subjects from the prospective osteoarthritis initiative (OAI) cohort. A radiological Kellgren-Lawrence (KL) grade ≥ 2 was indicative of knee OA. Individuals with knee OA at recruitment (n = 144) showed a higher PBL telomere loss after 6 years than those without knee OA at baseline (n = 137; p = 0.018). Moreover, individuals that developed knee OA during the follow-up (n = 39) exhibited a higher telomere loss compared to those that remained without OA (n = 98; p < 0.001). Logistic regression analysis showed that PBLs telomere loss was not significantly associated with knee OA at recruitment, but behaves as an independent risk factor associated with incidence after follow-up (OR: 1.043; p = 0.041), together with maximum KL grade (OR: 3.627; p = 0.011), body mass index-BMI (OR: 1.252; p < 0.001) and WOMAC-index (OR: 1.247; p = 0.021), at recruitment. The telomere decay in PBLs is faster in individuals with incident knee OA, possibly reflecting a systemic-global accelerated aging that enhances the cartilage degeneration.

RevDate: 2021-08-06

Tian XP, Qian D, He LR, et al (2021)

Corrigendum to "The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas" [Canc. Lett. 353 (2014) 104-114].

RevDate: 2021-08-04

Ban X, Mo S, Lu Z, et al (2021)

Alternative lengthening of telomeres phenotype predicts progression risk in non-insulinomas in a Chinese cohort.

Neuroendocrinology pii:000518413 [Epub ahead of print].

RevDate: 2021-08-04

Sun G, Cao H, Bai Y, et al (2021)

A novel multiplex qPCR method for assessing the comparative lengths of telomeres.

Journal of clinical laboratory analysis [Epub ahead of print].

BACKGROUND: The comparative length of telomeres is considered to be related to diseases such as cancer, aging, and cardiovascular diseases. qPCR is currently one of the main methods for detecting telomere length. However, due to the unique sequence of telomeres (highly repetitive six-base sequence), it is difficult to design primers and probes to expand and detect telomere and to put internal reference gene and telomere into the same tube for detection to reduce the possible inter-pore errors and improve amplification efficiency. Besides, the stability and accuracy of the test results are greatly affected by the difference between reference genes and telomere copy number.

METHODS: In this study, the single-copy genes were replaced with high-copy genes (300 copies) as the internal control to reduce the copy number difference of the internal genes and telomere. In addition, a multiplex qPCR system was constructed to detect the telomeres and an internal reference gene product. We also detected the lengths of telomeres in the genomic DNA in immortalized cells (293T and Hela) from different generations of cells.

RESULTS: We detected the comparative telomere lengths of 1500 random Chinese volunteers of different ages with the multiplex qPCR method; the result shows that the comparative length of telomeres is negatively related to age. In addition, we compared our qPCR detection method with a terminal restriction fragmentation (TRF) method. Both of them were highly consistent, indicating that the qPCR method was reliable.

CONCLUSIONS: In conclusion, we developed a stable, convenient, and accurate comparative telomere length detection method.

RevDate: 2021-08-03

Kodali HP, LN Borrell (2021)

Telomere length and mortality risk among adults in the United States: The role of age and race/ethnicity.

Annals of epidemiology pii:S1047-2797(21)00229-5 [Epub ahead of print].

PURPOSE: To examined whether there was an association of leucocyte telomere length (LTL) with all-cause, cardiovascular (CVD)- and cancer-specific mortality risks among US adults; and whether these associations vary with race/ethnicity and age.

METHODS: We conducted a retrospective cohort using data from the National Health and Nutritional Examination Survey, 1999-2002 and the 2015 Linked Mortality File on adults 25 years or older (n= 6,526 and 1,753 deaths). Cox proportional hazards regression was used to quantify the association of LTL with each outcome adjusting for baseline sociodemographic and health-related characteristics. We tested a three-way-interaction for LTL, race/ethnicity, and age groups.

RESULTS: After adjustment, the rate of dying for all-cause and CVD-specific mortality was at least 24% lower for a 1-kilobase increase in LTL. When compared with adults with the shortest telomere, the rates of dying were at least 17% lower for all-cause and CVD-specific mortality for those with longer LTL. For all-cause mortality, increase LTL was associated with lower rate of dying among non-Hispanic Blacks 45 years or older and non-Hispanic Whites 65 years or older.

CONCLUSIONS: We found increase telomere length was associated with lower all-cause and CVD-specific mortality rates among US adults. For all-cause mortality, this association varies within racial/ethnic groups across age groups.

RevDate: 2021-08-03

Schratz KE, Gaysinskaya V, Cosner ZL, et al (2021)

Somatic reversion impacts evolution of myelodysplastic syndromes and acute myeloid leukemia in the short telomere disorders.

The Journal of clinical investigation pii:e147598 [Epub ahead of print].

BACKGROUND: Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.

METHODS: We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and short telomere syndrome patients with and without MDS/AML and we tested the functional significance of these mutations.

RESULTS: While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least one (P<0.001) and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations which were present in 19%, we identified POT1 and TERF2IP mutations in 13%. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes, RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in six telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no MDS/AML patient had more than one reversion mutation.

CONCLUSIONS: Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML.

RevDate: 2021-08-04

Bühring J, Hecker M, Fitzner B, et al (2021)

Systematic Review of Studies on Telomere Length in Patients with Multiple Sclerosis.

Aging and disease, 12(5):1272-1286.

Telomeres are protective cap structures at the end of chromosomes that are essential for maintaining genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases. We aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS). A comprehensive literature search was conducted to identify original studies that presented data on TL in samples from persons with MS. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies. A total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in patients with MS were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes. Despite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.

RevDate: 2021-08-02

Park S, Lee S, Kim Y, et al (2021)

A Mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease.

Kidney international pii:S0085-2538(21)00730-4 [Epub ahead of print].

Chronic kidney disease (CKD) is highly prevalent in the elderly population. However, it is rarely investigated whether kidney function is causally linked to biological aging itself. In this Mendelian randomization study, genetic instruments for telomere attrition were applied to a CKDGen genome wide association study results for 41,395 cases of CKD among 480,698 individuals as summary-level Mendelian randomization. A replicative analysis was performed by polygenic score analysis using independent United Kingdom Biobank data for 8,118 cases of CKD among 321,024 white individuals of British ancestry. Reverse-direction Mendelian randomization analysis was performed utilizing genetic instruments for log-estimated glomerular filtration rate change with Z-standardized telomere length outcome data for 326,075 participants in the UK Biobank. Genetic predisposition toward telomere attrition (one Z score decrease in length) was found to be a causative factor for a higher CKD risk [Odds Ratio 1.20 (95% confidence interval 1.08‒1.33)], as supported by pleiotropy-robust Mendelian randomization sensitivity analyses implemented using the CKDGen data. Based on United Kingdom Biobank data, the polygenic score for telomere attrition was significantly associated with a higher risk of CKD [1.20 (1.04‒1.39)]. In reverse-direction Mendelian randomization, the genetically predicted kidney function decrease was significantly associated with a higher degree of telomere attrition [beta 0.039 (0.009‒0.069)]. Thus, our study supports the causal linkage between telomere attrition and kidney function impairment.

RevDate: 2021-08-03

Qi YY, Liu XR, He YX, et al (2021)

Association of the PINX1 Variant rs6984094, Which Lengthens Telomeres, with Systemic Lupus Erythematosus Susceptibility in Chinese Populations.

Journal of immunology research, 2021:7079359.

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified (P discovery = 4.13 × 10-2, OR = 0.58, 95% CI 0.35-0.98) and successfully replicated (P replication = 5.73 × 10-3, OR = 0.45, 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

RevDate: 2021-08-03

Marques A, Peralta M, Marconcin P, et al (2021)

A Systematic Review of the Association Between Muscular Fitness and Telomere Length Across the Adult Lifespan.

Frontiers in physiology, 12:706189.

This study aimed to systematically review the association between telomere length (TL) and muscular fitness. In October 2020, an articles search was applied to PubMed, Scopus, and Web of Science. Eligibility criteria included: cross-sectional, prospective, and experimental study design; outcomes included TL; results expressed the relationship between muscular fitness and TL; studies published in English, Portuguese, or Spanish. Nine studies were included in the review. Results from the four prospective studies are mixed. In one study, the changes in TL were associated with grip strength. Another study concluded that longer mid-life TL was associated with increased grip strength later in life. However, in the other two studies, the association between TL and sarcopenia was not strong. Nevertheless, longer TL was associated with a slower decline in grip strength in older people. From the four cross-sectional studies, three indicated that TL was associated with muscular fitness. On the other hand, in a study with powerlifters, TL remained within the range of values found in subjects with no history of regular strength training, supporting the notion that muscular fitness was not associated with TL. The cross-sectional and prospective studies showed that the relationship between TL and muscular fitness is not conclusive. It seems that there is a positive association between TL and muscular fitness in middle-aged and older adults. However, among younger adults, this relationship was not observed.

RevDate: 2021-08-06

Duan X, Wang H, Yang Y, et al (2021)

Genetic variants in telomerase-associated protein 1 are associated with telomere damage in PAH-exposed workers.

Ecotoxicology and environmental safety, 223:112558 pii:S0147-6513(21)00670-9 [Epub ahead of print].

Telomeres are functional complexes at the ends of linear chromosomes, and telomerase aids in their maintenance and replication. Additionally, accumulating evidence suggests that telomerase-associated protein 1 (TEP1) is a component of the telomerase ribonucleoprotein complex and is responsible for catalyzing the addition of new synthetic telomere sequences to chromosome ends. In our previous study, we found that genetic variants of the TERT gene participated in the regulation of telomere length. Exposure to particulate matter, environmental pollutants, oxidative stress, and pesticides is associated with shortening of telomere length. However, it is unknown whether genetic variants in the TEP1 gene may affect telomere length (TL) in polycyclic aromatic hydrocarbon (PAH)-exposed workers. Therefore, we measured the peripheral leukocyte TL and genotyped the polymorphism loci in the TEP1 gene among 544 PAH-exposed workers and 238 healthy controls. Covariance analysis showed that the individuals carrying TEP1 rs1760903 CC and TEP1 rs1760904 TT had longer TL in the control group (P < 0.05). In the generalized linear model, we found that rs1760903 CC was a protective factor against TL shortening, and PAH exposure could promote telomere shortening (P < 0.05). Thus, this study reinforces the roles of environmental factors and genetic variations in telomere damage, and provides a theoretical foundation for the early detection of susceptible populations and the establishment of occupational standards.

RevDate: 2021-08-06

Aviv A (2021)

Short telomeres and severe COVID-19: The connection conundrum.

EBioMedicine, 70:103513 [Epub ahead of print].

RevDate: 2021-08-01

Lyons LA (2021)

Cats - telomere to telomere and nose to tail.

Trends in genetics : TIG pii:S0168-9525(21)00142-6 [Epub ahead of print].

Feline genomic medicine can decode human variants of uncertain significance (VUSs). Telomere-to-telomere genome assemblies are feasible for all felid species, supporting genetic evolution and speciation studies. Their highly conserved genomic organization compared to humans suggests cats may also decipher the intergenic variation affecting the 3D chromosome structures influencing gene regulation.

RevDate: 2021-07-31

Penrice DD, Havlichek D, Kamath PS, et al (2021)

Outcomes Following Liver Transplant in Adults with Telomere Biology Disorders.

RevDate: 2021-08-03

Kosebent EG, S Ozturk (2021)

Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice.

Scientific reports, 11(1):15569.

Telomeres cap the ends of eukaryotic chromosomes to maintain genomic stability and integrity during an organism's lifespan. The length of telomeres inevitably shortens due to DNA replication, genotoxic agents, and biological aging. A limited number of cell types, e.g., stem cells, germline cells, and early embryos can elongate shortened telomeres via the enzymatic action of telomerase, which is composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (Terc). Additionally, telomere-associated proteins including telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), as well as protection of telomeres 1a (POT1a), bind to telomeres to maintain their structural integrity and length. During ovarian aging in mammals, telomeres progressively shorten, accompanied by fertility loss; however, the molecular mechanism underlying this attrition during follicle development remains unclear. In this study, the primary, secondary, preantral, and antral follicles were obtained either from 6-week-old adult (n = 19) or 52-week-old aged (n = 12) mice. We revealed that the Tert, Terc, Trf1, Trf2, and Pot1a gene expression (P < 0.001) and TERT protein (P < 0.01) levels significantly decreased in certain ovarian follicles of the aged group when compared to those of the adult group. Also, telomerase activity exhibited remarkable changes in the follicles of both groups. Consequently, altered telomere-associated gene expression and reduced TERT protein levels in the follicles of aged mice may be a determinant of telomere shortening during ovarian aging, and infertility appearing in the later decades of reproductive lifespan. Further investigations are required to determine the molecular mechanisms underlying these alterations in the follicles during ovarian aging.

RevDate: 2021-08-03

Wang C, Songyang Z, Y Huang (2021)

TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation.

Cell & bioscience, 11(1):149.

BACKGROUND: About 10-15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored.

RESULTS: Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA.

CONCLUSIONS: Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.

RevDate: 2021-08-06

Parolini M, De Felice B, Mondellini S, et al (2021)

Prenatal exposure to triclosan induced brain telomere shortening in a wild bird species.

Environmental toxicology and pharmacology, 87:103718 pii:S1382-6689(21)00136-8 [Epub ahead of print].

Exposure to the antimicrobial agent Triclosan (TCS) induces oxidative stress in diverse organisms, including birds. However, whether TCS-induced oxidative stress effectively translates into detrimental effects is still unclear. The present study examined whether prenatal TCS exposure induces oxidative stress and telomere shortening in the brain and the liver of near-term embryos of the yellow-legged gull (Larus michahellis). Prenatal TCS exposure caused a significant overproduction of reactive oxygen species (ROS) in the brain, but no oxidative damage occurred. Telomeres of TCS-exposed embryos had brain telomeres 30 % shorter compared to controls, probably because the relatively modest antioxidant defenses of this organ during prenatal development cannot counteract the impact of the TCS-induced ROS. No telomere shortening was observed in the liver. Our results demonstrated that prenatal exposure to TCS in wild bird species can modulate the oxidative status and induce telomere shortening in the brain of the yellow-legged gull embryos.

RevDate: 2021-07-29

Kohlrausch FB, Wang F, Chamani I, et al (2021)

Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development.

Obstetrical & gynecological survey, 76(7):429-436.

Importance: It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction.

Objective: In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos.

Evidence Acquisition: We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development.

Results: Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos.

Conclusions and Relevance: Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.

RevDate: 2021-07-29

Lee JH, Hong J, Zhang Z, et al (2021)

Regulation of telomere homeostasis and genomic stability in cancer by N 6-adenosine methylation (m6A).

Science advances, 7(31): pii:7/31/eabg7073.

The role of RNA methylation on N 6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m6A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.

RevDate: 2021-07-28

Rosin LF, Gil J, Drinnenberg IA, et al (2021)

Oligopaint DNA FISH reveals telomere-based meiotic pairing dynamics in the silkworm, Bombyx mori.

PLoS genetics, 17(7):e1009700 pii:PGENETICS-D-21-00432 [Epub ahead of print].

Accurate chromosome segregation during meiosis is essential for reproductive success. Yet, many fundamental aspects of meiosis remain unclear, including the mechanisms regulating homolog pairing across species. This gap is partially due to our inability to visualize individual chromosomes during meiosis. Here, we employ Oligopaint FISH to investigate homolog pairing and compaction of meiotic chromosomes and resurrect a classical model system, the silkworm Bombyx mori. Our Oligopaint design combines multiplexed barcoding with secondary oligo labeling for high flexibility and low cost. These studies illustrate that Oligopaints are highly specific in whole-mount gonads and on meiotic squashes. We show that meiotic pairing is robust in both males and females and that pairing can occur through numerous partially paired intermediate structures. We also show that pairing in male meiosis occurs asynchronously and seemingly in a transcription-biased manner. Further, we reveal that meiotic bivalent formation in B. mori males is highly similar to bivalent formation in C. elegans, with both of these pathways ultimately resulting in the pairing of chromosome ends with non-paired ends facing the spindle pole. Additionally, microtubule recruitment in both C. elegans and B. mori is likely dependent on kinetochore proteins but independent of the centromere-specifying histone CENP-A. Finally, using super-resolution microscopy in the female germline, we show that homologous chromosomes remain associated at telomere domains in the absence of chiasma and after breakdown and modification to the synaptonemal complex in pachytene. These studies reveal novel insights into mechanisms of meiotic homolog pairing both with or without recombination.

RevDate: 2021-07-28

Ren CY, Liu PP, Li J, et al (2021)

Changes in telomere length and serum neurofilament light chain levels in female patients with chronic insomnia disorder.

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine [Epub ahead of print].

STUDY OBJECTIVES: The aims of this study were to explore changes in the telomere length (relative telomere repeat copy/single-copy gene, T/S ratio) and serum neurofilament light chain (sNfL) levels in female patients with chronic insomnia disorder (CID), examine their relationships with emotional abnormalities and cognitive impairment, and determine whether these 2 indicators were independently associated with sleep quality.

METHODS: The CID group contained 80 patients diagnosed with CID, and 51 individuals constituted a healthy control group (HC). Participants completed sleep, emotion, and cognition assessments. Telomere length was detected through quantitative real-time polymerase chain reaction (qRT-PCR). Enzyme-linked immunosorbent assay was used to determine sNfL concentrations.

RESULTS: Relative to the HC group, the CID group had elevated Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety scale-14 (HAMA-14), and Hamilton Depression Rating scale-17 (HAMD-17) scores and reduced Montreal Cognitive Assessment scale (MoCA) scores, a decreased T/S ratio, and an increased sNfL concentration. Subgroup analysis according to various CID-associated sleep factors showed that poor sleep performance corresponded with a lower T/S ratio. Higher anxiety levels and more cognitive dysfunction correlated with shorter telomere lengths. The T/S ratio negatively correlated with age, whereas the sNfL concentration positively correlated with age in the CID group. The PSQI score negatively correlated with the T/S ratio but did not correlate with sNfL levels. Multiple linear regression analysis showed that the T/S ratio had a negative and independent effect on PSQI scores.

CONCLUSIONS: The CID group had shorter telomeres and higher sNfL concentrations, and reduced telomere length independently affected sleep quality.

RevDate: 2021-07-29

Yang SY, Chang EYC, Lim J, et al (2021)

G-quadruplexes mark alternative lengthening of telomeres.

NAR cancer, 3(3):zcab031.

About 10-15% of all human cancer cells employ a telomerase-independent recombination-based telomere maintenance method, known as alternative lengthening of telomere (ALT), of which the full mechanism remains incompletely understood. While implicated in previous studies as the initiating signals for ALT telomere repair, the prevalence of non-canonical nucleic acid structures in ALT cancers remains unclear. Extending earlier reports, we observe higher levels of DNA/RNA hybrids (R-loops) in ALT-positive (ALT+) compared to telomerase-positive (TERT+) cells. Strikingly, we observe even more pronounced differences for an associated four-stranded nucleic acid structure, G-quadruplex (G4). G4 signals are found at the telomere and are broadly associated with telomere length and accompanied by DNA damage markers. We establish an interdependent relationship between ALT-associated G4s and R-loops and confirm that these two structures can be spatially linked into unique structures, G-loops, at the telomere. Additionally, stabilization of G4s and R-loops cooperatively enhances ALT-activity. However, co-stabilization at higher doses resulted in cytotoxicity in a synergistic manner. Nuclear G4 signals are significantly and reproducibly different between ALT+ and TERT+ low-grade glioma tumours. Together, we present G4 as a novel hallmark of ALT cancers with potential future applications as a convenient biomarker for identifying ALT+ tumours and as therapeutic targets.

RevDate: 2021-07-29

Petrov N, Lee HS, Liskovykh M, et al (2021)

Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells.

Oncotarget, 12(15):1444-1456.

Telomerase/telomere-targeting therapy is a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability (CIN) and may be a barrier to tumor growth. We recently developed a dual-HAC (Human Artificial Chromosome) assay that enables identification and ranking of compounds that induce CIN as a result of telomere dysfunction. This assay is based on the use of two isogenic HT1080 cell lines, one carrying a linear HAC (containing telomeres) and the other carrying a circular HAC (lacking telomeres). Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC. Results: In this study, we used the dual-HAC assay for the analysis of the platinum-derived G4 ligand Pt-tpy and five of its derivatives: Pt-cpym, Pt-vpym, Pt-ttpy, Pt(PA)-tpy, and Pt-BisQ. Our analysis revealed four compounds, Pt-tpy, Pt-ttpy, Pt-vpym and Pt-cpym, that induce a specific loss of a linear but not a circular HAC. Increased CIN after treatment by these compounds correlates with the induction of double-stranded breaks (DSBs) predominantly localized at telomeres and reflecting telomere-associated DNA damage. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges (CBs) in late mitosis and cytokinesis. These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

RevDate: 2021-07-27

Xie H, Ma Y, Shao M, et al (2021)

Telomere length in patients with osteoarthritis: a systematic review and meta-analysis.

Aging clinical and experimental research [Epub ahead of print].

BACKGROUND: Telomere length (TL) as a biomarker of aging was associated with many age-related diseases. The relationship between TL and osteoarthritis (OA), the most common form of joint diseases, had been investigated in a number of studies, but with the result inconsistent.

AIMS: The purpose of this study was to systematically evaluate the relationship between TL and OA.

METHODS: Until January 1, 2021, PubMed, Web of Science and Cochrane Library were comprehensively retrieved for relevant literatures. Quality of included literature was assessed using the Newcastle-Ottawa Scale (NOS) assessment scale. The pooled standard mean difference (SMD) with 95% confidence interval (CI) of Leukocytes TL was calculated using random-effect model. Subgroup analysis and meta-regression were used to investigate the potential source of heterogeneity.

RESULTS: Six original studies containing 678 OA patients and 1457 healthy controls were included in this meta-analysis. All six included studies were case-control designed. Pooled results showed that patients with OA had a shorter TL in peripheral blood leukocytes (PBLs) compared with healthy controls, (SMD = - 0.32, 95% CI - 0.57 to - 0.06, Z = - 2.45, P = 0.014). Subgroup and meta-regression analysis showed that sex ratio and body mass index (BMI) were possible sources of heterogeneity. Publication bias was not observed.

CONCLUSION: The TL of PBLs in patients with OA was shorter than that of healthy controls, suggesting that PBLs TL may be closely associated with the pathogenesis and progression of OA.

RevDate: 2021-07-27

Loh NY, Noordam R, C Christodoulides (2021)

Telomere length and metabolic syndrome traits: A Mendelian randomisation study.

Aging cell [Epub ahead of print].

Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10-6) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure.

RevDate: 2021-08-05

Kim EJ, Koh SH, Ha J, et al (2021)

Increased telomere length in patients with frontotemporal dementia syndrome.

Journal of the neurological sciences, 428:117565 pii:S0022-510X(21)00259-8 [Epub ahead of print].

BACKGROUND: Telomeres are repetitive DNA sequences of TTAGGG at the ends of chromosomes. Many studies have shown that telomere shortening is associated with aging-related diseases, such as cardiovascular diseases, hypertension, diabetes, cancer, and various neurodegenerative diseases, including Alzheimer's disease, vascular dementia, Parkinson's disease, and dementia with Lewy bodies. However, changes in telomere length (TL) in patients with frontotemporal dementia (FTD) syndrome are unclear. Accordingly, in this study, we assessed TL in blood samples from patients with FTD syndrome.

METHODS: Absolute TL was measured in peripheral blood leukocytes from 53 patients with FTD syndromes (25 with behavioral variant FTD, 19 with semantic variant primary progressive aphasia [PPA], six with nonfluent/agrammatic variant PPA, and three with amyotrophic lateral sclerosis [ALS] plus) and 28 cognitively unimpaired (CU) controls using terminal restriction fragment analysis.

RESULTS: TL was significantly longer in the FTD group than in the CU group. All FTD subtypes had significantly longer TL than controls. There were no significant differences in TL among FTD syndromes. No significant correlations were found between TL and demographic factors in the FTD group.

CONCLUSIONS: Longer telomeres were associated with FTD syndrome, consistent with a recent report demonstrating that longer telomeres are related to ALS. Therefore, our results may support a shared biology between FTD and ALS. More studies with larger sample sizes are needed.

RevDate: 2021-08-06

Alcaraz MJ, Alcaraz A, Teruel-Montoya R, et al (2021)

Subclinical atherosclerosis and immune activation in young HIV-infected patients with telomere shortening.

Aging, 13(14):18094-18105.

BACKGROUND: To date, available data on premature aging in young HIV-infected adults are scarce and no reports offer comprehensive assessment of telomere shortening (TS) in relation to subclinical atherosclerosis (SCA). In this study, we investigate if telomere shortening and immune activation markers are associated with SCA, which is one of the main degenerative diseases in young HIV-infected adults.

METHODS: A descriptive cross-sectional study was carried out in 149 HIV-infected patients on stable antiretroviral regimen (ART). Carotid intima-media thickness (cIMT) was estimated by carotid ultrasound. Quantitative singleplex PCR was performed to evaluate TS. The expression of activation/senescence markers was evaluated by multiparametric flow cytometry.

RESULTS: TS was observed in 73 patients (49%). Higher cIMT was observed in patients with TS than those without it (0.86 vs. 0.80 mm; p=0.041). Patients under the age of 50 (defined as young adults) with TS showed higher absolute numbers of activated lymphocyte T cells CD8+CD38+ (3.94 vs. 2.34 cell/μl; p=0.07) and lymphocyte B cells CD19+CD38+ (3.07 vs. 2.10 cell/μl; p=0.004) compared to those without TS. In the multivariate analysis, the only factor independently associated with TS was the absolute number of lymphocyte T cells CD8+CD38+ T cells (OR = 1.18; 95%-CI = 1.00-1.39; p = 0.05).

CONCLUSION: Young HIV-infected adults show premature biological aging with accentuated immune activation. Chronic inflammation with excessive T-cells activation could be associated to TS, premature aging, and SCA in young HIV-infected adults.

RevDate: 2021-07-27

Novo CL (2021)

A Tale of Two States: Pluripotency Regulation of Telomeres.

Frontiers in cell and developmental biology, 9:703466.

Inside the nucleus, chromatin is functionally organized and maintained as a complex three-dimensional network of structures with different accessibility such as compartments, lamina associated domains, and membraneless bodies. Chromatin is epigenetically and transcriptionally regulated by an intricate and dynamic interplay of molecular processes to ensure genome stability. Phase separation, a process that involves the spontaneous organization of a solution into separate phases, has been proposed as a mechanism for the timely coordination of several cellular processes, including replication, transcription and DNA repair. Telomeres, the repetitive structures at the end of chromosomes, are epigenetically maintained in a repressed heterochromatic state that prevents their recognition as double-strand breaks (DSB), avoiding DNA damage repair and ensuring cell proliferation. In pluripotent embryonic stem cells, telomeres adopt a non-canonical, relaxed epigenetic state, which is characterized by a low density of histone methylation and expression of telomere non-coding transcripts (TERRA). Intriguingly, this telomere non-canonical conformation is usually associated with chromosome instability and aneuploidy in somatic cells, raising the question of how genome stability is maintained in a pluripotent background. In this review, we will explore how emerging technological and conceptual developments in 3D genome architecture can provide novel mechanistic perspectives for the pluripotent epigenetic paradox at telomeres. In particular, as RNA drives the formation of LLPS, we will consider how pluripotency-associated high levels of TERRA could drive and coordinate phase separation of several nuclear processes to ensure genome stability. These conceptual advances will provide a better understanding of telomere regulation and genome stability within the highly dynamic pluripotent background.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Good Beginner's Books

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

Electronic Scholarly Publishing
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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )