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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 20 Jul 2019 at 08:38 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: 2019-07-19

Nudelman KNH, Lin J, Lane KA, et al (2019)

Telomere Shortening in the Alzheimer's Disease Neuroimaging Initiative Cohort.

Journal of Alzheimer's disease : JAD pii:JAD190010 [Epub ahead of print].

BACKGROUND: Although shorter telomeres have been associated with Alzheimer's disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression.

OBJECTIVE: To investigate the association of telomere length change with AD diagnosis and progression.

METHODS: In 653 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses.

RESULTS: Shorter telomeres were associated with older age (Effect Size (ES) = -0.23) and male sex (ES = -0.26). Neither baseline T/S ratio (ES = -0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = -0.186).

CONCLUSIONS: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative.

RevDate: 2019-07-18

Kogure GS, Miranda-Furtado CL, Pedroso DCC, et al (2019)

Effects of Progressive Resistance Training on Obesity Indices in Polycystic Ovary Syndrome and the Relationship With Telomere Length.

Journal of physical activity & health pii:jpah.2018-0256 [Epub ahead of print].

BACKGROUND: Physical activity is prescribed as a component of primary management for polycystic ovary syndrome (PCOS). This nonrandomized, therapeutic, open, single-arm study investigated the effects of progressive resistance training (PRT) on obesity indices in women with PCOS, and the relationship between obesity indices and telomere content.

METHODS: A total of 45 women with PCOS and 52 with non-PCOS (controls), aged 18 to 37 years, with body mass indexes of 18 to 39.9 kg/m2, performed three 1-hour sessions of PRT per week, for 16 weeks. Before and after PRT, measures included anthropometric indices and regions of interest of fat mass distribution, quantified by dual-energy X-ray absorptiometry, metabolic and hormonal parameters, and telomere content. The general linear mixed models were used to determine the effects of PRT.

RESULTS: PRT did reduce the waist-to-height ratio, waist circumference, and the index of conicity among PCOS (P < .01). However, PRT did not influence regions of interest, body mass index, and WHR. After PRT, the telomere content was associated with regions of interest and anthropometric indices in whole group independent of PCOS (P < .05).

CONCLUSION: Resistance exercise improves obesity indices in PCOS, independent of changes in body weight, and the relationship between telomeres and obesity parameters in PCOS remain to be fully clarified.

RevDate: 2019-07-18

Ly K, Walker C, Berry S, et al (2019)

Telomere length in early childhood is associated with sex and ethnicity.

Scientific reports, 9(1):10359 pii:10.1038/s41598-019-46338-x.

Telomeres are repetitive DNA sequences at the end of chromosomes that function to protect chromosomes from degradation. Throughout the life course, telomere length decreases with age and is influenced by environmental factors and health conditions. This study aimed to determine the relative telomere lengths in a diverse cohort of about 4000 four-year-old children in New Zealand. Linear regression was used to investigate the relationship between telomere length, child gender, ethnicity, paternal age and deprivation. We observed substantial variation in telomere length according to sex and self-identified ethnicity. Telomere length was longer in females compared to males (coefficient of 0.042, 95% confidence interval (CI) 0.024-0.060). European children had shorter telomere than both the indigenous Māori (coefficient of 0.03, CI 0.007-0.055) and Pacific children (coefficient of 0.15, CI 0.12-0.18). The data suggest that telomere lengths are highly variable and variability between individuals arise from early age, influenced partly by sex and ethnicity. Longer telomeres in indigenous Māori and Pacific children may reflect the heritability of telomere length in genetically less complex populations. This study increases our understanding of telomere dynamics in young children since the majority of telomere studies are conducted in adults.

RevDate: 2019-07-19

Bateson M, Aviv A, Bendix L, et al (2019)

Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts.

Royal Society open science, 6(6):190420 pii:rsos190420.

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr-1 faster in smokers than in non-smokers (95% CI: -2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr-1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

RevDate: 2019-07-17

Kroupa M, Rachakonda SK, Liska V, et al (2019)

Relationship of telomere length in colorectal cancer patients with cancer phenotype and patient prognosis.

British journal of cancer pii:10.1038/s41416-019-0525-3 [Epub ahead of print].

BACKGROUND: Telomeres, repetitive DNA capping ends of eukaryotic chromosomes, are important in the maintenance of genomic integrity. Perturbed telomeres are common features of many human malignancies, including colorectal cancer.

METHODS: Telomere length (TL), measured by a Monochrome Multiplex Real-Time qPCR, was investigated in tumour tissues, adjacent mucosa, and blood from patients with colorectal cancer with different clinicopathological features and its impact on patient survival. TL was also measured in a limited number of liver metastases, non-cancerous liver tissues or corresponding tissues from the same patients.

RESULTS: TL in tumour tissues was shorter than in the adjacent mucosa (P < 0.0001). Shorter TL was observed in tumours with lower stage than in those with advanced stages (P = 0.001). TL was shorter in tumours at the proximal than at the distal sites of the colon (P < 0.0001). Shorter TL was also associated with microsatellite instability (P = 0.001) and mucinous tumour histology (P < 0.0001). Patients with a smaller TL ratio between tumour tissues and the adjacent mucosa were associated with increased overall survival (P = 0.022). Metastasised tumours had shorter telomeres than the adjacent non-cancerous liver tissues (P = 0.0005).

CONCLUSIONS: Overall, the results demonstrate differences in TL between tumours and the adjacent mucosa, between tumours located at different sites and association with patient survival.

RevDate: 2019-07-19

Liew PS, Chen Q, Ng AWR, et al (2019)

Phage N15 protelomerase resolves its tos recognition site into hairpin telomeres within mammalian cells.

Analytical biochemistry, 583:113361 pii:S0003-2697(19)30220-9 [Epub ahead of print].

Phage N15 protelomerase (TelN) cleaves double-stranded circular DNA containing a telomerase-occupancy-site (tos) and rejoins the resulting linear-ends to form closed-hairpin-telomeres in Escherichia coli (E. coli). Continued TelN expression is essential to support resolution of the linear structure. In mammalian cells, no enzyme with TelN-like activities has been found. In this work, we show that phage TelN, expressed transiently and stably in human and mouse cells, recapitulates its native activities in these exogenous environments. We found TelN to accurately resolve tos-DNA in vitro and in vivo within human and mouse cells into linear DNA-containing terminal telomeres that are resistant to RecBCD degradation, a hallmark of protelomerase processing. In stable cells, TelN activity was detectable for at least 60 days, which suggests the possibility of limited silencing of its expression. Correspondingly, linear plasmid containing a 100 kb human β-globin gene expressed for at least 120 h in non-β-globin-expressing mouse cells with TelN presence. Our results demonstrate TelN is able to cut and heal DNA as hairpin-telomeres within mammalian cells, providing a tool for creating novel structures by DNA resolution in these hosts. The TelN protelomerase may be useful for exploring novel technologies for genome interrogation and chromosome engineering.

RevDate: 2019-07-12

Endén K, Tainio J, Hou M, et al (2019)

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.

Pediatric transplantation [Epub ahead of print].

Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.

RevDate: 2019-07-16

Liu R, Liu J, Wang S, et al (2019)

Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death.

Cell death & disease, 10(7):527 pii:10.1038/s41419-019-1768-x.

G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.

RevDate: 2019-07-14

Shin YA (2019)

How Does Obesity and Physical Activity Affect Aging?: Focused on Telomere as a Biomarker of Aging.

Journal of obesity & metabolic syndrome, 28(2):92-104.

Obesity is known to continuously increase systemic inflammation and oxidative stress, leading to shorter telomere length. However, research regarding the correlation between physical activity, exercise, obesity, and telomere length is not consistent. Therefore, this review aims to summarize the effects of obesity, physical activity, and exercise on telomere length. Our search for effects of obesity, physical activity, and exercise, on telomeres was conducted using three computerized databases: Medline, PubMed, and EBSCO. Keywords in the search were "physical activity, exercise and obesity," "physical activity, exercise and telomere," and "obesity and telomere." Improving chronic inflammation and oxidative stress levels can prevent telomere attrition due to obesity. In addition, differences in the anti-aging effects of physical activity and exercise are shown in the post-middle-age period, when telomere length changes, rather than in past exercise habits. Maintaining high cardiorespiratory fitness levels through regular exercise and physical activity in the post-middle-age period minimizes obesity-related diseases and helps maintain telomere length, which is an index of cell senescence.

RevDate: 2019-07-10

Ma S, Sun G, Yang S, et al (2019)

Effects of telomere length on leukemogenesis.

RevDate: 2019-07-19

Hasegawa Y, Yamamoto M, Miyamori J, et al (2019)

Telomere DNA length-dependent regulation of DNA replication timing at internal late replication origins.

Scientific reports, 9(1):9946 pii:10.1038/s41598-019-46229-1.

DNA replication is initiated at replication origins on chromosomes at their scheduled time during S phase of the cell cycle. Replication timing control is highly conserved among eukaryotes but the underlying mechanisms are not fully understood. Recent studies have revealed that some telomere-binding proteins regulate replication timing at late-replicating origins throughout the genome. To investigate the molecular basis of this process, we analyzed the effects of excessive elongation of telomere DNA on replication timing by deleting telomere-associated shelterin proteins in Schizosaccharomyces pombe. We found that rap1∆ and poz1∆ cells showed abnormally accelerated replication at internal late origins but not at subtelomere regions. These defects were suppressed by removal of telomere DNA and by deletion of the telomere-binding protein Taz1. Furthermore, Sds21-a counter protein phosphatase against Dbf4-dependent kinase (DDK)-accumulated at elongated telomeres in a Taz1-dependent manner but was depleted at internal late origins, indicating that highly elongated telomeres sequester Sds21 at telomeres and perturb replication timing at internal regions. These results demonstrate that telomere DNA length is an important determinant of replication timing at internal regions of chromosomes in eukaryotes.

RevDate: 2019-07-10

Fitzpatrick LJ, Olsson M, Parsley LM, et al (2019)

Tail loss and telomeres: consequences of large-scale tissue regeneration in a terrestrial ectotherm.

Biology letters, 15(7):20190151.

Large-scale tissue regeneration has potential consequences for telomere length through increases in cell division and changes in metabolism which increase the potential for oxidative stress damage to telomeres. The effects of regeneration on telomere dynamics have been studied in fish and marine invertebrates, but the literature is scarce for terrestrial species. We experimentally induced tail autotomy in a lizard (Niveoscincus ocellatus) and assessed relative telomere length (RTL) in blood samples before and after partial tail regeneration while concurrently measuring reactive oxygen species (ROS) levels. The change in ROS levels was a significant explanatory variable for the change in RTL over the 60-day experiment. At the average value of ROS change, the mean RTL increased significantly in the control group (intact tails), but there was no such evidence in the regenerating group. By contrast, ROS levels decreased significantly in the regenerating group, but there was no such evidence in the control group. Combined, these results suggest that tail regeneration following autotomy involves a response to oxidative stress and this potentially comes at a cost to telomere repair. This change in telomere maintenance demonstrates a potential long-term cost of tail regeneration beyond the regrowth of tissue itself.

RevDate: 2019-07-11

Ji Y, Dang X, Nguyen LNT, et al (2019)

Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections.

Immunity & ageing : I & A, 16:12 pii:153.

Background: T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions.

Results: We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival.

Conclusion: These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.

RevDate: 2019-07-09

Whittemore K, Vera E, Martínez-Nevado E, et al (2019)

Telomere shortening rate predicts species life span.

Proceedings of the National Academy of Sciences of the United States of America pii:1902452116 [Epub ahead of print].

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

RevDate: 2019-07-18

Benyelles M, Episkopou H, O'Donohue MF, et al (2019)

Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.

EMBO molecular medicine, 11(7):e10201.

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

RevDate: 2019-07-18

Cherfils-Vicini J, E Gilson (2019)

Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells.

EMBO molecular medicine, 11(7):e10845.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: On one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers. Therefore, telomeres are considered potential anti-cancer targets and, to date, most of the studies have focused on telomerase inhibition. However, the development of clinically efficient telomerase targeting therapies is still in its infancy. In this context, the findings reported in this issue of EMBO Molecular Medicine by Bejarano et al (2019) open new avenues for alternative telomere therapies.

RevDate: 2019-07-18

Bejarano L, Bosso G, Louzame J, et al (2019)

Multiple cancer pathways regulate telomere protection.

EMBO molecular medicine, 11(7):e10292.

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo. Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.

RevDate: 2019-07-05

Nguyen MT, Lycett K, Vryer R, et al (2019)

Telomere length: population epidemiology and concordance in Australian children aged 11-12 years and their parents.

BMJ open, 9(Suppl 3):118-126 pii:bmjopen-2017-020263.

OBJECTIVES: To (1) describe the epidemiology of child and adult telomere length, and (2) investigate parent-child telomere length concordance.

DESIGN: Population-based cross-sectional study within the Longitudinal Study of Australian Children.

SETTING: Assessment centres in seven major Australian cities and eight selected regional towns; February 2015 to March 2016.

PARTICIPANTS: Of 1874 participating families, telomere data were available for analysis for 1206 children and 1343 parents, of whom 1143 were parent-child pairs. There were 589 boys and 617 girls; 175 fathers and 1168 mothers.

OUTCOME MEASURES: Relative telomere length (T/S ratio), calculated by comparing telomeric DNA (T) level with the single copy (S) beta-globin gene in venous blood-derived genomic DNA by quantitative real-time PCR.

RESULTS: Mean T/S ratio for all children, boys and girls was 1.09 (SD 0.56), 1.05 (SD 0.53) and 1.13 (SD 0.59), respectively. Mean T/S ratio for all parents, fathers and mothers was 0.81 (SD 0.37), 0.82 (SD 0.36) and 0.81 (SD 0.38), respectively. Parent-child T/S ratio concordance was moderate (correlation 0.24). In adjusted regression models, one unit higher parent T/S ratio was associated with 0.36 (estimated linear regression coefficient (β); 95% CI 0.28 to 0.45) higher child T/S ratio. Concordance was higher in the youngest parent-age tertile (β 0.49; 95% CI 0.34 to 0.64) compared with the middle (β 0.35; 95% CI 0.21 to 0.48) and oldest tertile (β 0.26; 95% CI 0.11 to 0.41; p-trend 0.04). Father-child concordance was 0.34 (95% CI 0.18 to 0.48), while mother-child was 0.22 (95% CI 0.17 to 0.28).

CONCLUSIONS: We provide telomere length population values for children aged 11-12 years and their mid-life parents. Relative telomere length was shorter in adults than children, as expected. There was modest evidence of parent-child concordance, which diminished with increasing parent age.

RevDate: 2019-07-04

Wynchank DS, Bijlenga D, Penninx BW, et al (2019)

Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length.

Sleep pii:5528107 [Epub ahead of print].

OBJECTIVES: We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging.

METHODS: Data from the Netherlands Study of Depression and Anxiety (N=2,936) were used at two waves six years apart, to measure LTL. Telomeres shorten during the lifespan and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analysed the associations between LTL, sleep and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity and childhood trauma.

RESULTS: Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B=-49.9, p=.004), late sleep-onset time (B=-32.4, p=.001), indication of DSPS (B=-73.8, p=.036) and moderately late chronotype in adulthood (B=-71.6, p=.003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B=161.40, p=.037). No predictors showed accelerated LTL attrition over 6 years.

CONCLUSIONS: Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.

RevDate: 2019-07-03

Szczotka M, Kocki J, Iwan E, et al (2019)

Determination of telomere length and telomerase activity in cattle infected with bovine leukaemia virus (BLV).

Polish journal of veterinary sciences, 22(2):391-403.

Telomeres are repetitive sequence structures at the ends of chromosomes. They consist of the double stranded DNA repeats followed by the short single stranded DNA. In humans and other verterbrates the telomeric sequence is composed of tandem of TTAGGG repeats. With each cells division telomeres shorten by up to 200 base pairs. Telomerase is an enzyme responsible for continuous cell growth and is repressed in most somatic cells, except proliferating progenitor cells, but in more than 85% of cancer cells telomerase expression is observed. Tumour cells with metastatic potential may demonstrate a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Determination of telomerase expression was performed with the use of PCR ELISA in samples isolated from bovine leukaemia virus (BLV) infected cows. Telomerase activity was found in almost all investigated samples. The relative telomerase activity (RTA) was higher in infected cows than in healthy animals and the differences were statistically significant (α=0.05). In blood lymphocytes of BLV-infected cows the mean values of telomerase expression determined in real-time PCR were 3534.12 copies, in the healthy group there were 1010.10 copies and these differences were also statistically significant. For telomere length evaluation the Telomere PNA/FITC FISH and Telomere PNA/FITC FISH for flow cytometry were used. The mean fluorescence intensity of telomere sequences calculated on the surface of interphase nuclei of leukaemic blood lymphocytes was lower than that in the control animals and the difference was statistically significant. The mean length of telomeres in BLV- infected and healthy cows was 31.63 ± 12.62 and 38.4 ± 4.03, (p=0.112), respectively.

RevDate: 2019-07-08

Ley B, Torgerson DG, Oldham JM, et al (2019)

Rare Protein-altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

American journal of respiratory and critical care medicine [Epub ahead of print].

RATIONALE: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).

OBJECTIVES: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.

METHODS: Next generation sequences from two CHP cohorts were analyzed to identify variants in TERT, TERC, DKC1, RTEL1, PARN, and TINF2. To qualify, variants were required to have a minor allele frequency <0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using qPCR.

MEASUREMENTS AND MAIN RESULTS: Qualifying variants were identified in 16/144 patients (11.1%, 95% CI 6.5-17.4) in the discovery cohort and 17/209 patients (8.1%, 95% CI 4.8-12.7) in the replication cohort. Age and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 base pairs [bp], 95% CI -933 to -190, p=0.003; replication: -612 bp, 95% CI -870 to -354, p=5.30x10-6) cohorts. Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-sex-ancestry-adjusted hazard ratio [HR] 3.73, 95% CI 1.92-7.28, p=0.0001; replication: HR 2.72, 95% CI 1.26-5.88, p=0.011).

CONCLUSIONS: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

RevDate: 2019-07-03

Cartwright IM (2019)

Modified PNA Telomere and Centromere FISH Protocols.

Methods in molecular biology (Clifton, N.J.), 1984:101-105.

Fluorescence in situ Hybridization (FISH) utilizes peptide nucleic acid (PNA) probes to identify specific DNA sequences. PNA probes have been effectively used to identify chromosome aberrations and have been shown to greatly aid in biodosimetery assays involved in identifying dicentrics. Traditional techniques have required the heat denaturing of the DNA in formamide followed by multiple hours at moderated temperatures to allow the probe to hybridize to its specific target. Over the past 30 years, advancements in both protocols and probes have made FISH a more reliable technique for both biological research and medical diagnostics, additionally the protocol has been shortened to several minutes. We will introduce two modified PNA FISH protocols, a rapid microwave-based approach and nonclassical hybridization protocol.

RevDate: 2019-07-03

Cartwright IM, Haskins JS, TA Kato (2019)

PNA Telomere and Centromere FISH Staining for Accurate Analysis of Radiation-Induced Chromosomal Aberrations.

Methods in molecular biology (Clifton, N.J.), 1984:95-100.

Dicentric and centric ring chromosomes are used for radiation-induced damage analysis and biodosimetry after radiation exposure. However, Giemsa stain-based cytogenetic analysis is labor-intense and time-consuming. Moreover, the disadvantage of Giemsa based chromosome analysis is a potential poor reproducibility when researchers are not fully trained for analysis. These problems come from analysis of morphological abnormality of chromosomal aberrations. Locus-specific FISH probes were used to overcome this problem. Centromere probes can visualize centromere locations and help identify dicentric chromosomes and centric rings. Telomere probes help to identify terminal deletion and telomere fusions. Probes were originally designed with a DNA probe but Peptide nucleic acid (PNA) probes took the place of DNA probes. This chapter introduces PNA telomere and centromere FISH staining and accurate analysis of chromosomal aberrations.

RevDate: 2019-07-03

Adwan Shekhidem H, Sharvit L, Leman E, et al (2019)

Telomeres and Longevity: A Cause or an Effect?.

International journal of molecular sciences, 20(13): pii:ijms20133233.

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

RevDate: 2019-07-04

Tian Y, Wang S, Jiao F, et al (2019)

Telomere Length: A Potential Biomarker for the Risk and Prognosis of Stroke.

Frontiers in neurology, 10:624.

Stroke is one of the leading causes of death and disability worldwide. Age is associated with increased risk of stroke, while telomere length shortening plays a pivotal role in the process of aging. Moreover, telomere length shortening is associated with many risk factors of stroke in addition to age. Accumulated evidence shows that short leukocyte telomere length is not only associated with stroke occurrence but also associated with post-stroke recovery in the elderly population. In this review, we aimed to summarize the association between leukocyte telomere length and stroke, and discuss that telomere length might serve as a potential biomarker to predict the risk and prognosis of stroke.

RevDate: 2019-07-04

Kachuri L, Helby J, Bojesen SE, et al (2019)

Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 28(7):1228-1237.

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus.

METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases.

RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3).

CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration.

IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

RevDate: 2019-07-02

Carugno M, Maggioni C, Crespi E, et al (2019)

Night Shift Work, DNA Methylation and Telomere Length: An Investigation on Hospital Female Nurses.

International journal of environmental research and public health, 16(13): pii:ijerph16132292.

Increased breast cancer risk has been reported in some night shift (NS) workers but underlying biological mechanisms are still unclear. We assessed the association between NS work and DNA methylation of tumor suppressor (TP53, CDKN2A, BRCA1, BRCA2) and estrogen receptor (ESR1, ESR2) genes, methylation of repetitive elements (LINE-1, Alu), and telomere length (TL). Forty six female nurses employed in NS for at least two years were matched by age (30-45 years) and length of service (≥1 year) with 51 female colleagues not working in NS. Each subject underwent a semi-structured interview and gave a blood sample. We applied linear regression and spline models adjusted for age, BMI, smoking habit, oral contraceptive use, parity and marital status/age at marriage. Currently working in NS was associated with ESR1 hypomethylation (β: -1.85 (95%CI: -3.03; -0.67), p = 0.003). In current and former NS workers we observed TP53 (-0.93 (-1.73; -0.12), p = 0.03) and BRCA1 (-1.14 (-1.71; -0.58), p <0.001) hypomethylation. We found an increase between TL and number of years in NS in subjects employed in NS <12 years (0.06 (0.03; 0.09), p <0.001), while a decrease if employed in NS ≥12 years (-0.07 -0.10; -0.04), p <0.001). Our findings show NS-associated markers potentially involved in cellular aging, genomic instability, and cancer development.

RevDate: 2019-07-04

Toland AE (2019)

POT1 pathogenic variants: not all telomere pathway genes are equal in risk of hereditary cutaneous melanoma.

The British journal of dermatology, 181(1):14-15.

RevDate: 2019-07-17

Konečná K, Lyčka M, Nohelová L, et al (2019)

Holocaust history is not reflected in telomere homeostasis in survivors and their offspring.

Journal of psychiatric research, 117:7-14 pii:S0022-3956(19)30161-X [Epub ahead of print].

Telomeres, nucleoprotein structures at the ends of eukaryotic chromosomes, are crucial for the maintenance of genome integrity. While the lengths of telomeres at birth are determined genetically, many factors including environmental and living conditions affect the telomere lengths during a lifespan. In this context, extreme and long-term stress has been shown to negatively impact telomeres and their protective function, with even offspring being influenced by the stress experienced by parents. Using quantitative PCR, the relative lengths of telomeres of survivors of the Holocaust during World War II and two generations of their offspring were analyzed. These data were related to those of control groups, persons of comparable age without a strong life stress experience. In contrast to previous studies of other stress-exposed groups, the relative lengths of telomeres were comparable in groups of persons exposed to Holocaust-related stress and their progenies, and in control groups. Interestingly, shorter telomeres of Holocaust survivors of the age under 12 in the year 1945 compared to Holocaust survivors of the age above 12 were detected. Our results are discussed with respect to certain exceptionality of persons having been able to cope with an extreme stress more than 70 years ago and living to a very old age.

RevDate: 2019-07-18

Welendorf C, Nicoletti CF, Pinhel MAS, et al (2019)

Obesity, weight loss, and its influence on telomere length: New insights for personalized nutrition.

Nutrition (Burbank, Los Angeles County, Calif.), 66:115-121 pii:S0899-9007(19)30026-7 [Epub ahead of print].

Telomeres are structures located at the ends of chromosomes associated with proteins, from the shelterin complex, which are responsible for the protection and preservation of the genetic material. The telomere length (TL) progressively decreases with each cell division, and recent evidence suggests that lifestyle can lead to telomere shortening. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. Thus, the aim of the present review was to show the relationship between obesity and TL in addition to the possible risk factors for its shortening and how the different strategies for weight loss can modulate TL. As the crucial result, we can consider the association between TL and weight loss and adiposity changes after different interventions, showing that TL may be used as a biomarker of responses to obesity treatment.

RevDate: 2019-06-29

Nault JC, Ningarhari M, Rebouissou S, et al (2019)

The role of telomeres and telomerase in cirrhosis and liver cancer.

Nature reviews. Gastroenterology & hepatology pii:10.1038/s41575-019-0165-3 [Epub ahead of print].

Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.

RevDate: 2019-07-02

Manna S, McCarthy C, FP McCarthy (2019)

Placental Ageing in Adverse Pregnancy Outcomes: Telomere Shortening, Cell Senescence, and Mitochondrial Dysfunction.

Oxidative medicine and cellular longevity, 2019:3095383.

Preeclampsia is a multisystemic pregnancy disorder and a major cause of maternal and neonatal morbidity and mortality worldwide. The exact pathophysiology of preeclampsia remains unclear; however, it is speculated that the various pathologies can be attributed to impaired vascular remodelling and elevated oxidative stress within the placenta. Oxidative stress plays a key role in cell ageing, and the persistent presence of elevated oxidative stress precipitates cellular senescence and mitochondrial dysfunction, resulting in premature ageing of the placenta. Premature ageing of the placenta is associated with placental insufficiency, which reduces the functional capacity of this critical organ and leads to abnormal pregnancy outcomes. The changes brought about by oxidative insults are irreversible and often lead to deleterious modifications in macromolecules such as lipids and proteins, DNA mutations, and alteration of mitochondrial functioning and dynamics. In this review, we have summarized the current knowledge of placental ageing in the aetiology of adverse pregnancy outcomes and discussed the hallmarks of ageing which could be potential markers for preeclampsia and fetal growth restriction.

RevDate: 2019-06-28

Arish N, Petukhov D, SB Wallach-Dayan (2019)

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications.

International journal of molecular sciences, 20(12): pii:ijms20122996.

Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell senescence. At a cellular level, telomere damage may result from genotoxic stress, decreased activity of telomerase enzyme complex, dysfunction of shelterin proteins, or changes in expression of telomere-associated RNA such as TERRA. Clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.). Thus, telomere length and maintenance can serve as an important prognostic factor as well as a potential target for new strategies of treatment for interstitial lung diseases (ILDs) and associated pulmonary pathologies.

RevDate: 2019-06-27

Lee EY, Oh SS, White MJ, et al (2019)

Ambient Air Pollution, Asthma Drug Response and Telomere Length in African American Youth.

The Journal of allergy and clinical immunology pii:S0091-6749(19)30820-6 [Epub ahead of print].

BACKGROUND: Telomere length can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between telomere length, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children.

OBJECTIVES: To investigate the associations between exposures to ambient air pollutants and telomere length (TL) in African American children and adolescents, and to examine whether African ancestry, asthma status and steroid medication use alter the association.

METHODS: Linear regression was used to examine associations between absolute TL and the estimated annual average residential ozone (O3) and fine particulate matter (PM2.5) exposures in a cross-sectional analysis of 1,072 children in an existing asthma case-control study. African ancestry, asthma status and the use of steroid medications were examined as effect modifiers.

RESULTS: Participants' absolute TL was measured by quantitative polymerase chain reaction. A 1-ppb and a 1-μg/m3 increase in annual average exposure to O3 and PM2.5 were associated with a decrease in absolute TL of 37.1 kb (95% CI: -66.7 kb to -7.4 kb) and 57.1 kb (95% CI: -118.1 kb to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and the pollutants. Past year exposure to O3 and PM2.5 were associated with shorter TL in patients without steroid use.

CONCLUSION: Exposure to air pollution was associated with shorter telomere length in non-asthmatic children and adolescents. This was not the case for asthmatic children as a group, but those on steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood may help to preserve telomere length.

RevDate: 2019-07-07

Minami R, Takahama S, M Yamamoto (2019)

Correlates of telomere length shortening in peripheral leukocytes of HIV-infected individuals and association with leukoaraiosis.

PloS one, 14(6):e0218996 pii:PONE-D-19-02380.

Telomere length (TL) is a marker of cellular and biological aging. Human immunodeficiency virus (HIV) infection has been reported to be associated with short TLs, which suggests that accelerated biological aging occurs in some cellular compartments of HIV+ individuals. In this study, we measured the TLs of peripheral leukocytes of HIV+ and healthy individuals and examined the biological and environmental correlates of TL. We also investigated the influence of TL on leukoaraiosis, an indicator of cerebral small vessel disease, in HIV+ individuals. Three hundred and twenty-five HIV+ individuals who received stable combination antiretroviral therapy (cART) for >1 year and achieved viral loads of <40 RNA copies/mL were enrolled along with 147 healthy individuals. Relative TLs of leukocytes were estimated by quantitative real-time polymerase chain reaction. Leukoaraiosis was assessed in 184 HIV+ individuals by fluid-attenuated inversion recovery magnetic resonance imaging. We analyzed several covariates, including markers of HIV infection, cART, and social/environmental factors; variables associated with TL length in univariate analyses were incorporated into multivariate models. The TLs of peripheral leukocytes of HIV+ individuals were significantly shorter than those of healthy individuals, and the rate of LT length decline with increasing age was greater. Linear regression analysis showed that in HIV+ individuals, increasing age, cART without integrase-stand transfer inhibitors (INSTI), failure to achieve viral loads of <40 copies/mL within 1 year of initiating cART, and substance use were significantly associated with shorter TLs, even after adjustment for the effects of age. Logistic regression analysis indicated an increasing risk of leukoaraiosis was associated with older age, shorter TLs, hypertension, and carotid artery plaque. Multivariate regression analysis indicated that older age and shorter TLs were significant risk factors for leukoaraiosis. In summary, our data showed that TL shortening in HIV+ individuals was independently associated with leukoaraiosis, and was associated with age, control of viral loads, use of INSTI, and substance use. Our results suggest that effective viral control and less toxic cART can help reduce TL shortening and improve outcomes among HIV+ individuals.

RevDate: 2019-06-27

Chen X, Wei S, Ma H, et al (2019)

Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.

Cancer medicine [Epub ahead of print].

BACKGROUND: Although high-risk human papillomavirus (HR-HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV-infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown.

METHODS: This case-control study included 591 cervical cancer patients and 373 cancer-free controls, all of whom were infected with HR-HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis.

RESULTS: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (Ptrend < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose-response relationship of shorter RTL on lower risk of cervical cancer (Ptrend < 0.001).

CONCLUSION: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR-HPV-positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.

RevDate: 2019-06-28

Wysoczanska B, Dratwa M, Gebura K, et al (2019)

Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia.

OncoTargets and therapy, 12:4309-4320 pii:198313.

Background: The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that is essential for maintenance of telomere length. We aimed to find out whether variability within the TERT gene could be associated with telomere length and development of the disease in non-treated patients with chronic lymphocytic leukemia (CLL). Materials and methods: Telomere length, rs2736100, rs2853690, rs33954691, rs35033501 single-nucleotide polymorphisms, and variable number of tandem repeats (VNTR-MNS16A) were assessed in patients at diagnosis. In addition, blood donors served as controls for the polymorphism studies. Results: The minor rs35033501 A variant was more frequent among CLL patients than in healthy controls (OR=3.488, p=0.039). CLL patients over 60 years of age were characterized with lower disease stage at diagnosis (p=0.001 and p=0.008, for the Rai and Binet criteria, respectively). The MNS16A VNTR-243 short allele was more frequent in patients with a low disease stage (p=0.020 and p=0.028, for the Rai and Binet staging system) and also among older patients having longer telomeres (p=0.046). Patients with Rai 0-I stage were characterized with longer telomeres than those with more advanced disease (p=0.030). This relationship was especially pronounced in patients carrying the rs2736100 C allele, independently of the criteria used, ie, Binet (p=0.048) or Rai (p=0.001). Conclusion: Our results showed that the genetic variation within the TERT gene seems to play a regulatory role in CLL and telomere length.

RevDate: 2019-06-28

Singchat W, Kraichak E, Tawichasri P, et al (2019)

Dynamics of telomere length in captive Siamese cobra (Naja kaouthia) related to age and sex.

Ecology and evolution, 9(11):6366-6377 pii:ECE35208.

Telomeres comprise tandem repeated DNA sequences that protect the ends of chromosomes from deterioration or fusion with neighboring chromosomes, and their lengths might vary with sex and age. Here, age- and sex-related telomere lengths in male and female captive Siamese cobras (Naja kaouthia) were investigated using quantitative real-time polymerase chain reaction based on cross-sectional data. A negative correlation was shown between telomere length and body size in males but not in females. Age-related sex differences were also recorded. Juvenile female snakes have shorter telomeres relative to males at up to 5 years of age, while body size also rapidly increases during this period. This suggests that an accelerated increase in telomere length of female cobra results from sex hormone stimulation to telomerase activity, reflecting sexually dimorphic phenotypic traits. This might also result from amplification of telomeric repeats on sex chromosomes. By contrast, female Siamese cobras older than 5 years had longer telomeres than males. Diverse sex hormone levels and oxidative stress parameters between sexes may affect telomere length.

RevDate: 2019-06-28

Rollings N, Friesen CR, Whittington CM, et al (2019)

Sex- And tissue-specific differences in telomere length in a reptile.

Ecology and evolution, 9(11):6211-6219 pii:ECE35164.

The usage of telomere length (TL) in blood as a proxy for the TL of other tissues relies on the assumption that telomere dynamics across all tissues are similar. However, telomere attrition can be caused by reactive oxygen species (ROS) which may vary with metabolic rate, which itself varies across organs depending upon the life history strategy of an organism. Thus, we chose to measure the telomeres of various cell types in juvenile painted dragon lizards, Ctenophorus pictus, given their unusual life history strategy. Individuals typically only experience a single mating season. We measured the TL of male and female dragons using qPCR and observed that TL varied with tissue type and sex. Telomeres of blood cells were longer than those of liver, heart, brain, and spleen, and females had longer telomeres than males. Brain telomeres in males were approximately half the length of those in females. Telomeric attrition in the male brain may be due to the need for rapid learning of reproductive tactics (territory patrol and defense, mate-finding). Significant correlations between the TL of tissue types suggest that blood TL may be a useful proxy for the TL of other tissues. Our comparison of organ-specific telomere dynamics, the first in a reptile, suggests that the usage of blood TL as a proxy requires careful consideration of the life history strategy of the organism.

RevDate: 2019-06-25

Banszerus VL, Vetter VM, Salewsky B, et al (2019)

Exploring the Relationship of Relative Telomere Length and the Epigenetic Clock in the LipidCardio Cohort.

International journal of molecular sciences, 20(12): pii:ijms20123032.

Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual's chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number of cytosine-phosphate-guanine sites (CpGs) selected by penalized regression analysis. Here, an established methylation-sensitive single nucleotide primer extension method was adapted, to estimate the epigenetic age of the 1005 participants of the LipidCardio Study, a patient cohort characterised by high prevalence of cardiovascular disease, based on a seven CpGs epigenetic clock. Furthermore, we measured relative leukocyte telomere length (rLTL) to assess the relationship between the established and the promising new measure of biological age. Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age= 69.68 ± 11.01 years; mean DNAm age acceleration = -0.01 ± 7.83 years). While we detected a significant correlation between chronological age and DNAm age (n = 779, R = 0.69), we found neither evidence of an association between rLTL and the DNAm age (β = 3.00, p = 0.18) nor rLTL and the DNAm age acceleration (β = 2.76, p = 0.22) in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age.

RevDate: 2019-06-23

Subedi P, Nembrini S, An Q, et al (2019)

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

GeroScience pii:10.1007/s11357-019-00080-4 [Epub ahead of print].

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.

RevDate: 2019-06-20

Nonaka K, Aida J, Takubo K, et al (2019)

Correlation between Differentiation of Adrenocortical Zones and Telomere Lengths measured by Q-FISH.

The Journal of clinical endocrinology and metabolism pii:5520382 [Epub ahead of print].

CONTEXT: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands.

OBJECTIVE: We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood.

METHODS: Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR), using quantitative fluorescence in situ hybridization.

RESULTS: NTCR of ZR cells was the longest, followed in decreasing order by that of ZG and ZF cells in subjects aged 20-68 years, but no significant differences in NTCR were detected among these three zones in the group under 20 years of age. NTCR of ZR increased with age in subjects aged 20-68 years, while no significant age-dependent changes in NTCR were detected in the group under 20 years of age.

CONCLUSION: The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.

RevDate: 2019-06-23

Tutton S, Deng Z, Gulve N, et al (2019)

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.

Oncotarget, 10(38):3581-3591 pii:26980.

Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

RevDate: 2019-07-17

Tarik M, Ramakrishnan L, Sinha S, et al (2019)

Association of birth outcomes and postnatal growth with adult leukocyte telomere length: Data from New Delhi Birth Cohort.

Maternal & child nutrition [Epub ahead of print].

Born small for gestational age due to undernutrition in utero and subsequent catch-up growth is associated with risk of developing chronic diseases in adulthood. Telomere length has been shown to be a predictor of these age-related diseases and may be a link between birth size, a surrogate for foetal undernutrition, and adult chronic diseases. We assessed the relationship of leukocyte telomere length in adult life with birth outcomes and serial change in body mass index (BMI) from birth to adulthood. Leukocyte relative telomere length (RTL) was measured by MMqPCR in 1,309 subjects from New Delhi Birth Cohort who participated in two phases of the study between 2006-2009 (Phase 6) and 2012-2015 (Phase 7) at a mean age of 39.08 (±3.29), and its association with birth outcomes and conditional BMI gain at 2, 11, and 29 years was assessed in a mixed regression model. We did not find any significant association of RTL with body size at birth including birthweight, birth length, and birth BMI. Gestational age was positively associated with RTL (P = .017, multivariate model: P = .039). Conditional BMI gain at 2 and 11 years was not associated with RTL. BMI gain at 29 year was negatively associated with RTL in multivariate model (P = .015). Born small for gestational age was not associated with RTL in adulthood. Leukocyte telomere attrition was observed in those born before 37 weeks of gestational age as well as in those who gained weight as adults, which may predispose to chronic diseases.

RevDate: 2019-06-18

Soumboundou M, Nkengurutse I, Dossou J, et al (2019)

Biological Dosimetry Network in Africa: Establishment of a Dose-response Curve Using Telomere and Centromere Staining.

Health physics [Epub ahead of print].

PURPOSE: Biological dosimetry, based on the relationship between the absorbed dose after exposure to ionizing radiation and the frequency of scored aberrations, has been and continues to be an important tool for estimating the dose after exposure. Dicentric chromosomes are considered to be the most specific and sensitive aberration related to radiation exposure. Here, we established the dose-response curve following in vitro irradiation of circulating lymphocytes from healthy donors from three African countries after scoring unstable chromosomal aberrations.

MATERIALS AND METHODS: Blood samples from 16 African donors were exposed to various doses (0 to 4 Gy) using an X-RAD320 x-ray system with a maximum photon energy of 250 kV at a dose rate of 0.1 Gy min. Blood lymphocytes were cultured for 48 h, and chromosomal aberrations were scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined.

RESULTS: No dicentric chromosomes were found after the analysis of 2,669 first-division metaphases before in vitro exposure. We established a linear-quadratic dose-response curve based on the frequency of dicentric and ring chromosomes and calculated double-strand breaks, taking into account all scored aberrations.

CONCLUSION: The generation of a specific dose-response curve for African donors will allow the practice of precise biological dosimetry in these countries. This work is the first step towards realizing an African biodosimetry network and the establishment of a biological dosimetry laboratory, which could play a major role in the application of radioprotection norms.

RevDate: 2019-06-18

Borbora D, Dutta HK, Devi KR, et al (2019)

Long telomeres cooperate with p53, MDM2, and p21 polymorphisms to elevate pediatric solid tumor risk.

Pediatrics international : official journal of the Japan Pediatric Society [Epub ahead of print].

BACKGROUND: While leukocyte telomere length has been linked with the altered risks of adult cancers, limited information is available regarding its association with the risk of pediatric solid tumors. We investigated the association of telomeric alterations with the risk of pediatric solid tumors. We also investigated, whether altered telomeres cooperated with the TP53 rs1042522, MDM2 rs2279744 and CDKN1A (p21cip1) rs1059234 single nucleotide polymorphisms to modify cancer risk.

METHODS: A total of 101 tumor cases and 202 controls were recruited for this age and gender matched case-control study. The relative telomere length (RTL) was determined in peripheral blood leukocytes using quantitative real-time PCR and the polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique.

RESULTS: By using median RTL in the healthy controls as a cutoff, children with longer telomeres were at an increased risk of developing a solid tumor (odds ratio [OR] 2.70; P < 0.01). When participants were categorized according to quartile RTL values of controls, a significant dose-response relation was observed (χ2 - 10.95; P < 0.001). The risk for tumors increased nearly 3-fold (P = 0.001) for the triple interaction among RTL * TP53 rs1042522 * p21 cip1 rs1059234 compared with the maximum effect of any single factor, although the interaction effect was less than additive. The MDM2 rs2279744 GG genotype reduced pediatric solid tumor risk significantly (OR 0.51).

CONCLUSION: These findings suggest that, combined analysis of telomeres and genetic polymorphisms in the TP53 pathway can provide important clues to understanding pediatric solid tumor etiology.

RevDate: 2019-06-18

Ramos-Ibeas P, Pericuesta E, Peral-Sanchez I, et al (2019)

Longitudinal analysis of somatic and germ-cell telomere dynamics in outbred mice.

Molecular reproduction and development [Epub ahead of print].

Although telomere length (TL) shortens with age in most tissues, an age-related increase in length has been described in sperm through a mechanism that is not yet fully understood. Changes in TL with age in the same individual have not been explored. This longitudinal study examines TL dynamics in somatic tissue and gametes during an entire lifespan in an outbred mouse population (from 8 to up to 114 weeks of age). Our findings indicate a reduced life expectancy in males compared to females (84.75 ± 9.23 vs. 113.16 ± 0.20 weeks) and significant variability in TL dynamics between individuals. While with aging, a clear reduction in TL was produced in somatic cells and oocytes, telomeres in sperm cells significantly lengthened. Finally, we found evidence indicating that telomere elongation in sperm during aging may be dependent on different mechanisms, such as the survival of spermatogonia with longer telomeres and the alternative lengthening of telomeres mechanism in meiotic and postmeiotic spermatogenic cells.

RevDate: 2019-07-16

Gong P, Wang H, Zhang J, et al (2019)

Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.

Translational oncology, 12(9):1164-1176 pii:S1936-5233(19)30202-5 [Epub ahead of print].

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

RevDate: 2019-07-12

Guérin TM, Béneut C, Barinova N, et al (2019)

Condensin-Mediated Chromosome Folding and Internal Telomeres Drive Dicentric Severing by Cytokinesis.

Molecular cell, 75(1):131-144.e3.

In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.

RevDate: 2019-06-16

Sutanto SSI, McLennan SV, Keech AC, et al (2019)

Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.

Journal of cell communication and signaling pii:10.1007/s12079-019-00521-x [Epub ahead of print].

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.

RevDate: 2019-07-07

Miura A, A Matsuura (2019)

Phosphatase-dependent fluctuations in DNA-damage checkpoint activation at partially defective telomeres.

Biochemical and biophysical research communications, 516(1):133-137.

Telomeres protect the ends of eukaryotic chromosomes, and telomere shortening causes irreversible cell-cycle arrest through activation of the DNA-damage checkpoint. In this study, we found that deletion of PPH3, encoding a 2A-like protein phosphatase, accelerated telomere-shortening-mediated senescence without affecting normal telomere length or the telomere erosion rate in Saccharomyces cerevisiae. Moreover, the loss of PPH3 increased sensitivity to telomere dysfunction. The detection of telomere abnormalities by DNA-damage sensors was not an all-or-none response, implying that Pph3 helps determine the border between normal and dysfunctional telomeres by suppressing premature activation of the DNA-damage checkpoint.

RevDate: 2019-06-15

Donati B, A Ciarrocchi (2019)

Telomerase and Telomeres Biology in Thyroid Cancer.

International journal of molecular sciences, 20(12): pii:ijms20122887.

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

RevDate: 2019-06-18

Xu X, Hu H, Lin Y, et al (2019)

Differences in Leukocyte Telomere Length between Coronary Heart Disease and Normal Population: A Multipopulation Meta-Analysis.

BioMed research international, 2019:5046867.

Coronary heart disease (CHD) is one of the most common causes of death in the world. Numerous studies have shown that as the degree of atherosclerotic disease increases, leukocyte telomere length gradually decreases. Short telomeres increase the risk of all-cause death and cardiovascular death. However, the reported results are not consistent, since the experimental design method, the measurement method, and the disease outcome are different. Therefore, we searched five major literature databases (Pubmed, Web of science, Embase, CNKI, and Wangfang) and finally included 18 eligible articles (including 5,150 patients with CHD and 9341 controls). We found that telomere length in patients with CHD was significantly shorter than that in controls, and the telomere length was inversely correlated with the severity of CHD. Subgroup analysis showed that telomere shortening was the most significant in Asian patients with CHD, in CHD patients with an average age <65 years, and in men with CHD. The mechanism of shortening the telomere length leading to the occurrence and development of CHD is worthy of further study.

RevDate: 2019-07-18

Cherfils-Vicini J, E Gilson (2019)

Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells.

EMBO molecular medicine pii:emmm.201910845 [Epub ahead of print].

RevDate: 2019-07-18

Bejarano L, Bosso G, Louzame J, et al (2019)

Multiple cancer pathways regulate telomere protection.

EMBO molecular medicine pii:emmm.201910292 [Epub ahead of print].

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.

RevDate: 2019-06-14

Zhang Y, Guo Y, Zhou G, et al (2019)

Regulation of Telomere Length and Atherosclerosis by Protection of Telomeres 1 Protein.

Journal of nanoscience and nanotechnology, 19(12):7953-7959.

The aim of this study was to investigate the manifestation and significance of changes in both telomere length and the expression of human telomere protective protein (hPOT1) in the peripheral blood leukocytes of patients with atherosclerosis (AS). One hundred subjects-excluding those with acute or chronic inflammation, cancer, and autoimmune diseases-were enrolled in this study and divided into two groups: the atherosclerosis group (AS group) and control group. We extracted peripheral blood leukocyte DNA along with its peripheral proteins. After purity testing, a digoxigeninlabeled telomere probe was used for Southern blotting; the length of the telomeres was obtained by image scanning and software analysis. After extracting the peripheral proteins, hPOT1 expression was detected by western blotting and scanned with an image analysis software system. We found that the telomere lengths in the peripheral blood leukocytes of AS and control groups were 7.45 ± 1.15 kb versus 8.11 ± 0.69 kb, respectively, and that the difference between them was statistically significant (p < 0.005). The expression level of hPOT1 protein in the peripheral blood leukocytes of the AS group was significantly higher than that of the control group (t = 3.77, p < 0.01). As can be determined from these results, telomere length in the peripheral blood leukocytes of AS patients was significantly shorter compared with that of the control group. The regulation of telomere length by hPOT1 by negative regulation may be one of the influencing factors in AS. Therefore, it is suggested that change in telomere length may play a role in the occurrence and development of AS.

RevDate: 2019-07-11
CmpDate: 2019-07-11

Zhang Y, Hua RN, Xiang D, et al (2019)

Single-molecule counting of oxidative DNA damage in telomeres from cancer cells.

Chemical communications (Cambridge, England), 55(53):7627-7630.

We demonstrate for the first time the single-molecule counting of oxidative DNA damage in telomeres from a human cervical carcinoma cell line (HeLa cells). This method exhibits high sensitivity towards oxidative DNA damage with a detection limit as low as 9.3 × 10-17 M and good discrimination capability down to the 0.001% oxidative damage level. Moreover, this method can quantify the number of oxidative damaged bases (34-44) in telomeres in each HeLa cell treated with 1000 μM H2O2.

RevDate: 2019-06-16

Khan RJ, Gebreab SY, Gaye A, et al (2019)

Associations of smoking indicators and cotinine levels with telomere length: National Health and Nutrition Examination Survey.

Preventive medicine reports, 15:100895 pii:100895.

The influence of smoking exposure on telomere length with a focus on the impact of race has rarely been discussed. We performed a cross sectional analysis into the associations of smoking indicators with leukocyte telomere length (LTL) by race among 5864 nationally representative sample of US adults (≥20 years). Data from 1999 to 2002 National Health and Nutrition Examination Survey was used for the analysis. Smoking indicators were assessed by interviews and serum cotinine levels. LTL was quantified by polymerase chain reaction. Multiple linear regressions were used to assess the association with adjustment for covariates, sample weights and design effects separately for Whites, Blacks and Mexican Americans. The intensity of smoking, measured by the average number of cigarettes consumed per day, was negatively associated with LTL among Whites (β: -3.87, 95% CI: -5.98 to -1.21) and among Blacks (β: -15.46, 95% CI: -29.79 to -2.12) participants. Compared with cotinine level < 0.05 ng/ml, cotinine level ≥3 ng/ml was associated with shorter LTL (β: -77.92, 95% CI = -143.05 to -11.70) among Whites, but not among Blacks. We found increased number of cigarette consumption to be associated with shorter LTL in both Blacks and Whites, indicating that the impact of smoking on life-shortening diseases could partly be explained by telomere biology. Increased cotinine concentration however, was associated with shorter LTL only among Whites, not among Blacks. This differential relationship that we observed may have implications in interpreting cotinine as an objective biomarker of smoking exposure across races and warrant additional prospective investigation.

RevDate: 2019-07-19

Cao D, Zhao J, Nguyan LN, et al (2019)

Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions.

Frontiers in immunology, 10:1152.

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.

RevDate: 2019-06-16

Bürgin D, O'Donovan A, d'Huart D, et al (2019)

Adverse Childhood Experiences and Telomere Length a Look Into the Heterogeneity of Findings-A Narrative Review.

Frontiers in neuroscience, 13:490.

Background: Adverse childhood experiences (ACEs) have been associated with poor mental and somatic health. Accumulating evidence indicates that accelerated biological aging-indexed by altered telomere-related markers-may contribute to associations between ACEs and negative long-term health outcomes. Telomeres are repeated, non-coding deoxyribonucleic acid (DNA) sequences at the end of chromosomes. Telomeres shorten during repeated cell divisions over time and are being used as a marker of biological aging. Objectives: The aim of the current paper is to review the literature on the relationship between ACEs and telomere length (TL), with a specific focus on how the heterogeneity of sample and ACEs characteristics lead to varying associations between ACEs and TL. Methods: Multiple databases were searched for relevant English peer-reviewed articles. Thirty-eight papers were found to be eligible for inclusion in the current review. Results: Overall, the studies indicated a negative association between ACEs and TL, although many papers presented mixed findings and about a quarter of eligible studies found no association. Studies with smaller sample sizes more often reported significant associations than studies with larger samples. Also, studies reporting on non-clinical and younger samples more often found associations between ACEs and TL compared to studies with clinical and older samples. Reviewing the included studies based on the "Stressor Exposure Characteristics" recently proposed by Epel et al. (2018) revealed a lack of detailed information regarding ACEs characteristics in many studies. Conclusion: Overall, it is difficult to achieve firm conclusions about associations of ACEs with TL due to the heterogeneity of study and ACE characteristics and the heterogeneity in reported findings. The field would benefit from more detailed descriptions of study samples and measurement of ACEs.

RevDate: 2019-06-12

Shah A, J Shah (2019)

Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes.

JAMA surgery pii:2735963 [Epub ahead of print].

RevDate: 2019-06-12

Morton J, Garg T, N Leva (2019)

Concerning Greater Social Contexts in Bariatric Surgery Availability and Telomere Length Outcomes-Reply.

JAMA surgery pii:2735964 [Epub ahead of print].

RevDate: 2019-06-15

Willis M, Staudinger UM, Factor-Litvak P, et al (2019)

Stress and Salivary Telomere Length in the Second Half of Life: A Comparison of Life-course Models.

Advances in life course research, 39:34-41.

Background: Previous research has explored the relationship between childhood and adulthood stressful life events (SLEs) and adult salivary telomere length (TL), but no research to date has tested different life-course models in which stress in adulthood may fully, partly, or not mediate the relationship between childhood stress and adult TL.

Methods: To fill this gap, we elaborate over previous work by Puterman et al. (2016) and other standard models that do not account for the temporal order of stressors in childhood and adulthood, by using structural equation modeling (SEM) for a sample of 5,754 Health and Retirement Study (HRS) participants to compare the fit of three nested life-course models-social trajectory, early critical period, and cumulative risk.

Results: Results indicated that the social trajectory model, in which the association between childhood SLEs and TL in later adulthood is fully mediated by adulthood SLEs, fit the data better than the early critical period (no mediation) and cumulative risk (partial mediation) models.

Conclusion: In the social trajectory model, childhood SLEs are related to TL in later life only through adulthood SLEs. The direct physiological effect of childhood SLEs on TL in later life would be overestimated if adulthood SLEs are overlooked.

RevDate: 2019-06-22

Weng Q, Deng K, Wu F, et al (2019)

Leukocyte telomere length, lipid parameters and gestational diabetes risk: a case-control study in a Chinese population.

Scientific reports, 9(1):8483 pii:10.1038/s41598-019-44968-9.

Telomere length (TL) is linked to various age-related diseases, but little is known about telomeres in gestational diabetes mellitus (GDM). We surveyed 509 subjects (113 GDM patients and 396 frequency matched controls) in Nanjing Drum Tower Hospital, Jiangsu province of eastern China. Relative telomere length (RTL) of genomic DNA extracted from peripheral blood leukocytes was measured using quantitative polymerase chain reaction (qPCR). Odds ratios (OR) and 95% confidence interval (CI) of GDM risk were calculated across tertiles of RTL using logistic regression model. Lipid parameters during the third trimesters of gestation (after 32 weeks) were collected from medical records. The general linear correlation test was used to explore the associations of lipid parameters with RTL. Our results showed that the RTL in GDM patients were significantly shorter than controls (0.302 ± 0.112 vs. 0.336 ± 0.164, P = 0.046). However, the GDM risk was significantly increased in subjects with median RTL (adjusted OR [aOR]: 1.936, 95% CI: 1.086, 3.453, P = 0.025) and the shortest RTL (aOR: 1.795, 95% CI: 1.004, 3.207, P = 0.048), compared to subjects with longest RTL. We also demonstrated that the lipid ratios (TC/TG, LDL/TG, HDL/TG, LDL/TC, TC/LDL) were significantly associated with RTL among controls. Overall, the present study indicated that attrition of telomeres would increase GDM risk among pregnant women, and the altered lipid levels may play an important role in RTL related GDM risk and pathogenesis.

RevDate: 2019-07-03

Vasilopoulos E, Fragkiadaki P, Kalliora C, et al (2019)

The association of female and male infertility with telomere length (Review).

International journal of molecular medicine, 44(2):375-389.

Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.

RevDate: 2019-06-19
CmpDate: 2019-06-17

Dorajoo R, Chang X, Gurung RL, et al (2019)

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Nature communications, 10(1):2491 pii:10.1038/s41467-019-10443-2.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

RevDate: 2019-07-19

Min J, Wright WE, JW Shay (2019)

Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52.

Genes & development, 33(13-14):814-827.

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.

RevDate: 2019-07-18

Benyelles M, Episkopou H, O'Donohue MF, et al (2019)

Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.

EMBO molecular medicine pii:emmm.201810201 [Epub ahead of print].

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

RevDate: 2019-07-15

Myers KO, Boubakari I, Yusuf KK, et al (2019)

The effect of maternal vitamin C intake on fetal telomere length.

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians [Epub ahead of print].

Background: A telomere is a nucleoprotein structure that is located at the end of a chromosome. Reduced telomere length manifests as physical ailments such as the increased risk of age-related illnesses. These age-related illnesses include heart disease and failure. Telomere length has been studied extensively in adults; however, limited information exists regarding maternal dietary influences on fetal telomere length. Objectives: The objective of this study is to investigate the relationship between maternal vitamin C intake and fetal telomere length. Methods: Data for this analysis were collected as part of a prospective cohort study that recruited pregnant women upon admission into labor and delivery. Umbilical cord serum was collected for 96 maternal-fetal dyads, and DNA analysis was performed using a quantitative polymerase chain reaction. The telomere to single copy gene ratio method was used to determine telomere length, and maternal vitamin C intake was measured using the Dietary History Questionnaire (DHQ). Statistical analysis was conducted using generalized linear modeling-based analyses. Results: The linear model indicates that maternal vitamin C intake (OR = 1.0032, 95%CI: 1.0014-1.0052, p ≤ .05) was positively associated with fetal telomere length. BMI (OR = 1.1096, 95%CI: 1.0619-1.1660, p ≤ .05) had a significant positive association with fetal telomere length while sodium intake was negatively associated with this outcome (OR = 0.9997, 95%CI: 0.9995-0.9998, p ≤ .05). Black ethnicity had a significant negative association with fetal telomere length (OR = 0.0186, 95%CI: 0.0031-0.0824, p ≤ .05). Conclusions: Our study shows a positive association between maternal vitamin C intake and fetal telomere length. These findings may provide a method of understanding and preventing adult-onset disease and mortality through intrauterine reprograming.

RevDate: 2019-06-30

Araújo Carvalho AC, Tavares Mendes ML, da Silva Reis MC, et al (2019)

Telomere length and frailty in older adults-A systematic review and meta-analysis.

Ageing research reviews, 54:100914 pii:S1568-1637(19)30037-6 [Epub ahead of print].

Telomere shortening has been proposed as a potentially useful biomarker of human ageing and age-related morbidity and mortality. We performed a systematic review and meta-analysis to summarize results from individual studies on the telomere length according to the frailty status and frailty index in older adults. We searched the PubMed, SCOPUS and Web of Science databases to identify studies that evaluated the telomere length in frail and non-frail older adults and the relationship between telomere length and frailty index score. We used the base pairs (bp) as a measure of the telomere length. Summary estimates were calculated using random-effects models. Nine studies were included in the present systematic review and a total of 10,079 older adults were analyzed. We found that the frail older adults (n = 355) had shorter telomeres than the non-frail (n = 1894) (Standardized Mean Difference [SMD] -0.41; 95% CI -0.73 to -0.09; P = 0.01; I2 = 82%). Significant differences in telomere length between frail and non-frail older adults were identified in Hispanic (SMD -1.31; 95% CI -1.71 to -0.92; P < 0.0001; I2 = 0%) but not in Non-Hispanic countries (SMD -0.13; 95% CI -0.26 to 0.00; P = 0.06; I2 = 0%). Similar results were found in the adjusted meta-analysis (SMD -0.56; 95% -1.12 to 0.00; P = 0.05; I2 = 85%). A significant but weak relationship was found between telomere length and frailty index analyzing 8244 individuals (SMD -0.06; 95% IC -0.10 to 0.01; P = 0.01; I2 = 0%). The current available evidence suggests that telomere length may be not a meaningful biomarker for frailty. Because the potential influence of ethnicity in shortening of telomeres and decline in physiologic reserves associated with aging, additional multiethnic studies are needed.

RevDate: 2019-07-11

Mantuano E, Peconi M, D Scarabino (2019)

Can leukocyte telomere shortening be a possible biomarker to track Huntington's disease progression?.

Neural regeneration research, 14(10):1709-1710.

RevDate: 2019-06-06

Bansal A, S Kukreti (2019)

The four repeat Giardia lamblia telomere forms tetramolecular G-quadruplex with antiparallel topology.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Guanine rich DNA sequences of regulatory genomic regions form secondary structures known as G-quadruplexes usually stabilized by tetrads of Hoogsteen hydrogen bonded guanines. The in vivo existence of G-quadruplexes ascertains their biological roles. Human telomeric repeats are the most studied G-rich sequences. The four repeat Giardia telomeric sequence (TAGGG)4 differs from its human counterpart (TTAGGG)4, by deletion of one T at the G-tract intervening site of each repeat. We show here that whilst the two repeat Giardia telomeric sequence (TAGGG)2 forms parallel and antiparallel quadruplexes with tetramolecular topology exclusively, the four repeat version (TAGGG)4 forms a tetramolecular (antiparallel) and unimolecular (parallel) quadruplexes in Na+. The tetramolecular (antiparallel) G-quadruplex formed by four repeats of Giardia telomeric sequence is stabilized by the additional Watson-Crick bonding between its intervening TA bases aligned in antiparallel fashion. Four stranded antiparallel quadruplex for four repeats of any telomeric sequence have not been characterized till date. We hypothesize that telomeric association in antiparallel fashion, (via G-overhangs to form tetramolecular quadruplex) could be a biologically relevant molecular event. Further, coexistence of Hoogsteen as well as Watson-Crick base pairing might give insight for recognition of conformationally diverse DNA structures by ligands. Communicated by Ramaswamy H. Sarma.

RevDate: 2019-06-10

Park WJ, JH Lee (2019)

Positive correlation between telomere length and mitochondrial copy number in breast cancers.

Annals of translational medicine, 7(8):183.

RevDate: 2019-06-05

Niedzwiedz CL, Katikireddi SV, Pell JP, et al (2019)

Sex differences in the association between salivary telomere length and multimorbidity within the US Health & Retirement Study.

Age and ageing pii:5511442 [Epub ahead of print].

BACKGROUND: Telomere length is associated with several physical and mental health conditions, but whether it is a marker of multimorbidity is unclear. We investigated associations between telomere length and multimorbidity by sex.

METHODS: Data from adults (N = 5,495) aged ≥50 years were taken from the US Health and Retirement Study (2008-14). Telomere length was measured in 2008 from salivary samples. The cross-sectional associations between telomere length and eight chronic health conditions were explored using logistic regression, adjusting for confounders and stratified by sex. Logistic, ordinal and multinomial regression models were calculated to explore relationships between telomere length and multimorbidity (using a binary variable and a sum of the number of health conditions) and the type of multimorbidity (no multimorbidity, physical multimorbidity, or multimorbidity including psychiatric problems). Using multilevel logistic regression, prospective relationships between telomere length and incident multimorbidity were also explored.

RESULTS: In cross-sectional analyses, longer telomeres were associated with reduced likelihood of lung disease and psychiatric problems among men, but not women. Longer telomeres were associated with lower risk of multimorbidity that included psychiatric problems among men (OR=0.521, 95% CI: 0.284 to 0.957), but not women (OR=1.188, 95% CI: 0.771 to 1.831). Prospective analyses suggested little association between telomere length and the onset of multimorbidity in men (OR=1.378, 95% CI: 0.931 to 2.038) nor women (OR=1.224, 95% CI: 0.825 to 1.815).

CONCLUSIONS: Although telomere length does not appear to be a biomarker of overall multimorbidity, further exploration of the relationships is merited particularly for multimorbidity including psychiatric conditions among men.

RevDate: 2019-06-13

Eberhard S, Valuchova S, Ravat J, et al (2019)

Molecular characterization of Chlamydomonas reinhardtii telomeres and telomerase mutants.

Life science alliance, 2(3): pii:2/3/e201900315.

Telomeres are repeated sequences found at the end of the linear chromosomes of most eukaryotes and are required for chromosome integrity. Expression of the reverse-transcriptase telomerase allows for extension of telomeric repeats to counteract natural telomere shortening. Although Chlamydomonas reinhardtii, a photosynthetic unicellular green alga, is widely used as a model organism in photosynthesis and flagella research, and for biotechnological applications, the biology of its telomeres has not been investigated in depth. Here, we show that the C. reinhardtii (TTTTAGGG)n telomeric repeats are mostly nondegenerate and that the telomeres form a protective structure, with a subset ending with a 3' overhang and another subset presenting a blunt end. Although telomere size and length distributions are stable under various standard growth conditions, they vary substantially between 12 genetically close reference strains. Finally, we identify CrTERT, the gene encoding the catalytic subunit of telomerase and show that telomeres shorten progressively in mutants of this gene. Telomerase mutants eventually enter replicative senescence, demonstrating that telomerase is required for long-term maintenance of telomeres in C. reinhardtii.

RevDate: 2019-06-16

Song L, Liu B, Zhang L, et al (2019)

Association of prenatal exposure to arsenic with newborn telomere length: Results from a birth cohort study.

Environmental research, 175:442-448.

OBJECTIVES: The telomere length at birth has important implications for telomere dynamics over the lifespan; however, few studies have explored the relationship between prenatal arsenic exposure and newborn telomere length (TL). We investigated whether newborn TL is related to prenatal arsenic exposure.

METHODS: We used data from a birth cohort study of 762 mother-newborn pairs conducted between November 2013 and March 2015 in Wuhan, China. We measured relative cord blood TL using quantitative real-time polymerase chain reaction. Arsenic concentrations were measured in spot urine samples collected during three trimesters using inductively coupled plasma mass spectrometry. We applied multiple informant models to explore the relationships between prenatal urinary arsenic concentrations and cord blood TL.

RESULTS: The geometric means of urinary arsenic concentrations were 21.7 μg/g creatinine, 27.3 μg/g creatinine, and 27.1 μg/g creatinine in the first, second, and third trimesters, respectively. After adjustment for potential confounders, a doubling of maternal urinary arsenic concentration during the third trimester was related to a 5.75% (95% CI: 1.70%, 9.95%) increase in cord blood TL, particularly in female infants. Similarly, mothers in the highest quartile of urinary arsenic during the third trimester had an 11.45% (95% CI: 1.91%, 21.88%) longer cord blood TL than those in the lowest quartile. However, no significant association was found between maternal urinary arsenic concentration and cord blood TL during the first and second trimesters.

CONCLUSION: Our findings suggested that maternal arsenic exposure during the third trimester was positively associated with newborn TL. The elongation of newborn telomeres due to prenatal arsenic exposure may offer new insights into the mechanisms underlying arsenic-related disorders.

RevDate: 2019-06-18

Janovič T, Stojaspal M, Veverka P, et al (2019)

Human Telomere Repeat Binding Factor TRF1 Replaces TRF2 Bound to Shelterin Core Hub TIN2 when TPP1 Is Absent.

Journal of molecular biology pii:S0022-2836(19)30322-5 [Epub ahead of print].

Human telomeric repeat binding factors TRF1 and TRF2 along with TIN2 form the core of the shelterin complex that protects chromosome ends against unwanted end-joining and DNA repair. We applied a single-molecule approach to assess TRF1-TIN2-TRF2 complex formation in solution at physiological conditions. Fluorescence cross-correlation spectroscopy was used to describe the complex assembly by analyzing how coincident fluctuations of differently labeled TRF1 and TRF2 correlate when they move together through the confocal volume of the microscope. We observed, at the single-molecule level, that TRF1 effectively substitutes TRF2 on TIN2. We assessed also the effect of another telomeric factor TPP1 that recruits telomerase to telomeres. We found that TPP1 upon binding to TIN2 induces changes that expand TIN2 binding capacity, such that TIN2 can accommodate both TRF1 and TRF2 simultaneously. We suggest a molecular model that explains why TPP1 is essential for the stable formation of TRF1-TIN2-TRF2 core complex.

RevDate: 2019-06-10

Alnafakh RAA, Adishesh M, Button L, et al (2019)

Telomerase and Telomeres in Endometrial Cancer.

Frontiers in oncology, 9:344.

Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the "end replication problem" as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80-90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.

RevDate: 2019-06-09

Guo Y, H Yu (2019)

Leukocyte Telomere Length Shortening and Alzheimer's Disease Etiology.

Journal of Alzheimer's disease : JAD, 69(3):881-885.

BACKGROUND: Several observational studies have found leukocyte telomere length (TL) to be associated with Alzheimer's diseases (AD) or dementia. However, these findings were based on small sample sizes and cannot clarify whether this relationship was causal. Genome-wide association studies (GWAS) have identified common variants associated with TL, providing a valuable resource for examining the causal effect of TL on AD using Mendelian Randomization (MR) methods.

OBJECTIVE: To examine if TL was causally associated with AD using GWAS summary statistics.

METHODS: Using a genetic risk score comprised of seven variants associated with leukocyte TL as an instrumental variable, we tested whether shorter TL was associated with a higher risk of AD by applying an MR approach to the summarized genome-wide association study data.

RESULTS: The genetic risk score for TL was associated with higher risk of AD [log-odds ratio (OR) = 0.003 for per TL-decreasing allele; 95% confidence interval (CI): 0.001, 0.005, p = 0.005]. Moreover, the MR analysis provided support for shorter TL to be causally associated with a higher risk of AD (log-OR = 0.04 per SD-decrease of TL; 95% CI: 0.01, 0.08, p = 0.01).

CONCLUSION: We suggest that TL has a causal effect on the risk of AD.

RevDate: 2019-06-03

Aloni R, Levin Y, Uziel O, et al (2019)

Premature aging among trauma survivors - The longitudinal implications of sleep disruptions on telomere length and cognitive performance.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:5510193 [Epub ahead of print].

OBJECTIVES: Sleep is necessary for brain function as well as physical and cognitive processes. Sleep disruptions, common with aging, intensify among trauma survivors. Moreover, former prisoners-of-war (ex-POWs) often experience premature aging. This study investigates the longitudinal effects of sleep disruptions for ex-POWs in relation to cognitive performance and telomere length as well as between cognition and telomeres.

METHOD: This study included Israeli veterans from the 1973 Yom Kippur War who participated in four assessments (1991, 2003, 2008, 2015): (1) ex-POWs (n=99), and (2) veterans who not were captured (controls) (n=101). Among both groups, sleep disruptions were assessed using a self-report item in all four assessments. Cognitive performance was assessed using the Montreal Cognitive Assessment (MOCA) and telomere length was assessed via total white blood cells (leukocytes) from whole blood samples using Southern blot, both were measured only among ex-POWs in 2015. We conducted descriptive statistics, repeated measures, correlations, and path analyses.

RESULTS: Sleep disruptions were related to lower cognitive performance but not to shorter telomeres. Moreover, cognitive performance and telomere length were found to be related when sleep disruptions were taken into consideration.

CONCLUSION: Interpersonal trauma was shown to be a unique experience resulting in sleep disruptions over time, leading to cognitive impairment. These findings highlight the importance of viewing trauma survivors at high-risk for sleep disruptions. Therefore, it is imperative to inquire about sleep and diagnose cognitive disorders to help identify and treat premature aging.

RevDate: 2019-06-10

Clouston SAP, Edelman NH, Aviv A, et al (2019)

Shortened leukocyte telomere length is associated with reduced pulmonary function and greater subsequent decline in function in a sample of World Trade Center responders.

Scientific reports, 9(1):8148 pii:10.1038/s41598-019-44625-1.

The objective of this study was to examine whether shorter leukocyte telomere length (LTL) is associated with more rapid pulmonary function decline in a longitudinal study of World Trade Center (WTC) responders. WTC responders (N = 284) participating in a monitoring study underwent blood sampling and were followed prospectively for spirometric outcomes. A single blood sample was taken to measure LTL using southern blotting. Outcomes included percent-predicted one-second forced expiratory volume (FEV1%), forced vital capacity (FVC%), and the FEV1/FVC ratio. In a subset, percent-predicted diffusing capacity (DLCO%) was also measured. Longitudinal modeling examined prospectively collected information over five years since blood was banked was used to examine the rate of change in pulmonary functioning over time. Severity of WTC exposure was assessed. Shorter LTL was associated with lower FEV1% and FVC% at baseline. For example, 29.9% of those with LTL <6.5 kbps had FEV1% <80% whereas only 12.4% of those with LTL ≥6.5 had FEV1% <80% (RR = 2.53, 95%CI = [1.70-3.76]). Lower DLCO% was also significantly associated with shorter LTL. Longitudinal models identified a prospective association between shorter LTL and greater yearly rates of decline in FEV1% (0.46%/year, 95%CI = [0.05-0.87]) and in the FEV1/FVC ratio (0.19%/year, 95%CI = [0.03-0.36]). There were no associations between severity of exposure and either LTL or pulmonary function. Longitudinal analyses revealed that shorter LTL, but not severity of WTC exposures, was associated with poorer pulmonary functioning and with greater subsequent decline in pulmonary functioning over time. These findings are consistent with the idea that shortened LTL may act as a biomarker for enhanced pulmonary vulnerability in the face of acute severe toxic inhalation exposures.

RevDate: 2019-06-14

Duan X, Yang Y, Zhang D, et al (2019)

Genetic polymorphisms, mRNA expression levels of telomere-binding proteins, and associates with telomere damage in PAHs-Exposure workers.

Chemosphere, 231:442-449.

Coke oven emissions (COEs), confirmed human carcinogens, are mainly composed of polycyclic aromatic hydrocarbons (PAHs). Telomere shortening in blood leukocytes has been associated with COEs, and polymorphisms in metabolic enzymes. However, the relationship between polymorphisms in telomere related genes and telomere shortening in COEs exposed workers has never been evaluated. Therefore, we measured telomere length and mRNA expression levels of telomere-binding proteins (TBPs) by qPCR method in leucocyte from 544 COEs exposed workers and 238 office staffs (referents). Flight mass spectrometry was used to perform the genotyping of selected functional and susceptible SNPs. The results showed that the telomere length in the exposure group 0.75(0.51,1.08) was significantly shorter than that in the control group 1.05(0.76,1.44) (P < 0.001). The mRNA expression levels of TPP1, TERF1 and TERF2 genes in the exposure group were significantly lower than those in the control group (P < 0.05), the mRNA expression level of POT1 in the exposure group was significantly higher than that in the control group (P < 0.05). We used the wild homozygous genotype as a reference, subjects carrying TERT rs2736109 AA, TERT rs3215401 CC and TERT rs2736100 GT + GG genotypes had significantly longer telomere length in the exposure group (P < 0.05). In conclusion, the workers exposed to COEs had shorter telomere length, which was regulated by the TPP1, TERF1, TERF2 and POT1 genes expression levels, and the gene polymorphisms of TERT gene were associated with the telomere length among PAHs-exposure workers.

RevDate: 2019-05-30

Grieshober L, Wactawski-Wende J, Blair RH, et al (2019)

A Cross-Sectional Analysis of Telomere Length and Sleep in the Women's Health Initiative.

American journal of epidemiology pii:5506600 [Epub ahead of print].

Telomere length is a heritable marker of cellular age that is associated with morbidity and mortality. Poor sleep behaviors, which are also associated with adverse health events, may be related to leukocyte telomere length (LTL). We studied a sub-population of 3,145 postmenopausal women enrolled 1993-1998 to the Women's Health Initiative (1,796 European American (EA), 1,349 African American (AA)) with Southern-blot measured LTL and self-reported usual sleep duration and sleep disturbance. LTL-sleep associations were analyzed separately for duration and disturbance using weighted and confounder-adjusted linear regression models in the entire sample (AA+EA; race-adjusted) and in race strata, as LTL differs by ancestry. Each additional hour of sleep beyond 5 hours, approximately, was associated with a 27 base pair (95% confidence interval (CI): 6, 48) longer LTL in AA+EA after covariate adjustment. Seep duration-LTL associations were strongest among AA (adjusted β = 37, 95% CI: 4, 70); a similar non-significant association was observed for EA (adjusted β = 20, 95% CI: -7, 48). Sleep disturbance was not associated with LTL in our study. Our models did not show departure from linearity (quadratic sleep terms P ≥ 0.55). Our results suggest that longer sleep duration is associated with longer LTL in postmenopausal women.

RevDate: 2019-06-05

Whittemore K, Derevyanko A, Martinez P, et al (2019)

Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice.

Aging, 11(10):2916-2948.

Neurodegenerative diseases associated with old age such as Alzheimer's disease present major problems for society, and they currently have no cure. The telomere protective caps at the ends of chromosomes shorten with age, and when they become critically short, they can induce a persistent DNA damage response at chromosome ends, triggering secondary cellular responses such as cell death and cellular senescence. Mice and humans with very short telomeres owing to telomerase deficiencies have an earlier onset of pathologies associated with loss of the regenerative capacity of tissues. However, the effects of short telomeres in very low proliferative tissues such as the brain have not been thoroughly investigated. Here, we describe a mouse model of neurodegeneration owing to presence of short telomeres in the brain as the consequence of telomerase deficiency. Interestingly, we find similar signs of neurodegeneration in very old mice as the consequence of physiological mouse aging. Next, we demonstrate that delivery of telomerase gene therapy to the brain of these mice results in amelioration of some of these neurodegeneration phenotypes. These findings suggest that short telomeres contribute to neurodegeneration diseases with aging and that telomerase activation may have a therapeutic value in these diseases.

RevDate: 2019-06-28

Nguyen MT, Vryer R, Ranganathan S, et al (2019)

Telomere Length and Vascular Phenotypes in a Population-Based Cohort of Children and Midlife Adults.

Journal of the American Heart Association, 8(11):e012707.

Background Telomere length has been inversely associated with cardiovascular disease in adulthood, but its relationship to preclinical cardiovascular phenotypes across the life course remains unclear. We investigated associations of telomere length with vascular structure and function in children and midlife adults. Methods and Results Population-based cross-sectional CheckPoint (Child Health CheckPoint) study of 11- to 12-year-old children and their parents, nested within the LSAC (Longitudinal Study of Australian Children). Telomere length (telomeric genomic DNA [T]/β-globin single-copy gene [S] [T/S ratio]) was measured by quantitative polymerase chain reaction from blood-derived genomic DNA. Vascular structure was assessed by carotid intima-media thickness, and vascular function was assessed by carotid-femoral pulse-wave velocity and carotid elasticity. Mean (SD) T/S ratio was 1.09 (0.55) in children (n=1206; 51% girls) and 0.81 (0.38) in adults (n=1343; 87% women). Linear regression models, adjusted for potential confounders, revealed no evidence of an association between T/S ratio and carotid intima-media thickness, carotid-femoral pulse-wave velocity, or carotid elasticity in children. In adults, longer telomeres were associated with greater carotid elasticity (0.14% per 10-mm Hg higher per unit of T/S ratio; 95% CI, 0.04%-0.2%; P=0.007), but not carotid intima-media thickness (-0.9 μm; 95% CI, -14 to 13 μm; P=0.9) or carotid-femoral pulse-wave velocity (-0.10 m/s; 95% CI, -0.3 to 0.07 m/s; P=0.2). In logistic regression analysis, telomere length did not predict poorer vascular measures at either age. Conclusions In midlife adults, but not children, there was some evidence that telomere length was associated with vascular elasticity but not thickness. Associations between telomere length and cardiovascular phenotypes may become more evident in later life, with advancing pathological changes.

RevDate: 2019-06-17
CmpDate: 2019-06-17

Lu R, O'Rourke JJ, Sobinoff AP, et al (2019)

The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).

Nature communications, 10(1):2252 pii:10.1038/s41467-019-10180-6.

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

RevDate: 2019-07-04

Saint-Leandre B, Nguyen SC, MT Levine (2019)

Diversification and collapse of a telomere elongation mechanism.

Genome research, 29(6):920-931.

In most eukaryotes, telomerase counteracts chromosome erosion by adding repetitive sequence to terminal ends. Drosophila melanogaster instead relies on specialized retrotransposons that insert exclusively at telomeres. This exchange of goods between host and mobile element-wherein the mobile element provides an essential genome service and the host provides a hospitable niche for mobile element propagation-has been called a "genomic symbiosis." However, these telomere-specialized, jockey family retrotransposons may actually evolve to "selfishly" overreplicate in the genomes that they ostensibly serve. Under this model, we expect rapid diversification of telomere-specialized retrotransposon lineages and, possibly, the breakdown of this ostensibly symbiotic relationship. Here we report data consistent with both predictions. Searching the raw reads of the 15-Myr-old melanogaster species group, we generated de novo jockey retrotransposon consensus sequences and used phylogenetic tree-building to delineate four distinct telomere-associated lineages. Recurrent gains, losses, and replacements account for this retrotransposon lineage diversity. In Drosophila biarmipes, telomere-specialized elements have disappeared completely. De novo assembly of long reads and cytogenetics confirmed this species-specific collapse of retrotransposon-dependent telomere elongation. Instead, telomere-restricted satellite DNA and DNA transposon fragments occupy its terminal ends. We infer that D. biarmipes relies instead on a recombination-based mechanism conserved from yeast to flies to humans. Telomeric retrotransposon diversification and disappearance suggest that persistently "selfish" machinery shapes telomere elongation across Drosophila rather than completely domesticated, symbiotic mobile elements.

RevDate: 2019-07-19
CmpDate: 2019-07-19

Feuerbach L, Sieverling L, Deeg KI, et al (2019)

TelomereHunter - in silico estimation of telomere content and composition from cancer genomes.

BMC bioinformatics, 20(1):272 pii:10.1186/s12859-019-2851-0.

BACKGROUND: Establishment of telomere maintenance mechanisms is a universal step in tumor development to achieve replicative immortality. These processes leave molecular footprints in cancer genomes in the form of altered telomere content and aberrations in telomere composition. To retrieve these telomere characteristics from high-throughput sequencing data the available computational approaches need to be extended and optimized to fully exploit the information provided by large scale cancer genome data sets.

RESULTS: We here present TelomereHunter, a software for the detailed characterization of telomere maintenance mechanism footprints in the genome. The tool is implemented for the analysis of large cancer genome cohorts and provides a variety of diagnostic diagrams as well as machine-readable output for subsequent analysis. A novel key feature is the extraction of singleton telomere variant repeats, which improves the identification and subclassification of the alternative lengthening of telomeres phenotype. We find that whole genome sequencing-derived telomere content estimates strongly correlate with telomere qPCR measurements (r = 0.94). For the first time, we determine the correlation of in silico telomere content quantification from whole genome sequencing and whole genome bisulfite sequencing data derived from the same tumor sample (r = 0.78). An analogous comparison of whole exome sequencing data and whole genome sequencing data measured slightly lower correlation (r = 0.79). However, this is considerably improved by normalization with matched controls (r = 0.91).

CONCLUSIONS: TelomereHunter provides new functionality for the analysis of the footprints of telomere maintenance mechanisms in cancer genomes. Besides whole genome sequencing, whole exome sequencing and whole genome bisulfite sequencing are suited for in silico telomere content quantification, especially if matched control samples are available. The software runs under a GPL license and is available at .

RevDate: 2019-06-25

Eisenberg DTA, Lee NR, Rej PH, et al (2019)

Older paternal ages and grandpaternal ages at conception predict longer telomeres in human descendants.

Proceedings. Biological sciences, 286(1903):20190800.

Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.

RevDate: 2019-05-28

Kobayashi CR, Castillo-González C, Survotseva Y, et al (2019)

Recent emergence and extinction of the protection of telomeres 1c gene in Arabidopsis thaliana.

Plant cell reports pii:10.1007/s00299-019-02427-9 [Epub ahead of print].

KEY MESSAGE: Duplicate POT1 genes must rapidly diverge or be inactivated. Protection of telomeres 1 (POT1) encodes a conserved telomere binding protein implicated in both chromosome end protection and telomere length maintenance. Most organisms harbor a single POT1 gene, but in the few lineages where the POT1 family has expanded, the duplicate genes have diversified. Arabidopsis thaliana bears three POT1-like loci, POT1a, POT1b and POT1c. POT1a retains the ancestral function of telomerase regulation, while POT1b is implicated in chromosome end protection. Here we examine the function and evolution of the third POT1 paralog, POT1c. POT1c is a new gene, unique to A. thaliana, and was derived from a duplication event involving the POT1a locus and a neighboring gene encoding ribosomal protein S17. The duplicate S17 locus (dS17) is highly conserved across A. thaliana accessions, while POT1c is highly divergent, harboring multiple deletions within the gene body and two transposable elements within the promoter. The POT1c locus is transcribed at very low to non-detectable levels under standard growth conditions. In addition, no discernable molecular or developmental defects are associated with plants bearing a CRISPR mutation in the POT1c locus. However, forced expression of POT1c leads to decreased telomerase enzyme activity and shortened telomeres. Evolutionary reconstruction indicates that transposons invaded the POT1c promoter soon after the locus was formed, permanently silencing the gene. Altogether, these findings argue that POT1 dosage is critically important for viability and duplicate gene copies are retained only upon functional divergence.

RevDate: 2019-05-27

Patanè S (2019)

Differential effects of training on telomerase activity and telomere length: the role of microRNAs regulation.

European heart journal pii:5498945 [Epub ahead of print].

RevDate: 2019-05-27

Jiménez-Pavón D, Carbonell-Baeza A, CJ Lavie (2019)

Are changes in telomerase activity and telomere length due to different exercise modalities, intensity, or methods: intermittency?.

European heart journal pii:5498942 [Epub ahead of print].

RevDate: 2019-05-27

Inoue H, Horiguchi M, Ono K, et al (2019)

Casein kinase 2 regulates telomere protein complex formation through Rap1 phosphorylation.

Nucleic acids research pii:5498753 [Epub ahead of print].

Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1-Bqt4 and Rap1-Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.

RevDate: 2019-05-26

Pusceddu I, Herrmann W, Kleber ME, et al (2019)

Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study.

European journal of nutrition pii:10.1007/s00394-019-01993-8 [Epub ahead of print].

PURPOSE: Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.

METHODS: Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years.

RESULTS: All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28-3.37) and 0.41(95% CI 0.33-0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29-3.39) and 0.40 (95% CI 0.33-0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = - 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = - 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = - 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.

CONCLUSIONS: In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.

RevDate: 2019-06-26

Yu EY, Cheung IY, Feng Y, et al (2019)

Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.

Neoplasia (New York, N.Y.), 21(7):689-701.

Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and C-strand, as well as extra-chromosomal circular telomeres. Our analysis pointed to substantial and variable degrees of telomere DNA damage in HRNB, including pervasive oxidative lesions. Moreover, unlike other cancers, neuroblastoma consistently harbored high levels of C-strand ssDNA overhangs and t-circles, which are consistent with active "telomere trimming". This feature is observed in both telomerase- and ALT-positive tumors and irrespective of telomere length distribution. Moreover, evidence for telomere trimming was detected in normal neural tissues, raising the possibility that TMMs in HRNB evolved in the face of a canonical developmental program of telomere shortening. Telomere trimming by itself appears to distinguish neuroectodermal derived tumors from other human cancers, a distinguishing characteristic with both biologic and therapeutic implications.

RevDate: 2019-05-25

Zhang M, Liu R, F Wang (2019)

Telomere and G-Quadruplex Colocalization Analysis by Immunofluorescence Fluorescence In Situ Hybridization (IF-FISH).

Methods in molecular biology (Clifton, N.J.), 1999:327-333.

Four-stranded G-quadruplexes consists of tracks of guanines that are stabilized by Hoogsteen base pairing. The formation of G-quadruplexes in genomic DNA contribute to numerous biological processes in vivo, including replication, transcription, and telomere maintenance. Here, we present a detailed method to detect the colocalization of G-quadruplexes with telomeres in vivo, using the BG4 antibody developed from Dr. Shankar Balasubramanian's lab.

RevDate: 2019-06-10

Gali H, Mason-Osann E, RL Flynn (2019)

Direct Visualization of DNA Replication at Telomeres Using DNA Fiber Combing Combined with Telomere FISH.

Methods in molecular biology (Clifton, N.J.), 1999:319-325.

The ability to analyze individual DNA fibers undergoing active DNA synthesis has emerged as a powerful technique in the field of DNA replication. Much of the initial analysis has focused on replication throughout the genome. However, more recent advancements in this technique have allowed for the visualization of replication patterns at distinct loci or regions within the genome. This type of locus-specific resolution will greatly enhance our understanding of the dynamics of DNA replication in regions that provide a challenge to the replication machinery. Here, we describe a protocol that will allow for the visualization of DNA replication through one of the most structurally complex regions in the human genome, the telomeric DNA.

RevDate: 2019-05-25

Fouquerel E, Barnes RP, Wang H, et al (2019)

Measuring UV Photoproduct Repair in Isolated Telomeres and Bulk Genomic DNA.

Methods in molecular biology (Clifton, N.J.), 1999:295-306.

Telomere repeats at chromosomal ends are essential for genome stability and sustained cellular proliferation but are susceptible to DNA damage. Repair of damage at telomeres is influenced by numerous factors including telomeric binding proteins, sequence and structure. Ultraviolet (UV) light irradiation induces DNA photoproducts at telomeres that can interfere with telomere maintenance. Here we describe a highly sensitive method for quantifying the formation and removal of UV photoproducts in telomeres isolated from UV irradiated cultured human cells. Damage is detected by immunospot blotting of telomeres with highly specific antibodies against UV photoproducts. This method is adaptable for measuring other types of DNA damage at telomeres as well.

RevDate: 2019-06-10

Mason-Osann E, Gali H, RL Flynn (2019)

Resolving Roadblocks to Telomere Replication.

Methods in molecular biology (Clifton, N.J.), 1999:31-57.

The maintenance of genome stability in eukaryotic cells relies on accurate and efficient replication along each chromosome following every cell division. The terminal position, repetitive sequence, and structural complexities of the telomeric DNA make the telomere an inherently difficult region to replicate within the genome. Thus, despite functioning to protect genome stability mammalian telomeres are also a source of replication stress and have been recognized as common fragile sites within the genome. Telomere fragility is exacerbated at telomeres that rely on the Alternative Lengthening of Telomeres (ALT) pathway. Like common fragile sites, ALT telomeres are prone to chromosome breaks and are frequent sites of recombination suggesting that ALT telomeres are subjected to chronic replication stress. Here, we will review the features of telomeric DNA that challenge the replication machinery and also how the cell overcomes these challenges to maintain telomere stability and ensure the faithful duplication of the human genome.

RevDate: 2019-06-05
CmpDate: 2019-06-05

Anitha A, Thanseem I, Vasu MM, et al (2019)

Telomeres in neurological disorders.

Advances in clinical chemistry, 90:81-132.

Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.


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

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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 )