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The effect of maternal folate status on the fetal central nervous system (CNS) is well recognized, while evidence is emerging that such an association also exists between fathers and offspring. The biological functions of telomeres and telomerase are also related to neural cell proliferation and apoptosis. The study aimed to investigate the effect of parental folate deficiency on the proliferation and apoptosis of neural stem cells (NSCs) in neonatal offspring and the role of telomeres in this effect. In this study, rats were divided into four groups: maternal folate-deficient and paternal folate-deficient diet (D-D) group; maternal folate-deficient and paternal folate-normal diet (D-N) group; maternal folate-normal and paternal folate-deficient diet (N-D) group; and the maternal folate-normal and paternal folate-normal diet (N-N) group. The offspring were sacrificed at postnatal day 0 (PND0), and NSCs were cultured from the hippocampus and striatum tissues of offspring for future assay. The results revealed that parental folate deficiency decreased folate levels, increased homocysteine (Hcy) levels of the offspring’s brain tissue, inhibited proliferation, increased apoptosis, shortened telomere length, and aggravated telomere attrition of offspring NSCs in vivo and in vitro. In vitro experiments further showed that offspring NSCs telomerase activity was inhibited due to parental folate deficiency. In conclusion, parental folate deficiency inhibited the proliferation and increased apoptosis of offspring NSCs, maternal folate deficiency had more adverse effects than paternal, and the mechanisms may involve the telomere attrition of NSCs.

Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging. Funding The ENVIRONAGE birth cohort is supported by grants from the European Research Council (Grant No. ERC-2012-StG310898), the Flemish Scientific Fund (FWO, Grant No. G073315N) and Kom Op Tegen Kanker DSM (FWO grant 12X9620N) is postdoctoral fellows of the Flanders Research Foundation. SL is the beneficiary of a post-doctoral fellowship (12L5216N) provided by The Research Foundation-Flanders (FWO) and the Flemish Institute of Technological Research (VITO). Acknowledgments We acknowledge the cohort participants, midwives, the staff of the maternity ward and the clinical laboratory of East-Limburg Hospital in Genk.

A common feature of aging is the accumulation of genetic damage throughout life. DNA damage can lead to genomic instability. Many diseases associated with premature aging are a result of increased accumulation of DNA damage. In order to minimize these damages, organisms have evolved a complex network of DNA repair mechanisms, including mismatch repair (MMR). In this review, we detail the effects of MMR on genomic instability and its role in aging emphasizing on the association between MMR and the other hallmarks of aging, serving to drive or amplify these mechanisms. These hallmarks include telomere attrition, epigenetic alterations, mitochondrial dysfunction, altered nutrient sensing and cell senescence. The close relationship between MMR and these markers may provide prevention and treatment strategies, to reduce the incidence of age-related diseases and promote the healthy aging of human beings.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, β=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

The occurrence of telomere attrition in brain may cause senescence and death of neurons, leading to cognitive decline. Folic acid (FA) has been reported to improve cognitive performance in mild cognitive impairment; however, its association with telomere remains unclear. The study aimed to investigate if alleviation of telomere attrition by FA supplementation could act as a potential mechanism to delay age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8). Aged SAMP8 mice were assigned to four treatment groups: FAdeficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group and high FAsupplemented diet (FA-H) group. There was also an age-matched senescence-accelerated mouse resistant 1 (SAMR1) control group (Con-R), and a young SAMP8 control group (Con-Y). The results demonstrated that FA supplementation delayed age-related cognitive decline and neurodegeneration in SAMP8 mice. Importantly, this effect could be attributed to the alleviated telomere attrition, which might be interpreted by the decreased levels of reactive oxygen species. Additionally, improved telomere integrity stimulated mitochondrial function via telomere-p53-mithondria pathway, consequently delayed neuronal degeneration. In conclusion, we demonstrate that FA supplementation delays age-related neurodegeneration and cognitive decline in SAMP8 mice, in which alleviated telomere attrition could serve as one influential factor in the process.

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

Objective Studies of multiple species have found that adverse early life experiences, including childhood trauma and maternal separation, can result in accelerated telomere shortening. The objective of this study was to determine if premature separation from the mother affected telomere length in domestic kittens (Felis catus). Subjects were 42 orphaned kittens and 10 mother-reared kittens from local animal rescue groups and shelters. DNA was extracted from whole blood collected from kittens at approximately 1 week and 2 months of age. Telomere length was assessed by qPCR (quantitative polymerase chain reaction) from a total of 86 samples and expressed as a ratio of telomere PCR relative to a single copy gene PCR (T/S). Results A generalized linear mixed model found there were no detectable differences in telomere length based on survival (F1, 76.2 = 3.35, p = 0.07), orphan status (F1, 56.5 = 0.44, p = 0.51), time point (F1, 43.5 = 0.19, p = 0.67), or the interaction between orphan status and time (F1, 43.5 = 0.86, p = 0.36). Although in other species telomere shortening is commonly associated with aging, even early in life, we did not find evidence for telomere shortening by two months of age. Our results suggest that the experience of early maternal separation in domestic cats who are subsequently hand-reared by humans does not accelerate telomere shortening compared to mother-reared kittens, at least in the first few months of life.

Objective Studies of multiple species have found that adverse early life experiences, including childhood trauma and maternal separation, can result in accelerated telomere shortening. The objective of this study was to determine if premature separation from the mother affected telomere length in domestic kittens (Felis catus). Subjects were 42 orphaned kittens and 10 mother-reared kittens from local animal rescue groups and shelters. DNA was extracted from whole blood collected from kittens at approximately 1 week and 2 months of age. Telomere length was assessed by qPCR (quantitative polymerase chain reaction) from a total of 86 samples and expressed as a ratio of telomere PCR relative to a single copy gene PCR (T/S). Results A generalized linear mixed model found there were no detectable differences in telomere length based on survival (F1, 76.2 = 3.35, p = 0.07), orphan status (F1, 56.5 = 0.44, p = 0.51), time point (F1, 43.5 = 0.19, p = 0.67), or the interaction between orphan status and time (F1, 43.5 = 0.86, p = 0.36). Although in other species telomere shortening is commonly associated with aging, even early in life, we did not find evidence for telomere shortening by two months of age. Our results suggest that the experience of early maternal separation in domestic cats who are subsequently hand-reared by humans does not accelerate telomere shortening compared to mother-reared kittens, at least in the first few months of life.

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Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.

This study investigated the effect of dietary sugars and advanced glycation end-products (AGE) on telomere dynamics in WIL2-NS cells. Dietary sugars [glucose (Glu) and fructose (Fru); 0.1 M each] were incubated with bovine serum albumin (BSA) (10 mg/ml) at 60 ± 1°C for 6 weeks to generate AGE-BSA. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed total AGE levels as 87.74 ± 4.46 nmol/mg and 84.94 ± 4.28 nmol/mg respectively in Glu-BSA and Fru-BSA model. Cell treatment studies using WIL2-NS cells were based on either glucose, fructose (each 2.5–40 mM) or AGE-BSA (200–600 µg/ml) in a dose-dependent manner for 9 days. Telomere length (TL) was measured using qPCR. Nitric oxide (NO) production and tumour necrosis factor-α (TNF-α) levels were measured in WIL2-NS culture medium. An increasing trend for TNF-α and NO production was observed with higher concentration of glucose (R2 = 0.358; P = 0.019; R2 = 0.307; P = 0.027) and fructose (R2 = 0.669; P = 0.001; R2 = 0.339; P = 0.006). A decreasing trend for TL (R2 = 0.828; P = 0.000), and an increasing trend for NO production (R2 = 0.352; P = 0.031) were observed with increasing Glu-BSA concentrations. Fru-BSA treatment did not show significant trend on TL (R2 = 0.135; P = 0.352) with increasing concentration, however, a significant reduction was observed at 600 µg/ml (P < 0.01) when compared to BSA treatment. No trends for TNF-α levels and a decreasing trend on NO production (R2 = 0.5201; P = 0.019) was observed with increasing Fru-BSA treatment. In conclusion, this study demonstrates a potential relationship between dietary sugars, AGEs and telomere attrition. AGEs may also exert telomere shortening through the production of pro-inflammatory metabolites, which ultimately increase the risk of diabetes complications and age-related disease throughout lifespan.

Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0&ndash, 40 &mu, mol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development.Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the “classical” telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures.Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity.Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

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.

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.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fevo.2019.00173/full#supplementary-material, We thank F. Miranda and Laboratory of Ecophysiology-EBD (ISO9001:2015 and ISO14001:2015) for assistance with lab analyses. E. Roldán, at the National Museum of Natural History-CSIC, helped with sample conservation and transport., Telomere length is a marker of cellular senescence that relates to different components of individual fitness. Oxidative stress is often claimed as a main proximate factor contributing to telomere attrition, although the importance of this factor in vivo has recently been challenged. Early development represents an ideal scenario to address this hypothesis because it is characterized by the highest rates of telomere attrition of the life and by an arguably high susceptibility to oxidative stress. We tested the effect of oxidative stress on telomere dynamics during early development by exposing pied flycatcher nestlings (Ficedula hypoleuca) to either an oxidative challenge (diquat injections), an antioxidant (vitamin E) or control treatments (PBS injections and supplementation with vehicle substance). We found no effects of treatments on average telomere change during the nestling period. However, vitamin E supplementation, which increased growth, removed the association between initial telomere length and telomere attrition. Diquat-treated nestlings, by contrast, showed no differences in growth or telomere dynamics with respect to controls. These results do not support the hypothesis that oxidative stress is the main direct mechanism explaining telomere attrition in vivo, and highlight the importance of micronutrient intake during early development on telomere dynamics. Studies addressing alternative action pathways of vitamins on growth and telomere dynamics, perhaps via restoration mechanisms, would provide important insights on the proximate factors affecting telomere attrition during this critical phase of life., LP-R was supported by Severo Ochoa (SEV-2012-0262) and SECTI (UCLM) postdoctoral contracts during data collection manuscript and writing, respectively. Funding was provided by Spanish Ministry of Economy and Competitiveness (SMEC); grant number CGL2014-55969-P. Additional funding came from the project “A test of the oxidative cost of a reliable signal,” granted to TR by the internal EBD proposal call Microproyectos and financed by the SMEC, through the Severo Ochoa Program for Centers of Excellence in R+D+I (SEV-2012-0262).

Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development. Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the “classical” telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures. Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity. Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.

Summary Longitudinal studies of human leucocyte telomere length often report a percentage of individuals whose telomeres appear to lengthen. However, based on theoretical considerations and empirical data, Steenstrup et al. (Nucleic Acids Research, 2013, vol 41(13): e131) concluded that this lengthening is unlikely to be a real biological phenomenon and is more likely to be an artefact of measurement error. We dispute the logic underlying this claim. We argue that Steenstrup et al.'s analysis is incomplete because it failed to compare predictions derived from assuming a scenario with no true telomere lengthening with alternative scenarios in which true lengthening occurs. To address this deficit, we built a computational model of telomere dynamics that allowed us to compare the predicted percentage of observed telomere length gainers given differing assumptions about measurement error and the true underling dynamics. We modelled a set of scenarios, all assuming measurement error, but both with and without true telomere lengthening. We found a range of scenarios assuming some true telomere lengthening that yielded either similar or better quantitative fits to the empirical data on the percentage of individuals showing apparent telomere lengthening. We conclude that although measurement error contributes to the prevalence of apparent telomere lengthening, Steenstrup et al.'s conclusion was too strong, and current data do not allow us to reject the hypothesis that true telomere lengthening is a real biological phenomenon in epidemiological studies. Our analyses highlight the need for process-level models in the analysis of telomere dynamics.

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

The recent increase in human life expectancy is accompanied with a more frequent occurrence of age-related diseases such as neurodegenerative diseases and cancers. An unprecedented effort has been dedicated to develop animal model systems to decipher the aging mechanisms, and the genetic study of short-lived animals, namely Drosophila and Caenorhabditis, brought important breakthroughs. Here we highlight the interest of additional model systems like the cnidarian Hydra polyp. Hydra provides a model where all tissues continuously renew from large stocks of proliferative adult stem cells, where amputation leads to regeneration with perfect replacement of any lost body structure and where signs of aging remain limited over the years. Aging is easily inducible in some Hydra species, providing a paradigm for deciphering the mechanisms that promote resistance to aging. A dynamic autophagic flux, a sustained proteostasis, the G2 pausing of stem cells and an efficient DNA-damage repair might play an essential role.

Preprint, associated R scripts and dataset. Summary: In analyses of longitudinal changes in leukocyte telomere length (LTL) it is common practice to control statistically for baseline LTL. However, theoretical considerations arising from collider bias suggest that this practice could lead to overestimation of the difference in LTL attrition between groups that have experienced different exposures. We used simulated LTL data to explore whether adjusting for baseline LTL results in biased estimates of the true difference in LTL attrition between individuals with different exposures using smokers and non-smokers as an example. We show that if baseline LTL is shorter in smokers than non-smokers and LTL measurement error is non-zero, then adjusting for baseline LTL results in overestimating the true difference in telomere attrition between smokers and non-smokers. The size of this latter bias increases with increasing LTL measurement error. Since it is a robust finding that smokers have shorter baseline LTL than non-smokers and LTL measurement error is substantial, we conclude that the type 1 error rate for reports of effects of smoking on telomere attrition is likely to be above 5%. Using real data from seven longitudinal cohorts we show that in line with our simulation results, the estimated difference in attrition between smokers and non-smokers is greater in models controlling for baseline LTL. Furthermore, as predicted by our simulations, the size of this latter difference is positively associated with signatures of LTL measurement error. On the basis of our analyses we recommend that models of LTL attrition should not control for baseline LTL. Although we have couched our analysis in terms of the effects of smoking, our findings are likely to have general relevance to other factors studied in relation to telomere attrition. Many claims of accelerated LTL attrition in individuals exposed to disease, stress or adversity will need to be re-assessed.

Preprint of mansuscript currently submitted for publication. Abstract: Smoking is associated with shorter leukocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking accelerates LTL attrition. However, an alternative hypothesis is that individuals with shorter telomeres are more likely to start smoking. Both hypotheses predict a cross-sectional difference in LTL between smokers and non-smokers, but the acceleration hypothesis additionally predicts an association between smoking and LTL attrition. 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 78.83 bp shorter in smokers (95% CI: 21.09 to 136.58). However, LTL attrition was a negligible 0.44 bp/year faster in smokers than in non-smokers (95% CI: -1.83 to 0.95), a difference that equates to only 1.23% of the estimated age-related loss of 35.71 bp/year. Assuming a linear effect of smoking, at least 177 years of smoking would be required to generate the observed cross-sectional difference in LTL. It is therefore unlikely that smoking causes the difference in LTL between smokers and non-smokers.

Aging is characterized by progressive deterioration of physiological integrity, decline in homeostasis, and degeneration of the tissues that occurs after the reproductive phase of life is complete, leading to impaired function. This deterioration is an important risk factor for chronic lung pathologies such as chronic obstructive pulmonary disease (COPD). COPD is a disease that develops gradually. Emphysematous changes in the lung take years to develop after exposure to cigarette smoke; hence, the vast majority of patients are elderly. There has been a dramatic increase in the life expectancy of the general population, resulting in an increased burden of chronic lung diseases. There is growing evidence that molecular mechanisms involved in aging may also play a role in COPD pathogenesis. Recently, the nine hallmarks of aging were identified. In this article, we will review the nine hallmarks of aging and how each hallmark contributes to the pathogenesis of COPD.

Background Senolytic drugs are thought to target senescent cells and might thereby rejuvenate tissues. In fact, such compounds were suggested to increase health and lifespan in various murine aging models. So far, effects of senolytic drugs have not been analysed during replicative senescence of human mesenchymal stromal cells (MSCs). Methods In this study, we tested four potentially senolytic drugs: ABT-263 (navitoclax), quercetin, nicotinamide riboside, and danazol. The effects of these compounds were analysed during long-term expansion of MSCs, until replicative senescence. Furthermore, we determined the effect on molecular markers for replicative senescence, such as senescence-associated beta-galactosidase staining (SA-β-gal), telomere attrition, and senescence-associated DNA methylation changes. Results Co-culture experiments of fluorescently labelled early and late passages revealed that particularly ABT-263 had a significant but moderate senolytic effect. This was in line with reduced SA-β-gal staining in senescent MSCs upon treatment with ABT-263. However, none of the drugs had significant effects on the maximum number of population doublings, telomere length, or epigenetic senescence predictions. Conclusions Of the four tested drugs, only ABT-263 revealed a senolytic effect in human MSCs—and even treatment with this compound did not rejuvenate MSCs with regard to telomere length or epigenetic senescence signature. It will be important to identify more potent senolytic drugs to meet the high hopes for regenerative medicine. Electronic supplementary material The online version of this article (10.1186/s13287-018-0857-6) contains supplementary material, which is available to authorized users.

Background Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging. Methods Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p

Altres ajuts: AB-G was supported by Grants from the Ministerio de Educación y Ciencia (SAF2014-59892), Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat with the support of ACCIÓ [Catalonia Trade & Investment; Generalitat de Catalunya] under the Catalonian ERDF [European Regional Development Fund] operational program, 2014-2020. Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes. Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n = 101) and at the 1-year follow-up (n = 54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14 ++ CD16 −), intermediate (CD14 ++ CD16 +), and nonclassical (CD14 + CD16 ++)-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3 ± 0.6 years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable. We found high correlations between TL values of different monocyte subsets: CD14 ++ CD16 + vs. CD14 ++ CD16 −, R = 0.95, p < 0.001; CD14 ++ CD16 + vs. CD14 + CD16 ++, R = 0.90, p < 0.001; and CD14 ++ CD16 − vs. CD14 + CD16 ++, R = 0.89, p < 0.001. Mean monocyte TL exhibited significant attrition from baseline to the 1-year follow-up (11.1 ± 3.3 vs. 8.3 ± 2.1, p < 0.001). TL did not significantly differ between monocyte subsets at either sampling time-point (all p values > 0.1). Cox regression analyses did not indicate that TL or ΔTL was associated with all-cause death or the composite endpoint. Overall, this longitudinal study demonstrated a ~ 22% reduction of TL in monocytes from ambulatory patients with HF within 1 year. TL and ΔTL were not related to outcomes over long-term follow-up. The online version of this article (10.1186/s12967-018-1412-z) contains supplementary material, which is available to authorized users.

Preprint, associated R scripts and dataset. Summary: In analyses of longitudinal leukocyte telomere length (LTL) data it is common practice to adjust for baseline LTL when modelling the factors that potentially affect LTL attrition. However, the apparent dependence of LTL attrition on baseline LTL is largely brought about by regression to the mean as a result of measurement error. We used simulated LTL data to explore whether adjusting for baseline LTL results in biased estimates of the true effect of smoking on attrition. We show that when baseline LTL is shorter in smokers than non-smokers and LTL measurement error is non-zero, adjusting for baseline LTL results in overestimating the true effect of smoking on telomere attrition. The size of this latter bias increases with increasing LTL measurement error. Since it is a robust finding that smokers have shorter LTL than non-smokers and LTL measurement error is substantial, we conclude that the type 1 error rate for reports of effects of smoking on telomere attrition is likely to be above 5%. We therefore recommend that models of LTL attrition should not be adjusted for baseline LTL. Although we have couched our analysis in terms of the effects of smoking, our findings are likely to have general relevance to other lifestyle factors and exposures studied in relation to telomere attrition.

Oxidative stress shortens telomeres in cell culture, but whether oxidative stress explains variation in telomere shortening in vivo at physiological oxidative stress levels is not well known. We therefore tested for correlations between six oxidative stress markers and telomere attrition in nestling birds (jackdaws Corvus monedula ) that show a high rate of telomere attrition in early life. Telomere attrition was measured between ages 5 and 30 days, and was highly variable (average telomere loss: 323 bp, CV = 45%). Oxidative stress markers were measured in blood at age 20 days and included markers of oxidative damage (TBARS, dROMs and GSSG) and markers of antioxidant protection (GSH, redox state, uric acid). Variation in telomere attrition was not significantly related to these oxidative stress markers (| r | ≤ 0.08, n = 87). This finding raises the question whether oxidative stress accelerates telomere attrition in vivo . The accumulation of telomere attrition over time depends both on the number of cell divisions and on the number of base pairs lost per DNA replication and, based on our findings, we suggest that in a growing animal cell proliferation, dynamics may be more important for explaining variation in telomere attrition than oxidative stress.

Leukocytes telomere length has been associated with hypertension, but, whether longitudinal telomeres change could serve as a useful predictive tool in hypertension remains uncertain. This study aimed to examine the longitudinal trajectory of leukocytes telomere length in a population-based prospective study of 1,108 individuals with hypertension. Leukocytes telomere length were measured at baseline and again after a median 2.2 (range 1.5-2.4) years of follow-up. Age as an independent predictor was inversely associated with baseline telomeres and follow-up telomeres. Annual telomere attrition rate was calculated as (follow-up telomeres-baseline telomeres)/follow-up years, and participants were categorized into the shorten and the lengthen groups. Results showed that telomere lengthening was significantly correlated with decreased systolic blood pressure (SBP) (β=-3.28; P=0.02) and pulse pressure (PP) (β=-2.53; P=0.02), and the differences were respectively -3.3 mmHg (95%CI, -6.2 to -0.3; P=0.03) in ∆SBP and -2.4 mmHg (95%CI, -4.9 to -0.1; P=0.04) in ∆PP between two groups after adjustment for vascular risk factors and baseline blood pressures. When stratified by age and gender, the correlations were observed in women and patients ≤60 years. Furthermore, among patients using calcium channel blocker (CCB) and angiotensin receptor blocker (ARB), those with telomeres lengthening showed a significantly lower level of ∆SBP and ∆PP. There was no correlation between telomere attrition and incidence of cardiovascular events. Our data indicated that increased telomere length of leukocytes was associated with decreased SBP and PP, particularly for patients who received CCB and ARB, supporting that telomere attrition may provide new sight in clinical intervention for hypertension.

Background In contrast to the postnatal period, little is known about telomere length (TL) during prenatal life. The decrease in placental TL remains unknown, although intra uterine growth retardation and preeclampsia are associated with shorter placental TL. The aim of this study is to assess the decrease of placental TL during the third trimester of gestation and to explore the role of potential “growth influencing factors”. Methods The study sample consisted of 329 live-born twins from the East Flanders Prospective Twin Survey. TL was determined using a multiplex quantitative PCR method. Gestational age, sex, birth order, placental characteristics, parity, maternal and paternal age, diabetes, hypertension, smoking, alcohol use, and socio economic status (SES) were considered “growth influencing factors”. Bivariable multilevel regression analysis with “growth influencing factors” was performed. Results Placental TL ranged from 4.3 kbp to 84.4 kbp with a median of 10.8 kbp. Ln(TL) decreased in a linear fashion with an estimated TL decreasing from 13.98 kbp at 28 weeks to 10.56 kbp at 42 weeks. The regression coefficient of gestational age became smaller if considered together with SES ( b = −0.017; p = 0.08) or diabetes ( b = −0.018; p = 0.07) and bigger if considered together with parity ( b = −0.022; p = 0.02), indicating that part of the association between gestational age and telomere length is explained by these three confounding factors. Conclusion Placental TL decreases during the third trimester of gestation of live-born twins with approximately 25% indicating that telomere shortening may play a role in aging of the placenta.

Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28–32 and 41–46 years were assessed at ages 48–52 for global cognitive function and its five specific component domains with a NeuroTrax computerized test battery. Multivariable regression and logistic models were applied for cognition treated as a continuous and categorical variable, respectively. We found that LTL attrition (adjusted for sex, baseline LTL and potential confounders including socioeconomic variables) was inversely associated with global cognition (standardized β = −.119, p = .004) and its component domains: information processing speed (β = −.102, p = .024), visual-spatial function (β = −.102, p = .017) and memory (β = −.093, p = .045), but less so for the attention and executive domains. The multivariable-adjusted odds ratio for low global cognition comparing the upper versus lower thirds of LTL attrition was 2.12 (95 % CI 1.11–4.08, p for trend = .023). There was no association of baseline or follow-up LTL with cognition. No effect modification was evident for sex, smoking or inflammatory markers. In conclusion, faster LTL attrition in young adulthood was associated with poorer global and domain-specific cognitive function in midlife, suggesting that more rapid LTL attrition may be predictive of cognitive aging in healthy young adults. Electronic supplementary material The online version of this article (doi:10.1007/s10654-015-0051-4) contains supplementary material, which is available to authorized users.

Telomere biology is central to the maintenance of genomic stability and telomeric dysfunction is thought to be an early stage in carcinogenesis. Reports of telomere lengths and their ascribed colorectal cancer risks have been discordant, with both very short and very long telomeres implicated. Nevertheless, telomeres appear to play a very central role in cancer initiation. Telomere length changes also appear to impact disease burden, progression and overall survival. This review covers contemporary views on telomere biology and colorectal cancer risk, with a brief overview of analytical methods employed in telomere measurement. We conclude with arguments in favor of including telomere assessment in the molecular profiling of colorectal cancers.

The free radical theory of aging proposes that ROS (reactive oxygen species) are major driving forces of aging, and are also critically involved in cellular senescence. Besides the mitochondrial respiratory chain, alternative sources of ROS have been described that might contribute to cellular senescence. Noxs (NADPH oxidases) are well-known sources of superoxide, which contribute to the antimicrobial capabilities of macrophages, a process involving the prototypical member of the family referred to as Nox2. However, in recent years non-phagocytic homologues of Nox2 have been identified that are involved in processes other than the host defence. Superoxide anions produced by these enzymes are believed to play a major role in signalling by MAPKs (mitogen-activated protein kinases) and stress-activated kinases, but could also contribute to cellular senescence, which is known to involve oxygen radicals. In HUVECs (human umbilical vein endothelial cells), Nox4 is predominantly expressed, but its role in replicative senescence of HUVECs remains to be elucidated. Using shRNA (small-hairpin RNA)-mediated knockdown of Nox4, implicating lentiviral vectors, we addressed the question of whether lifelong depletion of Nox4 in HUVECs would influence the senescent phenotype. We found a significant extension of the replicative lifespan of HUVECs upon knockdown of Nox4. Surprisingly, mean telomere length was significantly reduced in Nox4-depleted cells. Nox4 depletion had no discernable influence on the activity of MAPKs and stress-activated kinases, but reduced the degree of oxidative DNA damage. These results suggest that Nox4 activity increases oxidative damage in HUVECs, leading to loss of replicative potential, which is at least partly independent of telomere attrition.