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Telomere length, a reliable predictor of disease pathogenesis, can be affected by genetics, chronic stress and health behaviors. Cross-sectionally, highly stressed postmenopausal women have shorter telomeres, but only if they are inactive. However, no studies have prospectively examined telomere length change over a short period, and if rate of attrition is affected by naturalistic factors such as stress and engagement in healthy behaviors, including diet, exercise, and sleep. Here we followed healthy women over 1 year to test if major stressors that occurred over the year predicted telomere shortening, and whether engaging in healthy behaviors during this period mitigates this effect. In 239 postmenopausal, non-smoking, disease-free women, accumulation of major life stressors across a 1-year period predicted telomere attrition over the same period-for every major life stressor that occurred during the year, there was a significantly greater decline in telomere length over the year of 35 bp (P

The ribonucleoprotein (RNP) enzyme telomerase fromSaccharomyces cerevisiae adds telomeric DNA to chromosomal ends in short increments both in vivo and in vitro. Whether or not telomerase functions as a multimer has not been addressed previously. Here we show, first, that following polymerization, the telomerase RNP remains stably bound to its telomeric oligonucleotide reaction product. We then exploit this finding and a previously reported mutant telomerase RNA to demonstrate that, unexpectedly, the S. cerevisiae telomerase complex contains at least two functionally interacting RNA molecules that both act as templates for DNA polymerization. Here, functional telomerase contains at least two active sites.

We report the identification and cloning of the telomeres of the filamentous fungus,Aspergillus nidulans. We have identified three classes of cloned chromosomal ends based on the telomere-associated sequences (TASs) and demonstrated that the telomeric repeat sequence is TTAGGG, identical to that found in vertebrates, including humans, and some lower eukaryotes. One category of telomere clones was found to contain internal, variant TAAGGG repeats. The A.nidulans telomeric tract length is strikingly short (4-22 repeats). We demonstrate that telomere length is remarkably stable in different cell types and at altered growth temperatures, suggesting a highly regulated mechanism for length control.

SummaryThe spatiotemporal organization and dynamics of chromatin play critical roles in regulating genome function. However, visualizing specific, endogenous genomic loci remains challenging in living cells. Here, we demonstrate such an imaging technique by repurposing the bacterial CRISPR/Cas system. Using an EGFP-tagged endonuclease-deficient Cas9 protein and a structurally optimized small guide (sg) RNA, we show robust imaging of repetitive elements in telomeres and coding genes in living cells. Furthermore, an array of sgRNAs tiling along the target locus enables the visualization of nonrepetitive genomic sequences. Using this method, we have studied telomere dynamics during elongation or disruption, the subnuclear localization of the MUC4 loci, the cohesion of replicated MUC4 loci on sister chromatids, and their dynamic behaviors during mitosis. This CRISPR imaging tool has potential to significantly improve the capacity to study the conformation and dynamics of native chromosomes in living human cells.

Telomerase canonically maintains telomeres, but recent reports have suggested that the core protein mammalian telomerase reverse transcriptase (TERT) component, together with the chromatin remodeling factor BRG1 and β-catenin, may also bind to and promote expression of Wnt target genes. However, this proposed noncanonical role of TERT in Wnt signaling has been controversial. Here, we investigated the effects of human TERT (hTERT) on Wnt signaling in human breast cancer lines and HeLa cells. We failed to find evidence for physical association of hTERT with BRG1 or β-catenin; instead, we present evidence that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of hTERT with β-catenin. Furthermore, altering hTERT levels in four different breast cancer cell lines caused minimal and discordant effects on Wnt target and Wnt pathway gene expression. Although hTERT's role in Wnt signaling was addressed only indirectly, no significant representation of Wnt target genes was detected in chromatin immunoprecipitation-sequencing (ChIP-seq) and chromatin isolation by RNA purification and sequencing (ChIRP-seq) loci cooccupied in HeLa S3 cells by both BRG1 and hTR. In summary, our evidence fails to support the idea of a biologically consistent hTERT interaction with the Wnt pathway in human breast cancer cells, and any detectable influence of hTERT depended on cell type and experimental system.

Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p

The natural amide bond found in all biotinylated proteins has been replaced with a triazole through CuAAC reaction of an alkynyl biotin derivative. The resultant triazole-linked adducts are shown to be highly resistant to the ubiquitous hydrolytic enzyme biotinidase and to bind avidin with dissociation constants in the low pM range. Application of this strategy to the production of a series of biotinidase-resistant biotin-Gd-DOTA contrast agents is demonstrated.

Major depressive disorder (MDD) has been associated with reduced leukocyte telomere length (LTL). It is not known, however, whether psychosocial and behavioral protective factors moderate this association. In the current study, we examine whether multisystem resiliency – defined by healthy emotion regulation, strong social connections, and health behaviors (sleep and exercise) – predicts LTL and mitigates previously demonstrated associations between depression diagnosis and LTL. LTL was measured, using a quantitative PCR assay, in 954 patients with stable cardiovascular disease in the Heart and Soul Study. In a fully adjusted model, high multisystem resiliency predicted longer LTL (b = 80.00, SE = 27.17, p = .003), whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD-LTL association (p = .02). Specifically, MDD was significantly related to LTL at 1 SD below the mean of multisystem resiliency (b = −142.86, SE = 56.46, p = .01), but not at 1 SD above the mean (b = 49.07, SE = 74.51, p = .51). This study suggests that MDD associations with biological outcomes should be examined within a psychosocial–behavioral context, because this context shapes the nature of the direct relationship. Further research should explore the cognitive, neural, and other physiological pathways through which multisystem resiliency may confer biological benefit.

Peripheral blood leukocyte telomere length (LTL) is increasingly being used as a biomarker of aging, but its natural variation in human populations is not well understood. Several other biomarkers show seasonal variation, as do several determinants of LTL. We examined whether there was monthly variation in LTL in Costa Rica, a country with strong seasonal differences in precipitation and infection.We examined a longitudinal population-based cohort of 581 Costa Rican adults age 60 and above, from which blood samples were drawn between October 2006 and July 2008. LTL was assayed from these samples using the quantitative PCR method. Multivariate regression models were used to examine correlations between month of blood draw and LTL.Telomere length from peripheral blood leukocytes varied by as much as 200 base pairs depending on month of blood draw, and this difference is not likely to be due to random variation. A moderate proportion of this association is statistically accounted for by month and region specific average rainfall. We found shorter telomere length associated with greater rainfall.There are two possible explanations of our findings. First, there could be relatively rapid month-to-month changes in LTL. This conclusion would have implications for understanding the natural population dynamics of telomere length. Second, there could be seasonal differences in constituent cell populations. This conclusion would suggest that future studies of LTL use methods to account for the potential impact of constituent cell type.

Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3 day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and eating behaviors, stress, metabolic, cardiovascular, and cell aging factors among overweight women, but not among obese women due to lower circulating ghrelin levels and/or central resistance to ghrelin. Confirming previous studies demonstrating lowered plasma ghrelin in obesity, ghrelin levels were lower in the obese compared with overweight women. Among the overweight, ghrelin was positively correlated with caloric intake, giving in to cravings for highly palatable foods, and a flatter diurnal cortisol slope across 3 days. These relationships were non-significant among the obese group. Among overweight women, ghrelin was negatively correlated with insulin resistance, systolic blood pressure, and heart rate, and positively correlated with telomere length. Among the obese subjects, plasma ghrelin concentrations were negatively correlated with insulin resistance, but were not significantly correlated with blood pressure, heart rate or telomere length. Total plasma ghrelin and its associations with food intake, hedonic eating, and stress are decreased in obesity, providing evidence consistent with the theory that central resistance to ghrelin develops in obesity and ghrelin’s function in appetite regulation may have evolved to prevent starvation in food scarcity rather than cope with modern food excess. Furthermore, ghrelin is associated with metabolic and cardiovascular health, and may have anti-aging effects, but these effects may be attenuated in obesity.

Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β− or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology. Cancer Res; 73(9); 2817–28. ©2013 AACR.

Fluorescent nuclear actin reporters are used to determine the distribution of nuclear actin in live somatic cells and evaluate its potential functions. They reveal distinct monomeric and filamentous actin populations in nuclei of live somatic cells and implicate nuclear actin in mRNA processing and organization of the nucleoplasm., In addition to its long-studied presence in the cytoplasm, actin is also found in the nuclei of eukaryotic cells. The function and form (monomer, filament, or noncanonical oligomer) of nuclear actin are hotly debated, and its localization and dynamics are largely unknown. To determine the distribution of nuclear actin in live somatic cells and evaluate its potential functions, we constructed and validated fluorescent nuclear actin probes. Monomeric actin probes concentrate in nuclear speckles, suggesting an interaction of monomers with RNA-processing factors. Filamentous actin probes recognize discrete structures with submicron lengths that are excluded from chromatin-rich regions. In time-lapse movies, these actin filament structures exhibit one of two types of mobility: 1) diffusive, with an average diffusion coefficient of 0.06–0.08 μm2/s, or (2) subdiffusive, with a mobility coefficient of 0.015 μm2/s. Individual filament trajectories exhibit features of particles moving within a viscoelastic mesh. The small size of nuclear actin filaments is inconsistent with a role in micron-scale intranuclear transport, and their localization suggests that they do not participate directly in chromatin-based processes. Our results instead suggest that actin filaments form part of a large, viscoelastic structure in the nucleoplasm and may act as scaffolds that help organize nuclear contents.

The ribonucleoprotein telomerase, a specialized cellular reverse transcriptase, synthesizes one strand of the telomeric DNA of eukaryotes. We analyzed telomere maintenance in two immortalized human cell lines: the B-cell line JY616 and the T-cell line Jurkat E6-1, and determined whether known inhibitors of retroviral reverse transcriptases could perturb telomere lengths and growth rates of these cells in culture. Dideoxyguanosine (ddG) caused reproducible, progressive telomere shortening over several weeks of passaging, after which the telomeres stabilized and remained short. However, the prolonged passaging in ddG caused no observable effects on cell population doubling rates or morphology. Azidothymidine (AZT) caused progressive telomere shortening in some but not all T- and B-cell cultures. Telomerase activity was present in both cell lines and was inhibited in vitro by ddGTP and AZT triphosphate. Prolonged passaging in arabinofuranyl-guanosine, dideoxyinosine (ddI), dideoxyadenosine (ddA), didehydrothymidine (d4T), or phosphonoformic acid (foscarnet) did not cause reproducible telomere shortening or decreased cell growth rates or viabilities. Combining AZT, foscarnet, and/or arabinofuranyl-guanosine with ddG did not significantly augment the effects of ddG alone. Strikingly, with or without inhibitors, telomere lengths were often highly unstable in both cell lines and varied between parallel cell cultures. We propose that telomere lengths in these T- and B-cell lines are determined by both telomerase and telomerase-independent mechanisms.

Many ancient contemplative traditions believe presence of mind promotes greater longevity, a belief that is hard to test. Scientific evidence suggests that mind wandering predicts unhappiness, whereas presence in the moment predicts wellbeing. It is important to test whether a tendency toward mind wandering is associated with biological measures of longevity beyond self-reported measures of well-being. Telomere length has recently emerged as a proxy measure of biological aging and correlate of severe stress. We assessed the association between telomere length and tendency to be present versus tendency to mind wander in 239 healthy women. Those who reported high mind wandering had shorter telomeres, consistently across immune cell types (granulocytes, lymphocytes), than did those who reported low mind wandering, even after adjusting for stress. Telomere length varies widely between adults, and these findings suggest that presence of mind may explain some of these differences. A present attentional state may promote a healthy biochemical milieu and, in turn, cell longevity. © The Author(s) 2013.

The ribonucleoprotein enzyme telomerase adds telomeric DNA onto chromosome ends and is normally regulated so that telomeric DNA lengths are kept within defined bounds. In the telomerase RNA gene from the yeast Kluyveromyces lactis, specific mutations that alter telomeric DNA sequences result in telomeres elongating to up to 100 times their normal length and impair cell growth. Some mutations cause immediate elongation whereas others behave like genetic time bombs, causing elongation only after a latent period of hundreds of generations.

Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.

Meditation is becoming increasingly practiced, especially for stress-related medical conditions. Meditation may improve cellular health; however, studies have not separated out effects of meditation from vacation-like effects in a residential randomized controlled trial. We recruited healthy women non-meditators to live at a resort for 6 days and randomized to either meditation retreat or relaxing on-site, with both groups compared with ‘regular meditators’ already enrolled in the retreat. Blood drawn at baseline and post intervention was assessed for transcriptome-wide expression patterns and aging-related biomarkers. Highly significant gene expression changes were detected across all groups (the ‘vacation effect’) that could accurately predict (96% accuracy) between baseline and post-intervention states and were characterized by improved regulation of stress response, immune function and amyloid beta (Aβ) metabolism. Although a smaller set of genes was affected, regular meditators showed post-intervention differences in a gene network characterized by lower regulation of protein synthesis and viral genome activity. Changes in well-being were assessed post intervention relative to baseline, as well as 1 and 10 months later. All groups showed equivalently large immediate post-intervention improvements in well-being, but novice meditators showed greater maintenance of lower distress over time compared with those in the vacation arm. Regular meditators showed a trend toward increased telomerase activity compared with randomized women, who showed increased plasma Aβ42/Aβ40 ratios and tumor necrosis factor alpha (TNF-α) levels. This highly controlled residential study showed large salutary changes in gene expression networks due to the vacation effect, common to all groups. For those already trained in the practice of meditation, a retreat appears to provide additional benefits to cellular health beyond the vacation effect.

Mammalian telomeres are inherently heterochromatic. While enhanced telomere maintenance is evident in malignant cancers, some cancers appear to maintain telomeres by neither the common telomerase nor the alternative telomere repeat recombination mechanisms. Specifically, the roles of epigenetic modifications in telomere protection are largely unknown in human cancers. I have combined newly developed cellular and molecular approaches to show that in some cancer cell types, experimentally enhanced heterochromatinization localized specifically at telomeres reduced damage-induced foci at telomeres, suggesting augmentation of telomere stability. These results lead to the intriguing hypothesis that manipulating the epigenetic status at telomeres may be exploited to elicit damage at the telomeres of cancer cells as a novel approach to fight cancer. My current work in progress focuses on identifying novel chromatin modifiers that weaken telomere protection by modulating telomere compaction. It is especially urgent to understand the plasticity and modes of telomere protection by which some human cancers escape the requirement of telomerase activation to sustain immortalization. Results from this work can potentially advance the development of novel combinatorial telomere-directed cancer treatments. Citation Format: Tracy T. Chow, Elizabeth H. Blackburn. Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-161.

Site-directed mutagenesis of the telomerase RNA from Tetrahymena thermophila was used previously to demonstrate the templating function of a sequence within this RNA; this sequence specifies the sequence of telomeric DNA in vivo. The possible functional importance of a phylogenetically conserved nucleotide outside the telomerase RNA template region was investigated by a similar experimental approach. The telomerase RNA gene was altered by site-directed mutagenesis, cloned in a circular selectable transformation vector consisting of an rRNA gene carrying a selectable drug resistance marker, and introduced into macronuclei of vegetatively dividing Tetrahymena thermophila by microinjection. Changing an invariant A to U at position 16 of the telomerase RNA (A16U) had no effect detectable by phenotype on telomerase function in vivo. However these experiments showed that a telomerase template alteration that dictates the synthesis of the mutant telomeric DNA sequence GGGGTC leads to a profound change in the population of rDNA replicons. The addition of GGGGTC mutant repeats leads to selective pressure for the loss of high copy linear rDNA, and the rRNA genes are maintained in the form of the circular rDNA replicons introduced during transformation.

The rRNA genes in the somatic macronucleus of Tetrahymena thermophila are normally on 21 kb linear palindromic molecules (rDNA). We examined the effect on rRNA gene dosage of transforming T.thermophila macronuclei with plasmid constructs containing a pair of tandemly repeated rDNA replication origin regions unlinked to the rRNA gene. A significant proportion of the plasmid sequences were maintained as high copy circular molecules, eventually consisting solely of tandem arrays of origin regions. As reported previously for cells transformed by a construct in which the same tandem rDNA origins were linked to the rRNA gene [Yu, G.-L. and Blackburn, E. H. (1990) Mol. Cell. Biol., 10, 2070-2080], origin sequences recombined to form linear molecules bearing several tandem repeats of the origin region, as well as rRNA genes. The total number of rDNA origin sequences eventually exceeded rRNA gene copies by approximately 20- to 40-fold and the number of circular replicons carrying only rDNA origin sequences exceeded rRNA gene copies by 2- to 3-fold. However, the rRNA gene dosage was unchanged. Hence, simply monitoring the total number of rDNA origin regions is not sufficient to regulate rRNA gene copy number.

The enzyme telomerase lengthens telomeres—protective structures containing repetitive DNA sequences at chromosome ends. Telomere shortening is associated with diseases of ageing in mammals. Chronic stress has been related to shorter immune-cell telomeres, but telomerase activity under stress may be low, permitting telomere loss, or high, partially attenuating it. We developed an experimental model to examine the impacts of extended unpredictable stress on telomerase activity in male rats. Telomerase activity was 54 per cent higher in stressed rats than in controls, and associated with stress-related physiological and behavioural outcomes. This significant increase suggests a potential mechanism for resilience to stress-related replicative senescence.

ObjectiveIn adults, one of the major determinants of leukocyte telomere length (LTL), a predictor of age-related diseases and mortality, is cumulative psychosocial stress exposure. More recently we reported that exposure to maternal psychosocial stress during intrauterine life is associated with LTL in young adulthood. The objective of the present study was to determine how early in life this effect of stress on LTL is apparent by quantifying the association of maternal psychosocial stress during pregnancy with newborn telomere length.Study DesignIn a prospective study of N = 27 mother-newborn dyads maternal pregnancy-specific stress was assessed in early gestation and cord blood peripheral blood mononuclear cells were subsequently collected and analyzed for LTL measurement.ResultsAfter accounting for the effects of potential determinants of newborn LTL (gestational age at birth, weight, sex, and exposure to antepartum obstetric complications), there was a significant, independent, linear effect of pregnancy-specific stress on newborn LTL that accounted for 25% of the variance in adjusted LTL (β = −0.099; P = .04).ConclusionOur finding provides the first preliminary evidence in human beings that maternal psychological stress during pregnancy may exert a “programming” effect on the developing telomere biology system that is already apparent at birth, as reflected by the setting of newborn LTL.

A stark warning about the societal costs of stress comes from links between shortened telomeres, chronic stress and disease, say Elizabeth H. Blackburn and Elissa S. Epel.

There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.

Rationale/statement of the problem : Major depressive disorder (MDD) and other serious mental illnesses are associated with high rates of comorbid medical illnesses. Many of these comorbid conditions are more typically seen in the aged, raising the possibility that these psychiatric illnesses are associated with accelerated aging. An emerging biomarker of cell aging and of increased risk of medical illness is leukocyte telomere length, and several studies have now characterized leukocyte telomere length in MDD and other psychiatric illnesses. Fewer psychiatric studies have characterized the activity of telomerase, an enzyme that can elongate and preserve telomeric DNA, or have investigated the biochemical mediators of accelerated telomere shortening. Methods : Seven studies examining telomere length in MDD, three studies in schizophrenia, two studies in bipolar illness, two studies in PTSD, and one study in generalized anxiety disorder were reviewed, as were one study of telomerase activity in MDD and one study in schizophrenia. Additional studies in chronically stressed individuals and in individuals with histories of childhood adversity were also reviewed. Results : Shortened leukocyte telomeres have been demonstrated in MDD, bipolar illness, schizophrenia, anxiety disorders, and post-traumatic stress disorder, although in some studies, only subgroups of patients (e.g., those with longer lifetime exposure to the illness, those with poor responses to treatment, or those with preexisting histories of childhood adversity) showed shortened telomeres. Leukocyte telomere shortening is correlated with peripheral indices of increased oxidative stress and increased immune activation. Two studies (one in caregivers with high depression ratings and one in unmedicated patients with MDD) reported elevated peripheral blood mononuclear cell (PBMC) telomerase activity, perhaps representing a compensatory attempt by the body to preserve endangered telomeres. Preliminary data in MDD suggest that relatively low telomerase activity before treatment, and greater treatment-associated increases in telomerase activity, are associated with better antidepressant responses. This, plus the preliminary observation that PBMC telomerase activity is directly correlated with hippocampal volume (by MRI) in MDD, support emerging preclinical data that telomerase has intrinsic neurotrophic and antidepressant effects. Conclusion : Telomere shortening in MDD and certain other psychiatric conditions may, at least partially, reflect chronic exposure to inflammation and oxidation. As such, it may be a bellwether of increased medical risk, or it may play a more direct causal role in accelerated aging. The interplay of telomere integrity and telomerase activity may be an important determinant of psychiatric and medical outcome. Overall, the data are consistent with the view that MDD and certain other psychiatric illnesses have systemic manifestations beyond the brain and call into question the dichotomy of “mental” vs. “physical” illnesses.

The cellular enzyme elomerase replenishes telomeric DNA, which can be lost during repeated mitoses or during exposure to inflammation and oxidation. However, telomerase may have other, non-canonical functions, including (in animal models) antidepressant and neurogenesis-enhancing effects. In this study, we determined the relationship between telomerase activity [(measured in peripheral blood mononuclear cells (PBMCs)] and hippocampal (HC) volume in depressed individuals (MDDs) and matched controls.Nineteen medication-free subjects with MDD and 17 matched healthy controls underwent 4T MRI scanning and fasting morning venipuncture for assessment of unstimulated PBMC telomerase activity. Due to the exploratory nature of the study, corrections for multiple comparisons were not applied.Hippocampal volume was smaller, but not significantly so, in the MDDs than the controls. As reported previously, MDD subjects had significantly higher PBMC telomerase activity than the controls (p=0.007). Within the MDD group (but not in the control group or in the combined sample), PBMC telomerase activity was positively correlated with HC volume (r=0.49, p

Telomere length (TL) is an important marker of cellular aging that can be examined from birth to death and provide information about health status and disease risk. TL shortens in early childhood with the majority of the shortening occurring by age 4. TL is associated with stress and obesity in adults. It is possible that exposure to early life stressors and excess adiposity from birth and the first year of life may impact the rate of telomere shortening. Few studies have examined TL in the first years of life, and none of them have examined stress and obesity in infants.We examined TL by qPCR using genomic DNA from dried blood spots in a sample of 109 four-year-old, low-income Latino children and their mothers. TL is expressed as T/S (the ratio of telomeric product vs. single copy gene product). This group of children and their mothers were recruited prenatally in San Francisco at which time socio-demographic and health history was assessed. In addition, child weight and length and maternal body mass index (BMI) have been assessed annually from birth with the child's weight and length measured also at birth and 6 months of age. Maternal depressive symptoms were assessed prenatally, at 4–6 weeks postpartum and annually throughout the follow-up period. Child behavior was evaluated using the child behavior checklist (CBCL) at 3 and 4 years of age for internalizing and externalizing behaviors. Student's t-tests were performed to compare TL in relationship to different childhood exposures – maternal depression, child overweight and obesity, and socio-demographic factors such as child sex, ethnicity, and socioeconomic status. Factors that were significant at p

Background: Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening. Methods: The Heart and Soul Study is a longitudinal study of patients with stable coronary heart disease. Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFRCKD-EPI), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (n = 954) and 5 years later (n = 608). Linear regression models were used to test the association of kidney function with (i) baseline telomere length and (ii) change in telomere length over 5 years. Results: At baseline, mean eGFRCKD-EPI was 72.6 (±21.5) ml/min/1.73 m2, eGFRcys was 71.0 (±23.1) ml/min/1.73 m2 and ACR was 8.6 (±12.3) mg/g. Only lower baseline eGFRCKD-EPI was associated with shorter baseline telomere length (9.1 (95% CI 1.2–16.9) fewer base pairs for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). Lower baseline eGFRCKD-EPI (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 (95% CI 4.3–17.3) decrease in base pairs over 5 years for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). After adjustment for age, these associations were no longer statistically significant. Conclusions: In patients with coronary heart disease, reduced kidney function is associated with (i) shorter baseline telomere length and (ii) more rapid telomere shortening over 5 years; however, these associations are entirely explained by older age.

BackgroundPsychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs).MethodsWe enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n=47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance).ResultsBoth groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (p

Background: NDE1 and NDEL1 are neurodevelopmental and mitotic proteins with extended coiled-coil N termini, but unknown C-terminal structure. Results: Recombinant NDE1/NDEL1 form dimers and tetramers in which their C termini interact with their N-terminal domains. Conclusion: NDE1/NDEL1 each adopt a sharply bent back structure. Significance: This explains the existence of two distinct dynein-binding domains on NDE1/NDEL1 and instability of disease-associated mutants lacking C termini., Paralogs NDE1 (nuclear distribution element 1) and NDEL1 (NDE-like 1) are essential for mitosis and neurodevelopment. Both proteins are predicted to have similar structures, based upon high sequence similarity, and they co-complex in mammalian cells. X-ray diffraction studies and homology modeling suggest that their N-terminal regions (residues 8–167) adopt continuous, extended α-helical coiled-coil structures, but no experimentally derived information on the structure of their C-terminal regions or the architecture of the full-length proteins is available. In the case of NDE1, no biophysical data exists. Here we characterize the structural architecture of both full-length proteins utilizing negative stain electron microscopy along with our established paradigm of chemical cross-linking followed by tryptic digestion, mass spectrometry, and database searching, which we enhance using isotope labeling for mixed NDE1-NDEL1. We determined that full-length NDE1 forms needle-like dimers and tetramers in solution, similar to crystal structures of NDEL1, as well as chain-like end-to-end polymers. The C-terminal domain of each protein, required for interaction with key protein partners dynein and DISC1 (disrupted-in-schizophrenia 1), includes a predicted disordered region that allows a bent back structure. This facilitates interaction of the C-terminal region with the N-terminal coiled-coil domain and is in agreement with previous results showing N- and C-terminal regions of NDEL1 and NDE1 cooperating in dynein interaction. It sheds light on recently identified mutations in the NDE1 gene that cause truncation of the encoded protein. Additionally, analysis of mixed NDE1-NDEL1 complexes demonstrates that NDE1 and NDEL1 can interact directly.

Telomeric DNA sequences have generally been found to be remarkably conserved in evolution, typically consisting of repeated, very short sequence units containing clusters of G residues. Recently however the telomeric DNA of the asexual yeast Candida albicans was shown to consist of much longer repeat units. Here we report the identification of seven additional telomeric sequences from sexual and asexual budding yeast species. The telomeric repeat units from this group of relatively closely related species show more phylogenetic diversity in length (8-25 bp), sequence, and composition than has been seen previously throughout a wide phylogenetic range of other eukaryotes. We also show that certain strains of the asexual diploid species Candida tropicalis have two forms of telomeric repeats, which appear to differ by a single base pair. Despite their great diversity, the telomeric repeat units of C. albicans, Saccharomyces cerevisiae, and all of the species we have examined in this report share a conserved approximately 6-bp motif of T and G residues resembling more typical telomeric sequences.

Paramecium tetraurelia cells have a limited clonal life span and die after approximately 200 fissions if they do not undergo the process of autogamy or conjugation. To test the possibility that cellular senescence of this species is caused by telomere shortening, we analyzed the genomic DNA of the macronucleus during the clonal life span of P. tetraurelia. We found that telomeric DNA sequences were not shortened during the interval of decreased fission rate and cellular death, defined as senescence in these cells. However, the mean size of the macronuclear DNA was markedly decreased during the clonal life span. We present a model that expands upon previous proposals that accumulated DNA damage causes cellular senescence in P. tetraurelia.

During development of the somatic macronucleus of Tetrahymena thermophila, the rDNA is excised from its germ-line chromosome, rearranged into a palindrome, and amplified to 10(4) copies. We have identified a cis-acting germ-line mutation, rmm11/6, that prevents amplification of the rDNA in all but approximately 1 in 10(5) cells when it is the only rDNA allele in the developing macronucleus. The rmm11/6 mutation resides in a conserved element required for excision, the chromosome breakage sequence (Cbs) flanking the 3' end of the rDNA. Surprisingly, the rmm11/6 mutation only weakly affects excision of the rDNA from its germ-line location; at least 25% of cells heterozygous for this mutation correctly excise the affected rDNA allele. In heterozygotes, when this rDNA allele is excised, it is also poorly amplified. The rDNA amplification defect caused by this mutation is not overcome by delaying amplification with the DNA synthesis inhibitor aphidicolin, indicating that rDNA excision and amplification are not experimentally separable. Our experiments provide the first evidence that the capacity to amplify the rDNA is restricted in the developing macronucleus. We propose that the rmm11/6 mutation delays excision of the rDNA and that the developmental progression of the macronucleus past a restricted window for amplification is responsible for the severe amplification defect caused by this weak rDNA excision mutation.

Objective:To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children.Methods:The study sample comprised 78 children, aged 5 to 6 years, from a longitudinal cohort study of kindergarten social hierar

Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.

Theory suggests that chronic stress associated with disadvantaged social status may lead to acceleration in the rate of decline in physiological functioning. The purpose of this study is to examine the association between parental socioeconomic status (SES) and leukocyte telomere length (LTL), a marker of cell aging, in children. We examined SES and LTL in 70 white and black US children aged 7–13 who participated in the community-based AMERICO (Admixture Mapping for Ethnic and Racial Insulin Complex Outcomes) study. LTL was assessed using the polymerase chain reaction (PCR) method. Parental education was positively associated with child LTL, net of controls for sex, age, race/ethnicity, and family income. Compared to children with at least one college-educated parent, children whose parents never attended college had telomeres shorter by 1,178 base pairs, which is roughly equivalent to 6 years of additional aging. Socioeconomic disparities in cell aging are evident in early life, long before the onset of age-related diseases.

A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787–92. ©2011 AACR.

Objective: Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered as an emerging marker of biologic age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD. Methods: In a prospective cohort study, we measured leukocyte telomere length in 952 participants with stable CHD at baseline and in 608 of these participants after 5 years of follow-up. The presence of major depressive disorder in the past month was assessed using the computerized diagnostic interview schedule at baseline. We used linear and logistic regression models to evaluate the association of depression with baseline and 5-year change in leukocyte telomere length. Results: Of the 952 participants, 206 (22%) had major depression at baseline. After the adjustment for age and sex, the patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean [standard error] = 0.86 [0.02] versus 0.90 [0.01]; p = .02). This association was similar (but no longer statistically significant) after adjustment for body mass index, smoking, diabetes, left ventricular ejection fraction, statin use, antidepressant use, physical inactivity, and anxiety (0.85 [0.02] versus 0.89 [0.01], p = .06). Depression was not predictive of 5-year change in telomere length after adjustment for the mentioned covariates and baseline telomere length. Conclusions: Depression is associated with reduced leukocyte telomere length in patients with CHD but does not predict 5-year change in telomere length. Future research is necessary to elucidate the potential mechanisms underlying the association between depression and telomere length.

Background Hostility is associated with a significantly increased risk of age-related disease and mortality, yet the pathophysiological mechanisms involved remain unclear. Here we investigated the hypothesis that hostility might impact health by promoting cellular aging. Methods We tested the relationship between cynical hostility and two known markers of cellular aging, leukocyte telomere length (TL) and leukocyte telomerase activity (TA), in 434 men and women from the Whitehall II cohort. Results High-hostile men had significantly shorter leukocyte TL than their low-hostile counterparts. They also had elevated leukocyte TA, with a significantly increased likelihood of having both short TL and high TA, compared with low-hostile individuals. Conclusions Because telomerase is known to counteract telomere shortening by synthesizing telomeric DNA repeats, particularly in the context of shortened telomeres, heightened TA might represent a compensatory response in high-hostile individuals. The relationship between hostility and disease is stronger in men than in women, and men generally have a shorter life expectancy than women. Our findings suggest that telomere attrition might represent a novel mechanism mediating the detrimental effects of hostility on men's health.

The FK506 binding protein (FKBP) family of proteins provide an interesting series of drug targets since different isoforms modulate diverse cellular pathways. There are therapeutic opportunities in the fields of cancer therapy, neurodegenerative conditions and psychiatric disorders. X-ray crystallographic or NMR data are available for eight of fourteen human FKBPs covering ten of the twenty-two different FKBP domains. We have made a detailed sequence and structural comparison of human FKBP domains. These data show that the chemical scaffolds common to the immunosuppressive inhibitors FK506 and rapamycin bind to the most conserved region of the binding site. This observation opens the way to the design of isoform specific inhibitors.

Background: Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of ‘‘accelerated aging’’ in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation. Methodology: Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex. Principal Findings: The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p,0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure ($9.2 years’ cumulative duration) was 281 base pairs shorter than that in controls (p,0.05), corresponding to approximately seven years of ‘‘accelerated cell aging.’’ Telomere length was inversely correlated with oxidative stress in the depressed subjects (p,0.01) and in the controls (p,0.05) and with inflammation in the depressed subjects (p,0.05). Conclusions: These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.

Low socioeconomic status (SES) may be associated with accelerated biological aging, but findings relating SES with telomere length have been inconsistent. We tested the hypotheses that shorter telomere length and telomerase activity would be related more robustly to education, an early life indicator of socioeconomic position, than to current indicators of socioeconomic circumstances. Healthy men and women aged 53–76 years from the Whitehall II epidemiological cohort provided blood samples from which telomere length was assessed in 448 and telomerase activity in 416. Educational attainment was classified into four levels, while household income and grade of employment were measured as indicators of current socioeconomic circumstances. Age, gender, blood pressure, glycated hemoglobin, high density lipoprotein cholesterol, smoking, body mass index and physical activity were included as covariates. We found that lower educational attainment was associated with shorter telomere length after controlling statistically for biological and behavioral covariates. Neither household income nor employment grade was related to telomere length. The association between telomere length and education remained significant after adjusting for current socioeconomic circumstances. In men, highest levels of telomerase activity were found in the lowest education group. We conclude that low SES defined in terms of education but not current socioeconomic circumstances is associated with shortened telomeres. Low educational attainment may be an indicator of long-term SES trajectories, and be associated with accumulated allostatic load resulting in telomere shortening. Education may also promote problem-solving skills leading to reduced biological stress responsivity, with favorable consequences for biological aging.

Telomerase activity is a predictor of long-term cellular viability, which decreases with chronic psychological distress (Epel et al., 2004). Buddhist traditions claim that meditation decreases psychological distress and promotes well-being (e.g., Dalai Lama and Cutler, 2009). Therefore, we investigated the effects of a 3-month meditation retreat on telomerase activity and two major contributors to the experience of stress: Perceived Control (associated with decreased stress) and Neuroticism (associated with increased subjective distress). We used mediation models to test whether changes in Perceived Control and Neuroticism explained meditation retreat effects on telomerase activity. In addition, we investigated whether two qualities developed by meditative practice, increased Mindfulness and Purpose in Life, accounted for retreat-related changes in the two stress-related variables and in telomerase activity.Retreat participants (n=30) meditated for ∼6 h daily for 3 months and were compared with a wait-list control group (n=30) matched for age, sex, body mass index, and prior meditation experience. Retreat participants received instruction in concentrative meditation techniques and complementary practices used to cultivate benevolent states of mind (Wallace, 2006). Psychological measures were assessed pre- and post-retreat. Peripheral blood mononuclear cell samples were collected post-retreat for telomerase activity. Because there were clear, a priori hypotheses, 1-tailed significance criteria were used throughout.Telomerase activity was significantly greater in retreat participants than in controls at the end of the retreat (p0.05). Increases in Perceived Control, decreases in Neuroticism, and increases in both Mindfulness and Purpose in Life were greater in the retreat group (p0.01). Mediation analyses indicated that the effect of the retreat on telomerase was mediated by increased Perceived Control and decreased Neuroticism. In turn, changes in Perceived Control and Neuroticism were both partially mediated by increased Mindfulness and Purpose in Life. Additionally, increases in Purpose in Life directly mediated the telomerase group difference, whereas increases in Mindfulness did not.This is the first study to link meditation and positive psychological change with telomerase activity. Although we did not measure baseline telomerase activity, the data suggest that increases in perceived control and decreases in negative affectivity contributed to an increase in telomerase activity, with implications for telomere length and immune cell longevity. Further, Purpose in Life is influenced by meditative practice and directly affects both perceived control and negative emotionality, affecting telomerase activity directly as well as indirectly.

The ribonucleoprotein enzyme telomerase synthesizes one strand of telomeric DNA by copying a template sequence within the RNA moiety of the enzyme. Kinetic studies of this polymerization reaction were used to analyze the mechanism and properties of the telomerase from Tetrahymena thermophila. This enzyme synthesizes TTGGGG repeats, the telomeric DNA sequence of this species, by elongating a DNA primer whose 3' end base pairs with the template-forming domain of the RNA. The enzyme was found to act nonprocessively with short (10- to 12-nucleotide) primers but to become processive as TTGGGG repeats were added. Variation of the 5' sequences of short primers with a common 3' end identified sequence-specific effects which are distinct from those involving base pairing of the 3' end of the primer with the RNA template and which can markedly induce enzyme activity by increasing the catalytic rate of the telomerase polymerization reaction. These results identify an additional mechanistic basis for telomere and DNA end recognition by telomerase in vivo.

Yeast cells lacking a functional EST1 gene show progressive shortening of the terminal G 1–3 T telomeric repeats and a parallel increase in the frequency of cell death. Although the majority of the cells in an est1 − culture die, a minor subpopulation survives the potentially lethal consequences of the est1 mutation. We show that these est1 − survivors arise as a result of the amplification and acquisition of subtelomeric elements (and their deletion derivatives) by a large number of telomeres. Hence, even when the primary pathway for telomere replication is defective, an alternative backup pathway can restore telomere function and keep the cell alive.

Background Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS). Methodology Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects. Results The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (β = −0.19±0.04 kbp, p = 0.001). Conclusion Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.