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Leukocyte telomere length (LTL) has been inversely associated with sugar-sweetened beverage (SSB) consumption in cross-sectional studies, but no studies have examined whether dietary intake influences LTL over time. This study examined longitudinal associations between sugary foods and beverages and LTL. Participants were 65 overweight and obese pregnant women, aged 18-45 years, from a mindfulness intervention study conducted from early pregnancy (⩽16 weeks gestation) and followed through 9 months postpartum. During pregnancy and postpartum, dietary intake was measured with 24-h diet recalls, and LTL was assessed using quantitative PCR. Adjusting for sociodemographic and health characteristics, decreased SSB consumption from baseline to 9 months postpartum was associated with greater concurrent LTL lengthening (β=-0.102, 95% confidence interval (CI) -0.192, -0.013). No associations between sugary foods and LTL were found in either period. The finding that reduced SSB consumption is associated with increased LTL warrants investigation in large cohort studies.

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.

Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.

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

Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The aim of this study was to examine the relationship between depression, anxiety and telomere le

Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impa

Background. Accumulating evidence supports leukocyte telomere length (LTL) as a biological marker of cellular aging. Poor sleep is a risk factor for age-related disease; however, the extent to which sleep accounts for variation in LTL is unknown. Methods. The present study examined associations of self-reported sleep duration, onset latency, and subjective quality with LTL in a community-dwelling sample of 245 healthy women in midlife (aged 49-66 years). Results. While sleep duration and onset latency were unrelated to LTL, women reporting poorer sleep quality displayed shorter LTL (r = 0.14, P = 0.03), independent of age, BMI, race, and income (b = 55.48, SE = 27.43, P = 0.04). When analyses were restricted to participants for whom sleep patterns were chronic, poorer sleep quality predicted shorter LTL independent of covariates and perceived psychological stress. Conclusions. This study provides the first evidence that poor sleep quality explains significant variation in LTL, a marker of cellular aging. Copyright © 2011 Aric A. Prather et al.

Telomeres are the protein-nucleic acid structures at the ends of eukaryote chromosomes. Tandem repeats of telomeric DNA are templated by the RNA component (TER1) of the ribonucleoprotein telomerase. These repeats are bound by telomere binding proteins, which are thought to interact with other factors to create a higher-order cap complex that stabilizes the chromosome end. In the budding yeast Kluyveromyces lactis, the incorporation of certain mutant DNA sequences into telomeres leads to uncapping of telomeres, manifested by dramatic telomere elongation and increased length heterogeneity (telomere deregulation). Here we show that telomere deregulation leads to enlarged, misshapen "monster" cells with increased DNA content and apparent defects in cell division. However, such deregulated telomeres became stabilized at their elongated lengths upon addition of only a few functionally wild-type telomeric repeats to their ends, after which the frequency of monster cells decreased to wild-type levels. These results provide evidence for the importance of the most terminal repeats at the telomere in maintaining the cap complex essential for normal telomere function. Analysis of uncapped and capped telomeres also show that it is the deregulation resulting from telomere uncapping, rather than excessive telomere length per se, that is associated with DNA aberrations and morphological defects.

BACKGROUND: Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Telomere shortening is counteracted by the cellular enzyme telomerase. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). METHODS: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 24 patients had sufficient PBMCs needed for longitudinal analysis. This study is registered on the ClinicalTrials.gov website, number NCT00739791. FINDINGS: PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047). INTERPRETATION: Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. Larger randomised controlled trials are warranted to confirm the findings of this study. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (β = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (β = - .320 p = .017) and a cardiometabolic risk score (β = - .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response., (© 2023. The Author(s).)

Introduction: Telomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth., Methods and Materials: Participants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth., Results: After adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (β = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy., Discussion: These findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system., (Copyright © 2019. Published by Elsevier Inc.)

Background: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL., Methods: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log 2 transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL., Results: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex., Conclusions: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL., Competing Interests: S.E.A., C.A.S., E.J., L.C.S., C.P.Q., and S.K.V. are employees of The Permanente Medical Group. All other authors declare they have no actual or potential competing financial interests., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Environmental Epidemiology. All rights reserved.)

Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b = -0.01, p = 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b = 27.09, p < 0.001), even after controlling for global volume loss (b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b = -0.01, p = 0.012) and decreases in fornix fractional anisotropy (b = 0.004, p = 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced., Methods: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age., Results: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (χ 2  = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040)., Conclusion: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.

Objective: Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC., Methods: Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels., Results: LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL (p=0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL (p=0.055). Neither hormone was correlated with shorter LTL in MDD (p's>0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC (p=0.001), but not in MDD (p=0.96)., Conclusion: This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Chronic psychological stress has been associated with shorter telomeres, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses to stress exposure are involved., Objective: To test the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition., Design: We measured salivary cortisol responses to 2 challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later., Participants: We studied 411 initially healthy men and women aged 54 to 76 years., Main Outcome Measure: Leukocyte telomere length., Results: Cortisol responses to this protocol were small; we divided participants into cortisol responders (n = 156) and nonresponders (n = 255) using a criterion (≥20% increase in cortisol concentration) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (β = -0.061; standard error, 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than nonresponders on follow-up, after controlling statistically for age, sex, socioeconomic status, smoking, time of day of stress , and baseline telomere length (β = -0.10; standard error, 0.046; P = 0.029). The association was maintained after additional control for cardiovascular risk factors (β = -0.11; P = 0.031). The difference between cortisol responders and nonresponders was equivalent to approximately 2 years in aging., Conclusions: These findings suggest that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging.

Background: Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population., Methods and Findings: We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999-2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749--0.00206), waist circumference -0.00211 (95% CI -0.00325--0.000969), percentage of body fat -0.00516 (95% CI -0.00761--0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571-0.00301), triglycerides -0.000285 (95% CI -0.000555--0.0000158), pulse rate -0.00194 (95% CI -0.00317--0.000705), C-reactive protein -0.0363 (95% CI 0.0601--0.0124), cystatin C -0.0391 (95% CI -0.0772--0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685--0.0139), systolic blood pressure 0.0455 (95% CI 0.00137-0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126--0.00889). These associations were 10%-15% greater without controlling for leukocyte cell types. There were very few differences in the associations by age, race/ethnicity, gender, education, or income. Our findings are relevant to the relationships between these cardiovascular biomarkers in the general population but not to cardiovascular disease as a clinical outcome., Conclusions: LTL is most strongly associated with adiposity, but is also associated with biomarkers across several physiological systems. LTL may thus be a predictor of cardiovascular disease through its association with multiple risk factors that are physiologically correlated with risk for development of cardiovascular disease. Our results are consistent with LTL being a biomarker of cardiovascular aging through established physiological mechanisms., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JL is a cofounder and consultant to Telomere Diagnostic Inc. (formerly Telome Health).

Background: Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated., Methods: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality., Results: During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61-0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23-0.87)., Conclusions: In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality., Competing Interests: We have read the journal’s policy and acknowledge that authors of this manuscript have the following competing interests: Drs. Epel, Lin and Blackburn were co-founders of Telome Health (now Telomere Diagnostics). Dr. Lin currently serves as a scientific advisor to Telomere Diagnostics, but Drs. Blackburn and Epel are no longer affiliated with the company and hold no equity or financial interest in it.

Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to SSRI response in MDD. We assessed pre-treatment LTL, depression severity (using the Hamilton Depression Rating Scale [HDRS]), and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. Subjects then underwent open-label treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. "Non-responders" to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL, compared to "Responders" (p=0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p<0.010) but not with changes in positive affect (p=0.356). This preliminary study is the first to assess the relationship between LTL and SSRI response in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.

Telomeres cap the ends of chromosomes, protecting them from degradation and inappropriate DNA repair processes that can lead to genomic instability. A short telomere elicits increased telomerase action on itself that replenishes telomere length, thereby stabilizing the telomere. In the prolonged absence of telomerase activity in dividing cells, telomeres eventually become critically short, inducing a permanent cell cycle arrest (senescence). We recently showed that even early after telomerase inactivation (ETI), yeast cells have accelerated mother cell aging and mildly perturbed cell cycles. Here, we show that the complete disruption of DNA damage response (DDR) adaptor proteins in ETI cells causes severe growth defects. This synthetic-lethality phenotype was as pronounced as that caused by extensive DNA damage in wild-type cells but showed genetic dependencies distinct from such damage and was completely alleviated by SML1 deletion, which increases deoxynucleoside triphosphate (dNTP) pools. Our results indicated that these deleterious effects in ETI cells cannot be accounted for solely by the slow erosion of telomeres due to incomplete replication that leads to senescence. We propose that normally occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in two parallel pathways and that deletion of Sml1 prevents this stress., (Copyright © 2016 Jay et al.)

Background: Several psychiatric disorders may be characterized by peripheral telomere shortening. However, it is unclear whether telomere shortening is associated with these psychiatric disorders per se or, rather, with underlying dimensional parameters that are often, but not necessarily, associated with them. We explored the association between dimensional psychopathological measures and telomere length (TL) in granulocytes among veterans independent of psychiatric diagnosis., Methods: Seventy-six combat-exposed male veterans (41 psychiatrically healthy, 18 with Posttraumatic Stress Disorder [PTSD] and 17 with concomitant PTSD and Major Depressive Disorder [MDD]) had TL assayed. Assessments included Clinician-Administered PTSD Scale (CAPS), Beck Depression Inventory-II (BDI-II), Early Trauma Inventory (ETI), Symptom Checklist-90-R Global Severity Index (SCL-90-GSI), Perceived Stress Scale (PSS) and Positive and Negative Affect Schedule (PANAS). Correlations were corrected for age, BMI, antidepressants and ethnicity., Results: Across subjects, TL was negatively correlated with early trauma (p<0.001), global psychopathological severity (p=0.044) and perceived stress (p=0.019), positively correlated with positive affect (p=0.026), not significantly correlated with symptom severity of PTSD, depression or negative affect. Across these dimensions, early trauma and positive affect were associated with TL after excluding subjects with somatic illnesses., Limitations: The study was cross-sectional with a moderate sample size and only male combat-exposed subjects., Conclusions: These preliminary findings suggest that early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD, whereas positive affect is associated with longer TL. Larger-scale studies should assess TL associated with specific psychiatric dimensions, apart from only categorical psychiatric diagnoses, to develop more specific biologically-relevant endophenotypes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Mitochondrial abnormalities may be involved in PTSD, although few studies have examined this. Mitochondrial DNA copy number (mtDNAcn) in blood cells is an emerging systemic index of mitochondrial biogenesis and function. The present study assessed mtDNAcn in male combat-exposed veterans with PTSD compared to those without PTSD as well as its correlation with clinical scales., Methods: mtDNAcn was assessed with a TaqMan multiplex assay in granulocytes of 43 male combat veterans with (n=43) or without (n=44) PTSD. Twenty of the PTSD subjects had co-morbid major depressive disorder (MDD). The Clinician Administered PTSD Scale (CAPS), the Positive and Negative Affect Schedule (PANAS), the Early Trauma Inventory (ETI) and the Beck Depression Inventory II (BDI-II) were used for the clinical assessments. All analyses were corrected for age and BMI., Results: mtDNAcn was significantly lower in subjects with PTSD (p<0.05). Within the PTSD group, those with moderate PTSD symptom severity had relatively higher mtDNAcn than those with mild or severe symptoms (p<0.01). Within the PTSD group, mtDNAcn was positively correlated with PANAS positive subscale ratings (p<0.01) but was not significantly correlated with PANAS negative subscale, ETI or BDI-II ratings., Discussion: This study provides the first evidence of: (i) a significant decrease of mtDNAcn in combat PTSD, (ii) a possible "inverted-U" shaped relationship between PTSD symptom severity and mtDNAcn within PTSD subjects, and (iii) a direct correlation of mtDNAcn with positive affectivity within PTSD subjects. Altered mtDNAcn in PTSD may reflect impaired energy metabolism, which might represent a novel aspect of its pathophysiology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.

African American men in the US experience disparities across multiple health outcomes. A common mechanism underlying premature declines in health may be accelerated biological aging, as reflected by leukocyte telomere length (LTL). Racial discrimination, a qualitatively unique source of social stress reported by African American men, in tandem with poor mental health, may negatively impact LTL in this population. The current study examined cross-sectional associations between LTL, self-reported racial discrimination, and symptoms of depression and anxiety among 92 African American men 30-50 years of age. LTL was measured in kilobase pairs using quantitative polymerase chain reaction assay. Controlling for sociodemographic factors, greater anxiety symptoms were associated with shorter LTL (b=-0.029, standard error [SE]=0.014; p<0.05). There were no main effects of racial discrimination or depressive symptoms on LTL, but we found evidence for a significant interaction between the two (b=0.011, SE=0.005; p<0.05). Racial discrimination was associated with shorter LTL among those with lower levels of depressive symptoms. Findings from this study highlight the role of social stressors and individual-level psychological factors for physiologic deterioration among African American men. Consistent with research on other populations, greater anxiety may reflect elevated stress associated with shorter LTL. Racial discrimination may represent an additional source of social stress among African American men that has detrimental consequences for cellular aging among those with lower levels of depression., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases., (Copyright © 2015, American Association for the Advancement of Science.)

Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

Introduction: Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging. Some, but not all, evidence suggests that physical activity (PA) may play an important role in attenuating age-related diseases and may provide a protective effect for telomeres. The purpose of this study was to examine the association between PA and LTL in a national sample of US adults from the National Health and Nutrition Examination Survey., Methods: National Health and Nutrition Examination Survey data from 1999 to 2002 (n = 6503; 20-84 yr) were used. Four self-report questions related to movement-based behaviors (MBB) were assessed. The four MBB included whether individuals participated in moderate-intensity PA, vigorous-intensity PA, walking/cycling for transportation, and muscle-strengthening activities. An MBB index variable was created by summing the number of MBB an individual engaged in (range, 0-4)., Results: A clear dose-response relation was observed between MBB and LTL; across the LTL tertiles, respectively, the mean numbers of MBB were 1.18, 1.44, and 1.54 (Ptrend < 0.001). After adjustments (including age) and compared with those engaging in 0 MBB, those engaging in 1, 2, 3, and 4 MBB, respectively, had a 3% (P = 0.84), 24% (P = 0.02), 29% (P = 0.04), and 52% (P = 0.004) reduced odds of being in the lowest (vs highest) tertile of LTL; MBB was not associated with being in the middle (vs highest) tertile of LTL., Conclusions: Greater engagement in MBB was associated with reduced odds of being in the lowest LTL tertile.

Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis., (Copyright © 2015 by the Genetics Society of America.)

Background: This study examined the association between leukocyte telomere length--a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education., Methods: Data were from the National Health and Nutrition Examination Survey, 1999-2002 (n = 3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause- specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions., Results: Eight hundred and seventy deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (hazard ratio [HR]: 1.1, 95% confidence interval [CI]: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality., Conclusions: The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death.

Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes., (© American Sociological Association 2015.)

Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The aim of this study was to examine the relationship between depression, anxiety and telomere length, and to assess whether this relationship is moderated by race/ethnicity, gender and/or antidepressant use. Data were from the 1999-2002 National Health and Nutrition Examination Survey. Telomere length was assessed using the quantitative PCR method of telomere length relative to standard reference DNA. Past-year major depression (MD), generalized anxiety disorder (GAD) and panic disorder (PD), as well as depressed affect and anxious affect, were assessed using the Composite International Diagnostic Inventory (N=1290). Multiple linear regression was used to assess the relationship between depression and anxiety disorders and telomere length. Among women, those with GAD or PD had shorter telomeres than those with no anxious affect (β: -0.07, P<0.01), but there was no relationship among men (β: 0.08, P>0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (β: -0.26, P<0.05), but there was no association between MD and telomere length among those not using antidepressants (β: -0.00, P>0.05). Neither depressive nor anxiety disorders were directly associated with telomere length in young adults. There was suggestive evidence that pharmacologically treated MD is associated with shorter telomere length, likely reflecting the more severe nature of MD that has come to clinical attention.

Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even early after telomerase inactivation (ETI), yeast mother cells show transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI phenotypes occurred well before the population senescence caused late after telomerase inactivation (LTI). They were morphologically distinct from LTI senescence, were genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that, well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells and that a lack of telomerase accelerates otherwise normal aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Telomere biology plays a fundamental role in genomic integrity, cellular regeneration, physiology, aging, disease risk, and mortality. The initial setting of telomere length (TL) in early life has important implications for telomere maintenance and related disorders throughout the life span. However, little is known about the predictors of this initial setting., Objective: Given the established role of estrogen on adult TL and the role of estriol (E3) in the context of fetal development, the goal of this study was to test the hypothesis that higher maternal E3 concentration during early pregnancy is associated with longer infant telomere length., Design, Participants, and Setting: Study participants comprised a cohort of N = 100 infants followed prospectively from intrauterine life and birth through early childhood from a population-based, representative sample of pregnant mothers recruited in early pregnancy at university-based obstetric clinics in Southern California. Maternal unconjugated E3 concentrations were assessed in plasma in early gestation (around wk 15). Infant TL was assessed in buccal cells at approximately 15 months of age., Results: After accounting for the effects of potential confounding maternal and infant variables, there was a significant, independent effect of maternal E3 concentration on infant TL (unstandardized β = 0.297; P = .001; 95% Cl, 0.121-0.473). Specifically, a one-multiple-of-the-median (MoM) increase in maternal E3 concentration during early pregnancy was associated with a 14.42% increase in infant TL., Conclusions: This study supports the concept of developmental plasticity of the telomere biology system and highlights specifically the role of a potentially modifiable intrauterine factor for additional mechanistic and clinical investigation.

Background/aims: Telomere biology plays a fundamental role in genomic integrity and cell physiology. The newborn setting of telomere length (TL) likely has important implications for telomere dynamics over the lifespan; however, its determinants are poorly understood. Folate is essential for DNA integrity. The maternal compartment is the only source of folate for the developing fetus. We, therefore, tested the hypothesis that variation in maternal folate during pregnancy is associated with newborn TL., Methods: A prospective, longitudinal study was conducted in 119 mother-newborn dyads. Eligible mothers were enrolled at 9.5 (SD ±2.1) weeks gestation and followed through birth. Concentrations of maternal serum folate were measured in the first trimester of pregnancy. Newborn telomere length was measured in cord blood mononuclear cells (CBMC)., Results: After accounting for the effects of other established determinants of newborn TL, each 10 ng/ml increase in maternal total folate was associated with a 5.8% increase in median TL (p = 0.03). The median TL in newborns of mother in the lowest quartile of total folate levels was approximately 10% shorter than that of newborns of mothers in the highest folate quartile., Conclusions: Our findings suggest that fetal TL exhibits developmental plasticity, and provide evidence that maternal nutrition may exert a 'programming' effect on this system., (2015 S. Karger AG, Basel.)

Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long-term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasone-induced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease., (© 2014 by The American Society of Hematology.)