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Understanding the social determinants of telomere length is critical to evaluate the risk of early biological aging. We investigated sex differences on the association between socioeconomic status (SES) and demographic markers and leukocyte telomere length (LTL) in Brazilian adults. This cross-sectional study was conducted in a subsample (women=228; men=200) nested within the Pro-Saúde study, a prospective cohort study of university civil servants in Rio de Janeiro, Brazil (2012-2013). Adjusted multivariate models were used to test the relationship between SES markers (marital status, educational attainment, father's educational attainment, race/skin color, household income, and childhood experience of food deprivation) and LTL. After adjusting for age and potential health-related confounders, lower educational attainment was associated with shorter LTL among men (β=-0.05, 95% confidence interval (CI)=95%CI: -0.10, 0.00, P=0.03). In women, LTL was inversely associated with unmarried status (β=-0.05, 95%CI: -0.09, 0.00, P=0.03), lower father's educational attainment (β=-0.05, 95%CI: -0.13, 0.00, P=0.04), and childhood experience of food deprivation (β=-0.07, 95%CI: -0.13, 0.00, P=0.04). Our findings suggested that the association between SES markers and LTL differs according to sex. SES markers able to induce lifelong stress, reflected in LTL, appeared to be more related to individual factors in men, whereas in women they were family-related.

Objective: The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes, serum 25-hydroxyvitamin D [25(OH)D] concentrations, and leukocyte telomere length (LTL) in Brazilian adults., Methods: The study population comprised 461 participants (33-79 y of age; 51% women) from the Pró-Saúde Study, a cohort of civil servants at a university campus in Rio de Janeiro, Brazil. LTL, genotypes of vitamin D-related SNPs (rs12785878, rs10741657, rs6013897, and rs2282679), and serum 25(OH)D concentrations were determined cross-sectionally. Differences in age- and sex-adjusted LTL means by categories of genotypes and 25(OH)D serum concentrations were evaluated. LTL associations with genotypes and 25(OH)D were investigated using multiple linear regression models adjusted for sociodemographic characteristics and markers of health behavior., Results: Participants with CC genotype (rs2282679) had shorter age- and sex-adjusted mean LTL than those with AC and AA genotypes (mean ± SE: 0.51 ± 0.03, 0.58 ± 0.01 and 0.5 ± 0.01, respectively, P < 0.05). In adjusted analyses, the CC genotype (rs2282679) was inversely associated with LTL (β = -0.061; 95% confidence interval, -0.120 to -0.001). Other vitamin D-related SNPs and serum 25(OH)D concentrations were not associated with LTL., Conclusions: Genetic variations in the gene encoding vitamin D binding protein (GC - rs2282679) were associated with LTL, suggesting an influence of vitamin D status on telomere length that may start early in life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages., (© 2017 World Obesity Federation.)

Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.

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.

Background: Telomere length (TL) is a marker of cellular aging, with the majority of lifetime attrition occurring during the first 4 y. Little is known about risk factors for telomere shortening in childhood., Objective: We evaluated the relation between early life feeding variables and preschool TL., Design: We assessed the relation between dietary, feeding, and weight-associated risk factors measured from birth and TL from blood samples taken at 4 y of age (n = 108) and 5 y of age (n = 92) in a cohort of urban, Latino children (n = 121 individual children). Feeding variables were evaluated in children with repeat measurements (n = 77)., Results: Mean TL (in bp) was associated with exclusive breastfeeding at 4-6 wk of age (adjusted coefficient: 353.85; 95% CI: 72.81, 634.89; P = 0.01), maternal TL (adjusted coefficient: 0.32; 95% CI: 0.11, 0.54; P < 0.01), and older paternal age (adjusted coefficient: 33.27; 95% CI: 4.10, 62.44; P = 0.03). The introduction of other foods or drinks in addition to breast-milk or replacement-milk substitutes before 4-6 wk of age was associated with mean TL at 4 and 5 y of age (adjusted coefficient: -457.01; 95% CI: -720.50, -193.51; P < 0.01). Infant obesity at 6 mo of age and soda consumption at 4 y of age mediated the relation in part between exclusive breastfeeding at 4-6 wk of age and mean TL at 4 and 5 y of age. High soda consumption at 3 y of age was associated with an accelerated attrition from 4 to 5 y of age (adjusted coefficient: -515.14; 95% CI: -986.06, -41.22; P = 0.03)., Conclusion: Exclusive breastfeeding at 4-6 wk of age may have long-term effects on child health as evidenced by longer TL at 4 and 5 y of age., (© 2016 American Society for Nutrition.)

Telomeres are the protective complexes at the end of chromosomes, required for genomic stability. Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change. Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes. Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs. More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %). Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers. The strongest predictor for child telomere length change was child's baseline telomere length (r = -0.61, p < 0.01). Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01). After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI -0.03 to 0.43; p = 0.08). We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers. While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change.

Importance: Psychological stress contributes to numerous diseases and may do so in part through damage to telomeres, protective non-coding segments on the ends of chromosomes., Objective: We conducted a systematic review and meta-analysis to determine the association between self-reported, perceived psychological stress (PS) and telomere length (TL)., Data Sources: We searched 3 databases (PubMed, PsycInfo, and Scopus), completed manual searches of published and unpublished studies, and contacted all study authors to obtain potentially relevant data., Study Selection: Two independent reviewers assessed studies for original research measuring (but not necessarily reporting the correlation between) PS and TL in human subjects. 23 studies met inclusion criteria; 22 (totaling 8948 subjects) could be meta-analyzed., Data Extraction and Synthesis: We assessed study quality using modified MINORS criteria. Since not all included studies reported PS-TL correlations, we obtained them via direct calculation from author-provided data (7 studies), contact with authors (14 studies), or extraction from the published article (1 study)., Main Outcomes and Measures: We conducted random-effects meta-analysis on our primary outcome, the age-adjusted PS-TL correlation. We investigated potential confounders and moderators (sex, life stress exposure, and PS measure validation) via post hoc subset analyses and meta-regression., Results: Increased PS was associated with a very small decrease in TL (n=8724 total; r=-0.06; 95% CI: -0.10, -0.008; p=0.01; α=0.025), adjusting for age. This relationship was similar between sexes and within studies using validated measures of PS, and marginally (nonsignificantly) stronger among samples recruited for stress exposure (r=-0.13; vs. general samples: b=-0.11; 95% CI: -0.27, 0.01; p=0.05; α=0.013). Publication bias may exist; correcting for its effects attenuated the relationship., Conclusions and Relevance: Our analysis finds a very small, statistically significant relationship between increased PS (as measured over the past month) and decreased TL that may reflect publication bias, although fully parsing the effects of publication bias from other sample-size correlates is challenging, as discussed. The association may be stronger with known major stressors and is similar in magnitude to that noted between obesity and TL. All included studies used single measures of short-term stress; the literature suggests long-term chronic stress may have a larger cumulative effect. Future research should assess for potential confounders and use longitudinal, multidimensional models of stress., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Telomere length (TL) has important consequences for early disease and lifelong health. However, few studies have examined determinants of TL at birth., Study Design: Here we test associations between cord blood TL and parental and birth factors associated with exposure to stress and indicative of healthy intrauterine life in Latino infants. We tested associations that were significant in bivariate analysis in a multivariate regression model to identify independent predictors for shorter TL at birth., Result: Two novel and independent predictors emerged in our analysis of 54 infants. Female gender was associated with longer TL by ~350 base pairs (adjusted β-coefficient for male gender=-369.57, (95% confidence interval, -718.21 to (-)20.92), P=0.02); rho=-0.26, P=0.057). Increased maternal high-school education, as indicated by a high-school diploma or additional education beyond high school, was also associated with longer TL, by ~500 base pairs (adjusted β-coefficient for high-school diploma or greater=505.68 (95% confidence interval, 151.69 to 859.68), P<0.01); rho=0.36, P<0.01). Increasing head circumference trended towards statistical significance in association with longer TL (adjusted β-coefficient = 7.33; 95% confidence interval -0.52 to 15.18; P=0.07). When we removed all infants who had been exposed to high oxidative stress in pregnancy including those exposed to maternal hypertension, preeclampsia, gestational diabetes, and those who were low birth weight or preterm birth (n=7), increasing birth weight percentile was associated with longer TL (adjusted β-coefficient=8.04 (95% confidence interval 0.07 to 16.00), P=0.048)., Conclusion: Shorter TL at birth is associated with being male, low maternal education (less than a high school degree), and a trend towards lower birth weight and head circumference. Given the critical role of long TL in predicting health and disease, these findings contribute to the growing literature attempting to understand determinants of TL.

We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients., Competing Interests: JL is a co-founder and consultant to Telomere Diagnostics. The company has no role in this study. NR has been a consultant for the following companies: Shire Pharmaceuticals and Sunovion Pharmaceuticals. She has received research support from the following companies: Magceutics, ADA (American Diabetes Association) and Corcept Pharmaceuticals. None of these companies have a potential role in this study. The remaining authors declare no conflict of interest.

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.

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.

Exposure to psychological stress and depression are associated with shorter white blood cell telomere length (TL) in adults, possibly via associated lifelong oxidative stressors. Exposure to maternal depression increases risk for future depression and behavior problems in children, and Latino youth are at high risk. Few studies have evaluated the role of exposure to maternal depression or child behavior in relation to TL in children. We assessed early-childhood exposures to maternal depression from birth to the age of 5 years and child behavior from ages 3-5 years in a cohort of Latino children in relation to child leukocyte TL at ages 4 and 5 years. Children who had oppositional defiant behavior at 3, 4 or 5 years had shorter TL than those without by ~450 base pairs (P < 0.01). In multivariate analyses, independent predictors for shorter TL at 4 and 5 years of age included oppositional defiant disorder at 3, 4 or 5 years (β = -359.25, 95% CI -633.84 to 84.66; P = 0.01), exposure to maternal clinical depression at 3 years of age (β = -363.99, 95% CI -651.24 to 764.74; P = 0.01), shorter maternal TL (β = 502.92, 95% CI 189.21-816.63) and younger paternal age at the child's birth (β = 24.63, 95% CI 1.14-48.12). Thus, exposure to maternal clinical depression (versus depressive symptoms) in early childhood was associated with deleterious consequences on child cellular health as indicated by shorter TL at 4 and 5 years of age. Similarly, children with oppositional defiant behavior also had shorter TL, possibly related to early exposures to maternal clinical depression. Our study is the first to link maternal clinical depression and oppositional defiant behavior with shorter TL in the preschool years in a relatively homogenous population of low-income Latino children.

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<0.05). Yet, these effects were moderated by health behaviors (interaction B=0.19, P=0.04). Women who maintained relatively higher levels of health behaviors (1 s.d. above the mean) appeared to be protected when exposed to stress. This finding has implications for understanding malleability of telomere length, as well as expectations for possible intervention effects. This is the first study to identify predictors of telomere length change over the short period of a year.

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.

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 3day 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 3days. 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Leukocyte telomere length has been proposed as a biomarker of cellular aging and atherosclerosis. The aim of this study was to determine whether leukocyte telomere length is independently associated with incident coronary heart disease (CHD) in the general population. Telomere length was measured using a polymerase chain reaction method for participants enrolled in the 1995 Nova Scotia Health Survey (NSHS95; n = 1,917). The primary end point was the first occurrence of a fatal or nonfatal CHD event. During a mean follow-up period of 8.7 years, 164 fatal or nonfatal CHD events occurred. Compared with participants in the longest tertile of telomere length, those in the middle and shortest tertiles had increased incidence of CHD events (6.2, 11.2, and 12.2 per 1,000 person-years, respectively). After adjustment for demographics, traditional risk factors, and inflammatory markers including high-sensitivity C-reactive protein, interleukin-6, and soluble intercellular adhesion molecule-1, those in the middle tertile had significantly elevated risk for incident CHD (hazard ratio 1.63, 95% confidence interval 1.07 to 2.51, p = 0.02) compared with the longest tertile, whereas the risk for those in the shortest tertile was nonsignificantly elevated (hazard ratio 1.25, 95% confidence interval 0.82 to 1.90, p = 0.30). In conclusion, these findings do not support a linear association between leukocyte telomere length and incident CHD risk in the general population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: Telomere length, considered a measure of biological aging, is linked to morbidity and mortality. Psychosocial factors associated with shortened telomeres are also common in chronic pain; yet, little is known about telomere length in pain populations. Leukocyte telomere length was evaluated in 66 women with fibromyalgia and 22 healthy female controls. Participants completed questionnaires and a subgroup of fibromyalgia patients underwent quantitative sensory testing (QST; n = 12) and neuroimaging (n = 12). Telomere length was measured using the quantitative polymerase chain reaction method. Although patients had shorter telomere length than controls, the difference was not statistically significant. However, higher levels of pain within fibromyalgia were associated with shorter telomere length (P = .039). When pain and depression were combined, patients categorized as high-pain/high-depression had an age-adjusted telomere length 265 base pairs shorter than those with low-pain/low-depression (P = .043), a difference consistent with approximately 6 years of chronological aging. In the subset tested, telomere length was also related to pain threshold and pain sensitivity, as well as gray matter volume, such that patients with shorter telomeres were more sensitive to evoked pain and had less gray matter in brain regions associated with pain processing (eg, primary somatosensory cortex). These preliminary data support a relationship between pain and telomere length., Perspective: Our findings support a link between premature cellular aging and chronic pain. These preliminary data imply that chronic pain is a more serious condition than has typically been recognized in terms of bodily aging., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To evaluate whether telomerase activity, measured in circulating blood leukocytes, might be associated with prevalent atherosclerosis, or predict future coronary artery disease risk., Methods and Results: We examined associations of telomerase activity levels measured at year 15 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study with prevalent coronary artery calcium (CAC), progressive CAC at year 20, and incident CAC between years 15 and 20, in 440 black and white men aged 33-45 years. Telomere length was also measured in a subset of participants (N=129). In multivariate-adjusted analysis, higher quartiles of telomerase were cross-sectionally associated with greater odds of prevalent CAC at year 15 (quartile 2: OR=1.32, 95% CI: 0.54-3.23; quartile 3: OR=1.40, 95% CI: 0.60-3.30; quartile 4: OR=3.27, 95% CI: 1.39-7.71 compared with quartile 1, p-continuous=0.012) and progressive CAC at year 20, but telomerase was not significantly associated with incidence of newly detectable CAC. Higher telomerase activity levels predicted greater CAC progression at year 20 among persons with short telomere length; low telomerase and short TL predicted less CAC progression., Conclusion: Telomerase activity in leukocytes was associated with calcified atherosclerotic plaque, and was also a predictor of advancing plaque among persons with short telomeres., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effects of genetic, environmental and lifestyle factors on aging and aging-related diseases. It is timely to 'take stock' of where this work has led the field. This review summarizes studies that have examined associations between lifestyle factors and telomere length and telomerase activity. In most of the studies described in this chapter, telomere length was measured in leukocytes (LTL) or peripheral blood mononuclear cells (PBMCs), taken from blood draws from the study subjects. Much of this chapter focuses on psychological stress, a widespread factor often intimately tied in with lifestyle or behavioral factors that in turn are related to risks of clinical diseases. Together, these findings suggest that cellular aging is linked to a range of influences, with an individual's life events and lifestyle parameters playing significant roles. Lastly, we propose possible biochemical mechanisms that mediate these associations and discuss future directions., (Copyright © 2011. Published by Elsevier B.V.)

Background: Premature shortening of leukocyte telomere length has been proposed as a novel mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies demonstrating associations of depression and depressive symptoms with shorter leukocyte telomere length were small, included selected psychiatric outpatients, were based on convenience samples, and/or adjusted for a limited number of possible confounding factors., Methods and Findings: We examined the associations of depressive symptoms, probable depressive disorder, and specific depressive symptom clusters, as assessed by the Center for Epidemiological Studies--Depression (CES-D) scale, with leukocyte telomere length, measured by using a real-time PCR method, in 2,225 apparently healthy participants from the 1995 Nova Scotia Health Survey population-based study. The mean age was 48.2 ± 18.9 years; 49.9% of participants were female; and the mean CES-D score was 7.4 ± 7.9. The mean telomere length was 5,301 ± 587 base pairs. In an unadjusted model, depressive symptoms were significantly associated with longer leukocyte telomere length (B = 27.6 base pairs per standard deviation increase in CES-D, 95% confidence interval [CI] = 3.1-52.1, p = 0.027). This association was no longer significant after adjustment for age and sex (B = 9.5, 95% CI = -14.6-33.6, p = 0.44) or after further adjustment for body mass index, Framingham risk score and previous history of ischemic heart disease (all p's ≥ 0.37). Neither probable depressive disorder nor specific depressive symptom clusters were independently associated with leukocyte telomere length., Conclusions: Concurrent depressive symptoms were not associated with leukocyte telomere length in a large, representative, population-based study.

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 (eGFR(CKD-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 eGFR(CKD-EPI) was 72.6 (±21.5) ml/min/1.73 m(2), eGFRcys was 71.0 (±23.1) ml/min/1.73 m(2) and ACR was 8.6 (±12.3) mg/g. Only lower baseline eGFR(CKD-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 m(2) lower eGFR(CKD-EPI)). Lower baseline eGFR(CKD-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 m(2) lower eGFR(CKD-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., (Copyright © 2012 S. Karger AG, Basel.)

Background: Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD., Methods: Participants included 43 adults with chronic PTSD (n = 18 with multiple categories of childhood trauma) and 47 control subjects (none with multiple categories of childhood trauma) (mean age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with a quantitative polymerase chain reaction method., Results: As predicted, participants with PTSD had shorter age-adjusted LTL than control subjects. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma seemed to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than control subjects., Conclusions: Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood might be accompanied by equally enduring changes at the molecular level., (Copyright © 2011 Society of Biological Psychiatry. All rights reserved.)

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 hierarchies, biologic responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by real-time polymerase chain reaction, as the telomere-to-single-copy gene ratio. Parents provided demographic information; parents and teachers reported children's internalizing and externalizing behavior problems. Components of children's autonomic (heart rate, respiratory sinus arrhythmia [RSA], and preejection period [PEP]) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relationships between reactivity, internalizing and externalizing behaviors, and BTL, adjusted for age, race, and sex., Results: Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated to BTL. Internalizing behaviors were also inversely related to BTL (standardized β = -0.33, p = .004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP), and parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (n = 12) had significantly shorter BTL (0.80 versus 1.00; χ² = 7.6, p = .006), compared with other children., Conclusions: The combination of autonomic and adrenocortical reactivity was associated with shorter BTL in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biologic aging.

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.

Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized β=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized β=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients., Methods: In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs)., Results: 229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5-7 METS), and 381 had high physical fitness (>7 METS). Mean ± T/S ratio ranged from 0.86±0.21 (5349±3781 base pairs) in those with low physical fitness to 0.95±0.23 (5566±3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p = 0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60-3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18-3.20; p = 0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment., Conclusions: We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study.

Background: Chronic psychological stress is associated with detrimental effects on physical health, and may operate in part through accelerated cell aging, as indexed by shorter telomeres at the ends of chromosomes. However, not all people under stress have distinctly short telomeres, and we examined whether exercise can serve a stress-buffering function. We predicted that chronic stress would be related to short telomere length (TL) in sedentary individuals, whereas in those who exercise, stress would not have measurable effects on telomere shortening., Methodology and Principal Findings: 63 healthy post-menopausal women underwent a fasting morning blood draw for whole blood TL analysis by a quantitative polymerase chain reaction method. Participants completed the Perceived Stress Scale (Cohen et al., 1983), and for three successive days reported daily minutes of vigorous activity. Participants were categorized into two groups-sedentary and active (those getting Centers for Disease Control-recommended daily amount of activity). The likelihood of having short versus long telomeres was calculated as a function of stress and exercise group, covarying age, BMI and education. Logistic regression analyses revealed a significant moderating effect of exercise. As predicted, among non-exercisers a one unit increase in the Perceived Stress Scale was related to a 15-fold increase in the odds of having short telomeres (p<.05), whereas in exercisers, perceived stress appears to be unrelated to TL (B = -.59, SE = .78, p = .45)., Discussion: Vigorous physical activity appears to protect those experiencing high stress by buffering its relationship with TL. We propose pathways through which physical activity acts to buffer stress effects.

Telomeres are the DNA-protein complexes that protect the ends of eukaryotic chromosomes. The cellular enzyme telomerase counteracts telomere shortening by adding telomeric DNA. A growing body of literature links shorter telomere length and lower telomerase activity with various age-related diseases and earlier mortality. Thus, leukocyte telomere length (LTL) and telomerase activity are emerging both as biomarkers and contributing factors for age-related diseases. However, no clinical study has directly examined telomerase activity and telomere length in different lymphocyte subtypes isolated from the same donors, which could offer insight into the summary measure of leukocyte telomere maintenance. We report the first quantitative data in humans examining both levels of telomerase activity and telomere length in four lymphocyte subpopulations from the same donors-CD4+, CD8+CD28+ and CD8+CD28- T cells and B cells, as well as total PBMCs-in a cohort of healthy women. We found that B cells had the highest telomerase activity and longest telomere length; CD4+ T cells had slightly higher telomerase activity than CD8+CD28+ T cells, and similar telomere length. Consistent with earlier reports that CD8+CD28- T cells are replicatively senescent cells, they had the lowest telomerase activity and shortest telomere length. In addition, a higher percentage of CD8+CD28- T cells correlated with shorter total PBMC TL (r=-0.26, p=0.05). Interestingly, telomerase activities of CD4+ and CD8+CD28+ T cells from the same individual were strongly correlated (r=0.55, r<0.001), indicating possible common mechanisms for telomerase activity regulation in these two cell subtypes. These data will facilitate the understanding of leukocyte aging and its relationship to human health., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease., Methodology/principal Findings: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0)., Conclusions/significance: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.

Understanding the malleable determinants of cellular aging is critical to understanding human longevity. Telomeres may provide a pathway for exploring this question. Telomeres are the protective caps at the ends of chromosomes. The length of telomeres offers insight into mitotic cell and possibly organismal longevity. Telomere length has now been linked to chronic stress exposure and depression. This raises the question of mechanism: How might cellular aging be modulated by psychological functioning? We consider two psychological processes or states that are in opposition to one another-threat cognition and mindfulness-and their effects on cellular aging. Psychological stress cognitions, particularly appraisals of threat and ruminative thoughts, can lead to prolonged states of reactivity. In contrast, mindfulness meditation techniques appear to shift cognitive appraisals from threat to challenge, decrease ruminative thought, and reduce stress arousal. Mindfulness may also directly increase positive arousal states. We review data linking telomere length to cognitive stress and stress arousal and present new data linking cognitive appraisal to telomere length. Given the pattern of associations revealed so far, we propose that some forms of meditation may have salutary effects on telomere length by reducing cognitive stress and stress arousal and increasing positive states of mind and hormonal factors that may promote telomere maintenance. Aspects of this model are currently being tested in ongoing trials of mindfulness meditation.

The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.

Background: Leukocyte telomere shortening can serve as a biomarker of aging, as telomere length (TL) can decline with age and shortening is positively associated with morbidity and mortality. It is therefore important to identify psychological and behavioral factors linked to accelerated telomere shortening. Stress and poorer metabolic health (greater adiposity, insulin resistance, and cortisol) correlate with shorter telomeres. Self-reported dietary restraint (DR), defined as chronic preoccupation with weight and attempts at restricting food intake, is linked to greater perceived stress, cortisol, and weight gain, when assessed in community studies (versus in weight loss programs)., Objective: To test for an association between DR and TL in healthy women across a range of ages., Methods: We examined whether DR is linked to TL in two samples, one of premenopausal women (aged 20-50 years;N = 36) and one of postmenopausal women (aged 53-69 years; N = 20)., Results: In both samples, higher levels of DR were associated with shorter leukocyte TL, independent of body mass index, smoking, and age., Conclusions: Chronic DR, as assessed by self-report (i.e. not caloric restriction), may be a risk factor for premature telomere shortening. Potential mechanisms are discussed.