Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter.

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.

Depression, anxiety and telomere length in young adults: evidence from the National Health and Nutrition Examination Survey.

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 (ß: -0.07, P<0.01), but there was no relationship among men (ß: 0.08, P>0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (ß: -0.26, P<0.05), but there was no association between MD and telomere length among those not using antidepressants (ß: -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.

Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study.

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp). MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews. Compared with control subjects (mean bp=5541), sociodemographic-adjusted TL was shorter among remitted MDD patients (mean bp=5459; P=0.014) and current MDD patients (mean bp=5461; P=0.012). Adjustment for health and lifestyle variables did not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity (P<0.01) and longer symptom duration in the past 4 years (P=0.01) were associated with shorter TL. Our results demonstrate that depressed patients show accelerated cellular aging according to a 'dose-response' gradient: those with the most severe and chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD had shorter TL than controls.

Dispositional Mindfulness in People with HIV: Associations with Psychological and Physical Health.

We used a Stress and Coping model to examine the association of dispositional mindfulness, defined as the tendency to intentionally bring nonjudgmental attention and awareness to one's experience in the present moment, with psychological and physical health in adults with HIV. Data were collected at baseline of a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR). Four facets of mindfulness (acting with attention/awareness, nonjudging of inner experience, observing, and describing) were examined as correlates of appraisal, positive and negative affect, coping, and indicators of psychological well-being and physical health. We found that mindfulness was inversely related to depression, stress appraisal, and negative affect, and positively related to positive affect. Mindfulness was also inversely related to escape/avoidance and self-blame forms of coping. Mediational analyses indicate that perceived stress and negative affect were the most consistent mediators of the association of mindfulness and psychological well-being. The findings from this paper contribute to a growing understanding of the potential adaptive role of mindfulness in people living with the stress of serious illness.

Dysregulated relationship of inflammation and oxidative stress in major depression.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity.

BACKGROUND: This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms. METHODS: Thirty-nine family dementia caregivers (mean age 60.3 years old (SD = 10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 min per day for 8 weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre-intervention and post-intervention. RESULTS: The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared with the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale compared with 31.2% and 19%, respectively, in the relaxation group (p < 0.05). The meditation group showed 43% improvement in telomerase activity compared with 3.7% in the relaxation group (p = 0.05). CONCLUSION: This pilot study found that brief daily meditation practices by family dementia caregivers can lead to improved mental and cognitive functioning and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample.

Effects of Aerobic Exercise Training on Daily Psychological Processes in Family Caregivers: Secondary Analyses of a Randomized Controlled Trial.

The aim of this study was to examine the effects of a 24-week aerobic exercise training program on daily psychological processes and occurrence of stressors in a group of previously physically underactive family caregivers of patients with dementia. As part of the Fitness, Aging, and STress (FAST) randomized controlled trial, 68 participants (F = 55; M = 13) were randomized to either a staff-supported, 24-week aerobic training (N = 34) program or waitlist control (N = 34) group. Approximately 2 weeks prior to randomization, ecological momentary assessments were completed 6 times per day for 7 days and again in the 24th week of the trial to assess exposure to levels of momentary positive affect, negative affect, rumination, control, and the occurrence of stressors throughout the day. These secondary analyses with data from 56 of the participants revealed that the intervention group showed a significantly larger increase in daily positive affect and perceptions of control compared to control participants over the course of the intervention. A treatment effect was also found for negative affect and rumination, whereby both decreased to a greater extent in the intervention group when compared with participants in the control condition. The 24-week aerobic training program had significant impacts on daily psychological processes in family caregivers, deepening our understanding of the robust effects of exercise on mental health.

Association between socioeconomic markers and adult telomere length differs according to sex: Pro-Saúde study.

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 (ß=-0.05, 95% confidence interval (CI)=95%CI: -0.10, 0.00, P=0.03). In women, LTL was inversely associated with unmarried status (ß=-0.05, 95%CI: -0.09, 0.00, P=0.03), lower father's educational attainment (ß=-0.05, 95%CI: -0.13, 0.00, P=0.04), and childhood experience of food deprivation (ß=-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.

Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women.

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.

Sugary beverage and food consumption, and leukocyte telomere length maintenance in pregnant women.

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 (ß=-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.

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Meditation and vacation effects have an impact on disease-associated molecular phenotypes.

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 (Aß) 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 Aß42/Aß40 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.

Longevity factor klotho and chronic psychological stress.

Chronic psychological stress is associated with accelerated aging and premature morbidity and mortality; however, the biology linking chronic psychological stress and its maladaptive effects remains largely unknown. Klotho is a pleiotropic hormone that regulates the aging process and promotes better brain and body health. Whether klotho is linked to psychosocial stress or its negative impact in humans has not been investigated. To address this gap, we recruited 178 healthy women who were either chronically high-stress maternal caregivers for a child with autism spectrum disorder (n = 90) or low-stress control mothers of a typically developing child (n = 88). We found that women under high chronic stress displayed significantly lower levels of the longevity hormone klotho compared with low-stress controls (t(176) = 2.92, P = 0.004; d = 0.44), and the decrease among those under high stress was age-dependent. In addition, high-stress caregivers who reported more depressive symptoms displayed even lower klotho levels compared with low-stress participants. These findings provide the first evidence that klotho levels are sensitive to psychosocial stressors and raise the possibility that klotho may serve as a novel biological link connecting stress, depression and risk for accelerated disease development. Furthermore, these findings have important implications for understanding the plasticity of the aging process and may represent a therapeutic target for mitigating the deleterious effects of chronic psychological stress on health and well-being.

Association between socioeconomic markers and adult telomere length differs according to sex: Pro-Saúde study

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.

Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.

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.

Relationship of subjective and objective social status with psychological and physiological functioning: preliminary data in healthy white women.

This preliminary study compared the associations between objective and subjective socioeconomic status (SES) with psychological and physical variables among 157 healthy White women, 59 of whom subsequently participated in a laboratory stress study. Compared with objective indicators, subjective social status was more consistently and strongly related to psychological functioning and health-related factors (self-rated health, heart rate, sleep latency, body fat distribution, and cortisol habituation to repeated stress). Most associations remained significant even after controlling for objective social status and negative affectivity. Results suggest that, in this sample with a moderately restricted range on SES and health, psychological perceptions of social status may be contributing to the SES-health gradient.

Stress hormone-related psychopathology: pathophysiological and treatment implications.

Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology.

Body shape ideals across gender, sexual orientation, socioeconomic status, race, and age in personal advertisements.

OBJECTIVE: To assess body shape ideals across gender, sexual orientation, race, socio-economic status, and age, METHOD: An analysis of personal advertisements was conducted across seven different publications which targeted the groups of interest. RESULTS: Women advertised body weight much less often than men, and lesbians reported body shape descriptors significantly less often than heterosexual women. Gay men and African-American men described their body shape significantly more often than did other groups. However, their reported body mass indices (BMI) were significantly different-African-American men reported a higher BMI, and gay men a lower BMI, than Euro-American heterosexual men. DISCUSSION: Race and sexual orientation may influence the importance of size of body shape ideals for men. For women, however, their advertised weights conformed to the thin ideal across all groups surveyed. Gender roles affecting body shape ideals and mate attraction are discussed.

Stress and body shape: stress-induced cortisol secretion is consistently greater among women with central fat.

OBJECTIVE: Excessive central fat puts one at greater risk of disease. In animal studies, stress-induced cortisol secretion has been shown to increase central fat. The objective of this study was to assess whether women with central fat distribution (as indicated by a high waist-to-hip ratio [WHR]), across a range of body mass indexes, display consistently heightened cortisol reactivity to repeated laboratory stressors. METHODS: Fifty-nine healthy premenopausal women, 30 with a high WHR and 29 with a low WHR, were exposed to consecutive laboratory sessions over 4 days (three stress sessions and one rest session). During these sessions, cortisol and psychological responses were assessed. RESULTS: Women with a high WHR evaluated the laboratory challenges as more threatening, performed more poorly on them, and reported more chronic stress. These women secreted significantly more cortisol during the first stress session than women with a low WHR. Furthermore, lean women with a high WHR lacked habituation to stress in that they continued to secrete significantly more cortisol in response to now familiar challenges (days 2 and 3) than lean women with a low WHR. CONCLUSIONS: Central fat distribution is related to greater psychological vulnerability to stress and cortisol reactivity. This may be especially true among lean women, who did not habituate to repeated stress. The current cross-sectional findings support the hypothesis that stress-induced cortisol secretion may contribute to central fat and demonstrate a link between psychological stress and risk for disease.