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 impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR = 6.26, 95% CI = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.
Chronically stressed rodents who are allowed to eat calorie-dense “comfort” food develop greater mesenteric fat, which in turn dampens hypothalamic-pituitary-adrenocortical (HPA) axis activity. We tested whether similar relations exist in humans, at least cross-sectionally. Fifty-nine healthy premenopausal women were exposed to a standard laboratory stressor to examine HPA response to acute stress and underwent diurnal saliva sampling for basal cortisol and response to dexamethasone administration. Based on perceived stress scores, women were divided into extreme quartiles of low vs. high stress categories. We found as hypothesized that the high stress group had significantly greater BMI and sagittal diameter, and reported greater eating after stressful events. In response to acute lab stressor, the high stress group showed a blunted cortisol response, lower diurnal cortisol levels, and greater suppression in response to dexamethasone. These cross-sectional findings support the animal model, which suggests that long-term adaptation to chronic stress in the face of dense calories result in greater visceral fat accumulation (via ingestion of calorie-dense food), which in turn modulates HPA axis response, resulting in lower cortisol levels.
abdominal fat; cortisol; stress; stress eating; hypothalamic-pituitary-adrenal axis
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.
Concurrent depressive symptoms were not associated with leukocyte telomere length in a large, representative, population-based study.
Post-traumatic 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.
Participants included 43 adults with chronic PTSD (n=18 with multiple categories of childhood trauma) and 47 controls (none with multiple categories of childhood trauma) (M 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 quantitative polymerase chain reaction.
As predicted, participants with PTSD had shorter age-adjusted LTL than controls. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma appeared 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 controls.
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 may be accompanied by equally enduring changes at the molecular level.
anxiety; biological aging; childhood trauma; post-traumatic stress disorder; telomere length
Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered an emerging marker of biological age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD.
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. Presence of major depressive disorder (MDD) in the past month was assessed using the computerized Diagnostic Interview Schedule (CDIS-IV) 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.
Of the 952 participants, 206 (22%) had major depression at baseline. After adjustment for age and sex, patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean ± SE: 0.86±0.02 vs. 0.90±0.01, P= 0.02). 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 vs. 0.89±0.01, P= 0.06). Depression was not predictive of 5-year change in telomere length after adjustment for the above covariates and baseline telomere length.
Depression is associated with reduced leukocyte telomere length in patients with coronary heart disease 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.
Depression; telomere length; stable CHD
Physically active individuals have lower rates of morbidity and mortality, and recent evidence indicates that physical activity may be particularly beneficial to those experiencing chronic stress. The tendency to ruminate increases and prolongs physiological stress responses, including hypothalamic-pituitary adrenal (HPA) axis responses as indexed by cortisol reactivity to stressful experiences. We examined the association between ruminating in response to a laboratory stressor task and HPA axis reactivity and recovery, and whether a physically active lifestyle moderates the associations between rumination and cortisol output trajectories.
Forty-six post-menopausal women underwent the Trier Social Stress Test while salivary cortisol was repeatedly measured. Twenty-five minutes after the end of the stressor, participants reported level of rumination in response to the stress.
Findings indicate that physical activity moderated the initial rate (B = −.10, SE = .04, p < .05) and curvature (B = −.03, SE = .01, p = .06) of the relationship between rumination and log-transformed cortisol trajectory. Among sedentary participants, those who responded to the stressor with higher levels of rumination had a more rapid initial increase in cortisol (0.26 vs 0.21, p < .001), a later peak (56 vs. 39 minutes), and a delayed recovery (curvature −0.07 vs. −0.08, p < .001) compared to those with lower levels of rumination. In active participants, cortisol trajectories were equivalent, regardless of level of rumination.
In sum, individuals who maintain a physically active lifestyle may be protected against the effects of rumination on HPA axis reactivity to and recovery from acute stress.
acute stress; rumination; physical activity; mixed modeling; cortisol reactivity
To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children.
The study sample comprised 78 five- and six-year-old children from a longitudinal cohort study of kindergarten social hierarchies, biological 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 realtime PCR, as the telomere-to-single copy gene (T/S) ratio. Parents provided demographic information; parents and teachers reported children’s internalizing and externalizing behavior problems. Components of children’s autonomic (heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP)) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relations between reactivity, internalizing and externalizing behavior, and BTL, adjusted for age, race, and gender.
Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated. Internalizing behaviors were also inversely related to BTL (standardized β=−0.33, p=0.004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP) and high 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 vs. 1.00, χ2=7.6, p=0.006), compared with other children.
Autonomic and adrenocortical reactivity in combination were associated with shorter buccal cell telomere length in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biological aging.
autonomic reactivity; adrenocortical reactivity; buccal cell telomeres; internalizing; stress; children
The “neurotrophin hypothesis” of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. . It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response.
Thirty un-medicated depressed subjects were treated with escitalopram (N=16) or sertraline (N=14) for eight weeks. Twenty-five of the depressed subjects completed 8 weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8 weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8 weeks of treatment in the depressed subjects.
Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p= 0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p< 0.001), and BDNF levels increased with treatment (p= 0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p<0.01), and “Responders” to treatment (≥ 50% improvement in depression ratings) had higher pre-treatment BDNF levels than did “Non-responders” (p< 0.05).
These results confirm low serum BDNF levels in unmedicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants.
Depression; brain-derived neurotrophic factor (BDNF); neurotrophin; antidepressant; SSRI
Psychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs).
We enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n = 47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance).
Both groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (p < 0.001). Nonsignificant trends showed that greater attendance was associated with increases in telomerase, and telomerase increases were 18% higher among ‘as treated’ participants compared to controls. Across groups, changes in chronic stress, anxiety, dietary restraint, dietary fat intake, cortisol, and glucose were negatively correlated with changes in telomerase activity. In exploratory analyses, decreases in dietary fat intake partially mediated the association between dietary restraint and telomerase activity with marginal significance.
While there was no clear effect of the intervention on telomerase activity, there was a striking pattern of correlations between improvements in psychological distress, eating behavior, and metabolic health and increases in telomerase activity. These findings suggest that telomerase activity may be in part regulated by levels of both psychological and metabolic stress.
Stress; Anxiety; Mindfulness; Dietary restraint; Telomerase; Cell aging; Cortisol
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 post-menopausal 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.
Cortisol; Allostasis; Allostatic load; Telomere; Cellular aging; Stress; HPA axis
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 χ2=3.7, p=0.04) and with lower telomerase activity (standardized β=−0.09, Wald χ2=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.
Section: Regulatory Systems
estrogen exposure; hormone therapy; telomere; telomerase; cardiovascular disease; cognition
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.
Telomere; Telomerase; Immune cells; Aging; Aging-related diseases
Many factors affect recovery from arthroscopic partial meniscectomy, including patient sex. However, sex differences in time to maximal recovery of knee function and factors influencing differential rates of recovery are unknown.
We determined (1) preoperative sex differences, (2) sex differences in rate and extent of recovery through 1 year postoperatively, and (3) clinical and fitness variables that could explain potential sex differences in recovery from partial meniscectomy.
Patients and Methods
The study sample consisted of 180 patients undergoing arthroscopic partial meniscectomy. Sex, age, body mass index, history of prior injury, length of time between knee injury/impairment and surgical evaluation, weekly exercise frequency, and self-reported fitness were assessed preoperatively, and extent of osteoarthritis was recorded postoperatively. We used the Tegner-Lysholm scale to assess knee function preoperatively and postoperatively at Weeks 1, 3, 8, 16, 24, and 48 followups.
Females had worse knee function and delayed maximal recovery, requiring 1 year, compared with males, who required only 4 months. History of prior knee injury and lower self-reported fitness were associated with slower recovery in females but not in males. Osteoarthritis was associated with slower recovery but not related to sex. Body mass index, length of time between injury/impairment and surgical evaluation, and weekly exercise frequency did not influence rate of recovery.
Females have delayed recovery after arthroscopic partial meniscectomy. Prior knee injury and self-reported low fitness are associated with delayed recovery for females but not for males.
Level of Evidence
Level I, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
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.
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).
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.
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. 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.
Chronic or severe acute elevations in plasma glucose are associated with decreases in the number and function of circulating angiogenic cells (CACs). However, less is known about whether fasting plasma glucose levels (FPG) within the normal or pre-diabetic range among healthy individuals are associated with decreased CAC function. Establishing this relationship is an important step in developing a line of research that may ultimately lead to preventative lifestyle interventions intended to maximize endogenous CAC function and reduce cardiometabolic disease risk.
1) To examine whether increases in FPG are associated with decreases in CAC migration among healthy individuals with FPG levels below the threshold for hyperglycemia, and 2) to contrast effect of FPG on CAC migration toward a pro-angiogenic stimulus (vascular endothelial growth factor; VEGF) with effect on intrinsic cell migratory capacity (i.e., random migration with no stimulus).
28 men and women ranging from 20-57 years of age and free of cardiovascular disease participated in a pilot study, involving a fasting blood draw for FPG and isolation of peripheral blood mononuclear cells. CAC migration toward VEGF and random cell migration (control) were assessed in vitro. VEGF-induced migration that was normalized to control migration, representing the VEGF-response component of chemotaxis independent of motility, was calculated to determine whether any impairment in migration to VEGF was due to lower specific response to VEGF or to lower non-specific migratory capacity.
Increased levels of FPG were associated in a dose-response fashion with a significantly lower random migration under control conditions (CTRL: r= -.408, p=.031), no differences in migration to VEGF (r= -.039, p=.842) and a borderline association with VEGF-induced migration normalized to control migration (VEGF/CTRL: r=.349, p=.069). The relationship between FPG and random migration under control conditions remained significant when controlling for gender and body mass index (p's<.05), and became borderline significant when controlling for age (p=.062). Conclusions: Among healthy individuals, higher fasting glucose levels, despite falling below the diabetic range, are associated with decreased random CAC migration. These findings suggest a need for further studies investigating the effects of lifestyle or dietary interventions on glucose regulation and CAC function.
Impaired fasting glucose; metabolism; endothelial progenitor cells (EPCs); circulating angiogenic cells (CACs); chemotaxis; chemokinesis; motility; migration; angiogenesis; cardiovascular; pre-diabetic
Psychological distress and elevated cortisol secretion promote abdominal fat, a feature of the Metabolic Syndrome. Effects of stress reduction interventions on abdominal fat are unknown. Forty-seven overweight/obese women (mean BMI = 31.2) were randomly assigned to a 4-month intervention or waitlist group to explore effects of a mindfulness program for stress eating. We assessed mindfulness, psychological distress, eating behavior, weight, cortisol awakening response (CAR), and abdominal fat (by dual-energy X-ray absorptiometry) pre- and posttreatment. Treatment participants improved in mindfulness, anxiety, and external-based eating compared to control participants. Groups did not differ on average CAR, weight, or abdominal fat over time. However, obese treatment participants showed significant reductions in CAR and maintained body weight, while obese control participants had stable CAR and gained weight. Improvements in mindfulness, chronic stress, and CAR were associated with reductions in abdominal fat. This proof of concept study suggests that mindfulness training shows promise for improving eating patterns and the CAR, which may reduce abdominal fat over time.
Major life events involving social rejection are strongly associated with onset of depression. To account for this relation, we propose a psychobiological model in which rejection-related stressors elicit a distinct and integrated set of cognitive, emotional, and biological changes that may evoke depression. In this model, social rejection events activate brain regions involved in processing negative affect and rejection-related distress (e.g., anterior insula, dorsal anterior cingulate cortex). They also elicit negative self-referential cognitions (e.g., “I’m undesirable,” “Other people don’t like me”) and related self-conscious emotions (e.g., shame, humiliation). Downstream biological consequences include upregulation of the hypothalamic-pituitary-adrenal axis, sympathetic-adrenal-medullary axis, and inflammatory response. Pro-inflammatory cytokines play an important role in this process because they induce a constellation of depressotypic behaviors called sickness behaviors. Although these changes can be short-lived, sustained inflammation may occur via glucocorticoid resistance, catecholamines, sympathetic innervation of immune organs, and immune cell aging. This response also may be moderated by several factors, including prior life stress, prior depression, and genes implicated in stress reactivity.
Life stress; Social rejection; Depression; Dorsal anterior cingulate cortex; Cortisol; Inflammation; Glucocorticoid resistance; Immune cell aging; Stress sensitization; 5-HTTLPR
We investigated whether, over time, baseline obesity is associated with change in depressive symptoms or if baseline symptoms of depression are associated with change in body mass index (BMI) and waist circumference.
We used latent growth curve modeling to examine data from years 5, 10, 15, and 20 of the Coronary Artery Risk Development in Young Adults study (n = 4643). We assessed depressive symptomatology with the Center for Epidemiological Studies Depression scale.
Respondents who started out with higher levels of depressive symptoms experienced a faster rate of increase in BMI (for Whites only) and waist circumference (for Blacks and Whites) over time than did those who reported fewer symptoms of depression in year 5. Initial BMI and waist circumference did not influence the rate of change in symptoms of depression over time.
Depressive symptomatology likely plays a role in the development of physical health problems, such as cardiovascular disease, through its association with increases in relative weight and abdominal obesity over time.
Leukocyte telomere length (LTL) is an emerging marker of biological age.
Chronic inflammatory activity is commonly proposed as a promoter of
biological aging in general, and of leukocyte telomere shortening in
particular. In addition, senescent cells with critically short telomeres
produce pro-inflammatory factors. However, in spite of the proposed causal
links between inflammatory activity and LTL, there is little clinical
evidence in support of their covariation and interaction.
To address this issue, we examined if individuals with high levels of the
systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis
factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for
short LTL. Our sample included 1,962 high-functioning adults who
participated in the Health, Aging and Body Composition Study (age range:
70–79 years). Logistic regression analyses indicated that individuals
with high levels of either IL-6 or TNF-α had significantly higher odds
for short LTL. Furthermore, individuals with high levels of both IL-6 and
TNF-α had significantly higher odds for short LTL compared with those
who had neither high (OR = 0.52,
CI = 0.37–0.72), only IL-6 high
(OR = 0.57, CI = 0.39–0.83)
or only TNF-α high (OR = 0.67,
CI = 0.46–0.99), adjusting for a wide variety of
established risk factors and potential confounds. In contrast, CRP was not
associated with LTL.
Results suggest that cumulative inflammatory load, as indexed by the
combination of high levels of IL-6 and TNF-α, is associated with
increased odds for short LTL. In contrast, high levels of CRP were not
accompanied by short LTL in this cohort of older adults. These data provide
the first large-scale demonstration of links between inflammatory markers
and LTL in an older population.
Telomerase activity plays an essential role in cel0l survival, by lengthening telomeres and promoting cell growth and longevity. It is now possible to quantify the low levels of telomerase activity in human leukocytes. Low basal telomerase activity has been related to chronic stress in people and to chronic glucocorticoid exposure in vitro. Here we test whether leukocyte telomerase activity changes under acute psychological stress. We exposed 44 elderly women, including 22 high stress dementia caregivers and 22 matched low stress controls, to a brief laboratory psychological stressor, while examining changes in telomerase activity of peripheral blood mononuclear cells (PBMC). At baseline, caregivers had lower telomerase activity levels than controls, but during stress telomerase activity increased similarly in both groups. Across the entire sample, subsequent telomerase activity increased by 18% one hour after the end of the stressor (p<0.01). The increase in telomerase activity was independent of changes in numbers or percentages of monocytes, lymphocytes, and specific T cell types, although we cannot fully rule out some potential contribution from immune cell redistribution in the change in telomerase activity. Telomerase activity increases were associated with greater cortisol increases in response to the stressor. Lastly, psychological response to the tasks (greater threat perception) was also related to greater telomerase activity increases in controls. These findings uncover novel relationships of dynamic telomerase activity with exposure to an acute stressor, and with two classic aspects of the stress response -- perceived psychological stress and neuroendocrine (cortisol) responses to the stressor.
stress; telomerase activity; cortisol; caregiving; immune cell trafficking
Leukocyte telomere shortening can serve as a biomarker of aging, as telomere length 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, weight gain, when assessed in community studies (vs. in weight loss programs).
To test for an association between DR and telomere length in healthy women across a range of ages.
We examined whether DR is linked to telomere length in two samples, one of premenopausal women (aged 20–50; N = 36) and one of postmenopausal women (aged 53–69; N = 20).
In both samples, higher levels of DR were associated with shorter leukocyte telomere length, independent of BMI, smoking, and age.
Chronic DR, as assessed by self-report, may be a risk factor for premature telomere shortening. Potential mechanisms are discussed.
telomere length; dietary restraint; stress; aging; obesity
Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.
Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.
The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).
These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.
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 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.
meditation; mindfulness; stress; appraisal; rumination; telomere length; telomerase
Latino children are at increased risk for mirconutrient deficiencies and problems of overweight and obesity. Exposures in pregnancy and early postpartum may impact future growth trajectories.
To evaluate the relationship between prenatal and postnatal maternal depressive symptoms experienced in pregnancy and infant growth from birth to 2 years of age in a cohort of Latino infants.
We recruited pregnant Latina mothers at two San Francisco hospitals and followed their healthy infants to 24 months of age. At 6, 12 and 24 months of age, infants were weighed and measured. Maternal depressive symptoms were assessed prenatally and at 4-6 weeks postpartum. Women who had high depressive symptoms at both time periods were defined as having chronic depression. Logistic mixed models were applied to compare growth curves and risk for overweight and underweight based on exposure to maternal depression.
We followed 181 infants to 24 months. At 12 and 24 months, respectively, 27.4% and 40.5% were overweight, and 5.6% and 2.2% were underweight. Exposure to chronic maternal depression was associated with underweight (OR = 12.12, 95%CI 1.86-78.78) and with reduced weight gain in the first 2 years of life (Coef = -0.48, 95% CI -0.94—0.01) compared with unexposed infants or infants exposed to episodic depression (depression at one time point). Exposure to chronic depression was also associated with reduced risk for overweight in the first 2 years of life (OR 0.28, 95%CI 0.03-0.92).
Exposure to chronic maternal depression in the pre- and postnatal period was associated with reduced weight gain in the first two years of life and greater risk for failure to thrive, in comparison with unexposed infants or those exposed episodically. The infants of mothers with chronic depression may need additional nutritional monitoring and intervention.