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1.  Good Stress, Bad Stress and Oxidative Stress: Insights from Anticipatory Cortisol Reactivity 
Psychoneuroendocrinology  2013;38(9):1698-1708.
Chronic psychological stress appears to accelerate biological aging, and oxidative damage is an important potential mediator of this process. However, the mechanisms by which psychological stress promotes oxidative damage are poorly understood. This study investigates the theory that cortisol increases in response to an acutely stressful event have the potential to either enhance or undermine psychobiological resilience to oxidative damage, depending on the body's prior exposure to chronic psychological stress. In order to achieve a range of chronic stress exposure, forty-eight post-menopausal women were recruited in a case-control design that matched women caring for spouses with dementia (a chronic stress model) with similarly aged control women whose spouses were healthy. Participants completed a questionnaire assessing perceived stress over the previous month and provided fasting blood. Three markers of oxidative damage were assessed: 8-iso-prostaglandin F2α (IsoP), lipid peroxidation, 8-hydroxyguanosine (8-OxoG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), reflecting oxidative damage to RNA/DNA respectively. Within approximately one week, participants completed a standardized acute laboratory stress task while salivary cortisol responses were measured. The increase from 0 to 30 min was defined as “peak” cortisol reactivity, while the increase from 0 to 15 min was defined as “anticipatory” cortisol reactivity, representing a cortisol response that began while preparing for the stress task. Women under chronic stress had higher 8-oxoG, oxidative damage to RNA (p<.01). A moderated mediation model was tested, in which it was hypothesized that heightened anticipatory cortisol reactivity would mediate the relationship between perceived stress and elevated oxidative stress damage, but only among women under chronic stress. Consistent with this model, bootstrapped path analysis found significant indirect paths from perceived stress to 8-OxoG and IsoP (but not 8-OHdG) via anticipatory cortisol reactivity, showing the expected relations among chronically stressed participants (p≤.01.) Intriguingly, among those with low chronic stress exposure, moderate (compared to low) levels of perceived stress were associated with reduced levels of oxidative damage. Hence, this study supports the emerging model that chronic stress exposure promotes oxidative damage through frequent and sustained activation of the Hypothalamic-Pituitary-Adrenal axis. It also supports the less studied model of ‘eustress’ - that manageable levels of life stress may enhance psychobiological resilience to oxidative damage.
doi:10.1016/j.psyneuen.2013.02.004
PMCID: PMC4028159  PMID: 23490070
Oxidative stress; biological aging; chronic stress; acute stress; DNA/RNA damage; cortisol; hypothalamic-pituitary-adrenal axis; eustress; resilience; reactive oxygen species
2.  Stress and Telomere Biology: A Lifespan Perspective 
Psychoneuroendocrinology  2013;38(9):1835-1842.
In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes ver the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.
doi:10.1016/j.psyneuen.2013.03.010
PMCID: PMC3735679  PMID: 23639252
Telomere length; telomerase; stress; lifespan; prenatal; fetal/developmental programming; childhood stress; mental health; depression; lifestyle
3.  Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder 
Biological psychology  2013;93(1):150-158.
Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.
doi:10.1016/j.biopsycho.2013.01.018
PMCID: PMC3687535  PMID: 23410758
Stress; Depression; Diurnal cortisol slope; Cortisol awakening response; Dexamethasone suppression test; Inflammation; Health; Disease
4.  BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease 
Current Alzheimer research  2012;9(7):815-821.
Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimer’s disease (AD). However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with cognitive tests and patterns of brain atrophy using voxel-based morphometry. We found small negative correlations between BDNF serum concentrations and some of the cognitive tests assessing learning, information processing speed and cognitive control in complex situationshowever, BDNF did not predict disease group membership despite adequate power. These findings suggest that BDNF serum concentration may not be a reliable diagnostic biomarker to distinguish among neurodegenerative diseases.
PMCID: PMC3176995  PMID: 21605064
Alzheimer’s disease; BDNF; frontotemporal dementia; mild cognitive impairment; neurotrophin; VBM
5.  Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length 
Brain, Behavior, and Immunity  2012;26(4):573-579.
Chronic psychological stressis a risk factor formultiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N= 50; M age = 62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic care giving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β = −.32, p = .03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β = −.36, p = .006)and retrospective (β = −.29, p = .03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, care giving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.
doi:10.1016/j.bbi.2012.01.007
PMCID: PMC3322317  PMID: 22293459
cellular aging; challenge; chronic stress; stress appraisals; threat; telomere length
6.  Physical activity moderates stressor-induced rumination on cortisol reactivity 
Psychosomatic medicine  2011;73(7):604-611.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/PSY.0b013e318229e1e0
PMCID: PMC3167008  PMID: 21873586
acute stress; rumination; physical activity; mixed modeling; cortisol reactivity
7.  Serum BDNF Levels Before Treatment Predict SSRI Response in Depression 
OBJECTIVES
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1016/j.pnpbp.2011.06.013
PMCID: PMC3159044  PMID: 21749907
Depression; brain-derived neurotrophic factor (BDNF); neurotrophin; antidepressant; SSRI
8.  Divergent Trajectories of Physical, Cognitive, and Psychosocial Aging in Schizophrenia 
Schizophrenia Bulletin  2011;37(3):451-455.
Aging is not a uniform process. In the general population, there is a paradox of aging: age-associated decline in physical and some cognitive functions stands in contrast to an enhancement of subjective quality of life and psychosocial functioning. This paradox is even more striking in people with schizophrenia. Compared with the overall population, individuals with schizophrenia have accelerated physical aging (with increased and premature medical comorbidity and mortality) but a normal rate of cognitive aging, although with mild cognitive impairment starting from premorbid period and persisting throughout life. Remarkably, psychosocial function improves with age, with diminished psychotic symptoms, reduced psychiatric relapses requiring hospitalization and better self-management. Many older adults with schizophrenia successfully adapt to the illness, with increased use of positive coping techniques, enhanced self-esteem and increased social support. Although complete remission is uncommon, most individuals with schizophrenia experience significant improvement in their quality of well-being. Cohort effect and survivor bias may provide a partial explanation for this phenomenon. However, the improvement also may reflect some brain changes that are beneficial for the course of schizophrenia along with neuroplasticity of aging. The proposed hypothesis has several implications. As significant medical morbidity in schizophrenia takes years to develop, studies of changes in sensitive biomarkers of aging during the course of illness may point to new treatments aimed at normalizing the rate of biological aging in schizophrenia. At the same time, effective psychotherapeutic interventions can affect brain structure and function and produce lasting positive behavioral changes in aging adults with schizophrenia.
doi:10.1093/schbul/sbr026
PMCID: PMC3080682  PMID: 21505111
psychosis; geriatric; quality of life; psychotherapy; neuropsychological; biomarkers
9.  Greater endogenous estrogen exposure is associated with the telomere maintenance in postmenopausal women at risk for cognitive decline 
Brain research  2010;1379:224-231.
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
doi:10.1016/j.brainres.2010.10.033
PMCID: PMC3057451  PMID: 20965155
estrogen exposure; hormone therapy; telomere; telomerase; cardiovascular disease; cognition
10.  Higher fasting glucose levels are associated with reduced circulating angiogenic cell migratory capacity among healthy individuals 
Background
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.
Objectives
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).
Methods
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.
Results
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.
PMCID: PMC3257152  PMID: 22254209
Impaired fasting glucose; metabolism; endothelial progenitor cells (EPCs); circulating angiogenic cells (CACs); chemotaxis; chemokinesis; motility; migration; angiogenesis; cardiovascular; pre-diabetic
11.  Serum Brain Derived Neurotrophic Factor Predicts Responses to Escitalopram in Chronic Posttraumatic Stress Disorder 
Introduction
Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats.
Objectives
This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response.
Methods
Medically healthy male subjects (N=16) with chronic PTSD completed a 12-week open label trial of flexible dose (5–20mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12.
Results
PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r = 0.58, p= 0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial.
Conclusions
PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.
doi:10.1016/j.pnpbp.2010.07.008
PMCID: PMC2939182  PMID: 20643177
BDNF; biomarker; escitalopram; posttraumatic stress disorders; predictor of response
12.  Dynamics of telomerase activity in response to acute psychological stress 
Brain, behavior, and immunity  2009;24(4):531-539.
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.
doi:10.1016/j.bbi.2009.11.018
PMCID: PMC2856774  PMID: 20018236
stress; telomerase activity; cortisol; caregiving; immune cell trafficking
13.  Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings 
PLoS ONE  2011;6(3):e17837.
Background
Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.
Methodology
Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.
Principal Findings
The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).
Conclusions
These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.
doi:10.1371/journal.pone.0017837
PMCID: PMC3063175  PMID: 21448457
14.  Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS) 
DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.
doi:10.1016/j.yfrne.2008.11.002
PMCID: PMC2725024  PMID: 19063914
Dehydroepiandrosterone; DHEA; DHEAS; neuroprotection; neurogenesis; apoptosis; depression; schizophrenia; dementia; cortisol

Results 1-14 (14)