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1.  Associations of childhood adversity and adulthood trauma with C-reactive protein: a cross-sectional population-based study 
Brain, behavior, and immunity  2015;53:105-112.
Mounting evidence highlights specific forms of psychological stress as risk factors for ill health. Particularly strong evidence indicates that childhood adversity and adulthood trauma exposure increase risk for physical and psychiatric disorders, and there is emerging evidence that inflammation may play a key role in these relationships. In a population-based sample from the Health and Retirement Study (n = 11,198, mean age 69 ± 10), we examine whether childhood adversity, adulthood trauma, and the interaction between them are associated with elevated levels of the systemic inflammatory marker high sensitivity C-reactive protein (hsCRP). All models were adjusted for age, gender, race, education, and year of data collection, as well as other possible confounds in follow-up sensitivity analyses. In our sample, 67% of individuals had experienced at least one traumatic event during adulthood, and those with childhood adversity were almost three times as likely to have experienced trauma as an adult. Childhood adversities and adulthood traumas were independently associated with elevated levels of hsCRP (β = 0.03, p = 0.01 and β = 0.05, p < 0.001, respectively). Those who had experienced both types of stress had higher levels of hsCRP than those with adulthood trauma alone, Estimate = −0.06, 95% CI [−0.003, −0.12], p = 0.04, but not compared to those with childhood adversity alone, Estimate = −0.06, 95% CI [0.03, −0.16], p = 0.19. There was no interaction between childhood and adulthood trauma exposure. To our knowledge, this is the first study to examine adulthood trauma exposure and inflammation in a large population-based sample, and the first to explore the interaction of childhood adversity and adulthood trauma with inflammation. Our study demonstrates the prevalence of trauma-related inflammation in the general population and suggests that childhood adversity and adulthood trauma are independently associated with elevated inflammation.
doi:10.1016/j.bbi.2015.11.015
PMCID: PMC5189980  PMID: 26616398
childhood adversity; adulthood trauma; C-reactive protein; immune system; inflammation
3.  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, 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-hour diet recalls and LTL was assessed using quantitative polymerase chain reaction. Adjusting for sociodemographic and health characteristics, decreased SSB consumption from baseline to 9 months postpartum was associated with greater concurrent LTL lengthening (β= −0.102, 95% 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.
doi:10.1038/ejcn.2016.93
PMCID: PMC5014682  PMID: 27302671
4.  Putting the brakes on the "drive to eat": Pilot effects of naltrexone and reward based eating on food cravings among obese women 
Eating behaviors  2015;19:53-56.
Purpose
Obese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food).
Methods
Forty-four obese, pre-menopausal women completed the Reward-based Eating Drive (RED) scale at study start and daily food-craving intensity on 5 days on which they ingested either a pill-placebo (2 days), a 25mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days).
Results
Craving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced this positive association between reward-driven eating and craving intensity to non-significance.
Conclusions
Opioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity.
doi:10.1016/j.eatbeh.2015.06.008
PMCID: PMC4644449  PMID: 26164674
Obesity; craving intensity; reward based eating drive; naltrexone; opioidergic blockade
5.  Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults 
PLoS Medicine  2016;13(11):e1002188.
Background
Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population.
Methods and Findings
We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999–2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749–-0.00206), waist circumference -0.00211 (95% CI -0.00325–-0.000969), percentage of body fat -0.00516 (95% CI -0.00761–-0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571–0.00301), triglycerides -0.000285 (95% CI -0.000555–-0.0000158), pulse rate -0.00194 (95% CI -0.00317–-0.000705), C-reactive protein -0.0363 (95% CI 0.0601–-0.0124), cystatin C -0.0391 (95% CI -0.0772–-0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685–-0.0139), systolic blood pressure 0.0455 (95% CI 0.00137–0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126–-0.00889). These associations were 10%–15% greater without controlling for leukocyte cell types. There were very few differences in the associations by age, race/ethnicity, gender, education, or income. Our findings are relevant to the relationships between these cardiovascular biomarkers in the general population but not to cardiovascular disease as a clinical outcome.
Conclusions
LTL is most strongly associated with adiposity, but is also associated with biomarkers across several physiological systems. LTL may thus be a predictor of cardiovascular disease through its association with multiple risk factors that are physiologically correlated with risk for development of cardiovascular disease. Our results are consistent with LTL being a biomarker of cardiovascular aging through established physiological mechanisms.
David Rehkopf and colleagues analyze the association of leukocyte telomere length with cardiovascular disease risk biomarkers.
Author Summary
Why Was This Study Done?
Leukocyte telomere length (LTL) is a biomarker of white blood cell division and is strongly associated with age.
There are still mixed findings on how LTL is related to different types of mortality.
Observational evidence and quasi-experimental studies suggest that there is an association between shorter LTL and cardiovascular disease mortality.
It is unclear, however, whether or not LTL is completely independent of already known biological pathways of cardiovascular disease.
What Did the Researchers Do and Find?
We examined US nationally representative data on participants ages 25 to 84 that had LTL measured along with 17 other cardiovascular risk biomarkers.
We found associations between LTL and measures of adiposity (BMI, waist circumference, percentage of body fat), along with C-reactive protein, cystatin C, high-density lipoprotein (HDL) cholesterol, triglycerides, insulin resistance, systolic blood pressure, diastolic blood pressure, and pulse rate.
We did not find that there were a meaningful number of differences in these relationships by age, race/ethnicity, or socioeconomic position, suggesting that the associations we find are generally consistent across different population groups.
What Do These Findings Mean?
Our findings suggest that LTL is associated with cardiovascular risk factors across different physiological systems.
The study findings do not have any implications for whether LTL is a cause of cardiovascular disease.
doi:10.1371/journal.pmed.1002188
PMCID: PMC5127504  PMID: 27898678
6.  Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study 
PLoS ONE  2016;11(10):e0160748.
Background
Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated.
Methods
In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality.
Results
During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61–0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23–0.87).
Conclusions
In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality.
doi:10.1371/journal.pone.0160748
PMCID: PMC5081189  PMID: 27783614
7.  Effects of a mindfulness‐based weight loss intervention in adults with obesity: A randomized clinical trial 
Obesity (Silver Spring, Md.)  2016;24(4):794-804.
Objective
To determine whether adding mindfulness‐based eating and stress management practices to a diet‐exercise program improves weight loss and metabolic syndrome components.
Methods
In this study 194 adults with obesity were randomized to a 5.5‐month program with or without mindfulness training and identical diet‐exercise guidelines. Intention‐to‐treat analyses with multiple imputation were used for missing data. The primary outcome was 18‐month weight change.
Results
Estimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, −1.9 kg (95% CI: −4.5, 0.8; P = 0.17), and 18 months, −1.7 kg (95% CI: −4.7, 1.2; P = 0.24), though not statistically significant; (b) changes in fasting glucose at 12 months, −3.1 mg/dl (95% CI: −6.3, 0.1; P = 0.06), and 18 months, −4.1 mg/dl (95% CI: −7.3, −0.9; P = 0.01); and (c) changes in triglyceride/HDL ratio at 12 months, −0.57 (95% CI: −0.95, −0.18; P = 0.004), and 18 months, −0.36 (95% CI: −0.74, 0.03; P = 0.07). Estimates for other metabolic risk factors were not statistically significant, including waist circumference, blood pressure, and C‐reactive protein.
Conclusions
Mindfulness enhancements to a diet‐exercise program did not show substantial weight loss benefit but may promote long‐term improvement in some aspects of metabolic health in obesity that requires further study.
doi:10.1002/oby.21396
PMCID: PMC4898945  PMID: 26955895
8.  From Ideas to Efficacy: The ORBIT Model for Developing Behavioral Treatments for Chronic Diseases 
Objective
Given the critical role of behavior in preventing and treating chronic diseases, it is important to accelerate the development of behavioral treatments that can improve chronic disease prevention and outcomes. Findings from basic behavioral and social science research hold great promise for addressing behaviorally-based clinical health problems, yet there is currently no established pathway for translating fundamental behavioral science discoveries into health-related treatments ready for Phase III efficacy testing. This article provides a systematic framework for guiding efforts to translate basic behavioral science findings into behavioral treatments for preventing and treating chronic illness.
Methods
The ORBIT model for behavioral treatment development is described as involving a flexible and progressive process, pre-specified clinically significant milestones for forward movement, and return to earlier stages for refinement and optimization.
Results
This article presents the background and rationale for the ORBIT model, a summary of key questions for each phase, a selection of study designs and methodologies well-suited to answering these questions, and pre-specified milestones for forward or backward movement across phases.
Conclusions
The ORBIT model provides a progressive, clinically-relevant approach to increasing the number of evidence-based behavioral treatments available to prevent and treat chronic diseases.
doi:10.1037/hea0000161
PMCID: PMC4522392  PMID: 25642841
Health behavior; Behavioral intervention development; Translation of basic behavioral research into behavioral treatments; Behavioral study designs and methods; Prevention and management of chronic disease
9.  PSYCHIATRIC DISORDERS AND LEUKOCYTE TELOMERE LENGTH: UNDERLYING MECHANISMS LINKING MENTAL ILLNESS WITH CELLULAR AGING 
Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell’s mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.
doi:10.1016/j.neubiorev.2015.05.007
PMCID: PMC4501875  PMID: 25999120
aging; telomeres; telomerase; inflammation; oxidative stress; stress; early life adversity; depression; major depressive disorder; bipolar affective disorder; manic-depression; post-traumatic stress disorder; anxiety; schizophrenia; psychosis; disease; mortality; antidepressant; neurotrophic; leukocytes
10.  Acute responses to opioidergic blockade as a biomarker of hedonic eating among obese women enrolled in a mindfulness-based weight loss intervention trial 
Appetite  2015;91:311-320.
There are currently no commonly used or easily accessible ‘biomarkers’ of hedonic eating. Physiologic responses to acute opioidergic blockade, indexed by cortisol changes and nausea, may represent indirect functional measures of opioid-mediated hedonic eating drive and predict weight loss following a mindfulness-based intervention for stress eating. In the current study, we tested whether cortisol and nausea responses induced by oral ingestion of an opioidergic antagonist (naltrexone) correlated with weight and self-report measures of hedonic eating and predicted changes in these measures following a mindfulness-based weight loss intervention. Obese women (N=88; age=46.7±13.2 years; BMI=35.8±3.8) elected to complete an optional sub-study prior to a 5.5-month weight loss intervention with or without mindfulness training. On two separate days, participants ingested naltrexone and placebo pills, collected saliva samples, and reported nausea levels. Supporting previous findings, naltrexone-induced cortisol increases were associated with greater hedonic eating (greater food addiction symptoms and reward-driven eating) and less mindful eating. Among participants with larger cortisol increases (+1 SD above mean), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b=−0.95, SE(b=0.40, 95% CI [−1.74, −0.15], p=.021. Naltrexone-induced nausea was marginally associated with reward-based eating. Among participants who endorsed naltrexone-induced nausea (n=38), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b=−1.00, 95% CI [−1.85, −0.77], p=.024, and trended toward reduced reward-based eating, binge eating, and weight, post-intervention. Single assessments of naltrexone-induced cortisol increases and nausea responses may be useful time- and cost-effective biological markers to identify obese individuals with greater opioid-mediated hedonic eating drive who may benefit from weight loss interventions with adjuvant mindfulness training that targets hedonic eating.
doi:10.1016/j.appet.2015.04.062
PMCID: PMC4485926  PMID: 25931433
Hedonic Eating; Mindfulness Intervention; Naltrexone; Cortisol; Nausea
11.  Tired Telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women 
Brain, behavior, and immunity  2014;47:155-162.
Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean = 35.4, SD = 3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b = −56.8 base pairs per one point increase in PSQI, SE = 20.4, p=0.007) and CD4+ T cells (b = −37.2, SE = 15.9, p = 0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and disease risk in obese individuals.
doi:10.1016/j.bbi.2014.12.011
PMCID: PMC4468027  PMID: 25535858
sleep quality; sleep duration; telomere length; stress; obesity
12.  Leukocyte Telomere Length and Mortality in the National Health and Nutrition Examination Survey, 1999–2002 
Epidemiology (Cambridge, Mass.)  2015;26(4):528-535.
Background
This study examined the association between leukocyte telomere length – a marker of cell aging – and mortality in a nationally representative sample of US adults aged 50–84. We also examined moderating effects of age, sex, race/ethnicity, and education.
Methods
Data were from the National Health and Nutrition Examination Survey (NHANES), 1999–2002 (n=3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions.
Results
870 deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (HR: 1.1, 95% CI: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality.
Conclusions
The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death.
doi:10.1097/EDE.0000000000000299
PMCID: PMC4679150  PMID: 26039272
13.  The impact of group prenatal care on pregnancy and postpartum weight trajectories 
OBJECTIVE
The objective of the study was to investigate whether group prenatal care (Centering Pregnancy Plus [CP+]) has an impact on pregnancy weight gain and postpartum weight loss trajectories and to determine whether prenatal depression and distress might moderate these trajectories.
STUDY DESIGN
This was a secondary analysis of a cluster-randomized trial of CP+ in 14 Community Health Centers and hospitals in New York City. Participants were pregnant women aged 14–21 years (n = 984). Medical record review and 4 structured interviews were conducted: in the second and third trimesters and 6 and 12 months postpartum. Longitudinal mixed modeling was utilized to evaluate the weight change trajectories in the control and intervention groups. Prenatal distress and depression were also assessed to examine their impact on weight change.
RESULTS
There were no significant differences between the intervention and control groups in baseline demographics. Thirty-five percent of the participants were overweight or obese, and more than 50% had excessive weight gain by Institute of Medicine standards. CP+ was associated with improved weight trajectories compared with controls (P < .0001): women at clinical sites randomized to group prenatal care gained less weight during pregnancy and lost more weight postpartum. This effect was sustained among women who were categorized as obese based on prepregnancy body mass index (P < .01). Prenatal depression and distress were significantly associated with higher antepartum weight gain and postpartum weight retention. Women with the highest levels of depression and prenatal distress exhibited the greatest positive impact of group prenatal care on weight trajectories during pregnancy and through 12 months postpartum.
CONCLUSION
Group prenatal care has a significant impact on weight gain trajectories in pregnancy and postpartum. The intervention also appeared to mitigate the effects of depression and prenatal distress on antepartum weight gain and postpartum weight retention. Targeted efforts are needed during and after pregnancy to improve weight gain trajectories and overall health.
doi:10.1016/j.ajog.2015.06.066
PMCID: PMC4910388  PMID: 26164694
excessive gestational weight gain; group prenatal care; postpartum weight loss
14.  Race/Ethnicity, Poverty, Urban Stressors and Telomere Length in a Detroit Community-Based Sample 
Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multi-stage probability sample of three Detroit neighborhoods. We drew venous blood and measured Telomere Length (TL), an indicator of stress-mediated biological aging, linking respondents’ TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial/ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race/ethnicity. They point to health impacts of social identity as contingent, the products of structurally-rooted biopsychosocial processes.
doi:10.1177/0022146515582100
PMCID: PMC4621968  PMID: 25930147
15.  Factors related to telomere length 
doi:10.1016/j.bbi.2015.12.001
PMCID: PMC4869862  PMID: 26851133
16.  Aging: a common driver of chronic diseases and a target for novel interventions 
Cell  2014;159(4):709-713.
Mammalian aging can be delayed with genetic, dietary and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand Geroscience research directed at extending human healthspan.
doi:10.1016/j.cell.2014.10.039
PMCID: PMC4852871  PMID: 25417146
17.  PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression 
Psychiatry research  2015;232(1):58-64.
Accelerated cell aging, indexed in peripheral leukocytes by telomere length and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.
doi:10.1016/j.pscychresns.2015.01.007
PMCID: PMC4404215  PMID: 25773002
Telomeres; Telomerase; Hippocampus; Leukocytes; Brain; Depression
18.  Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes 
Journal of Immunology Research  2016;2016:5371050.
Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28− T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28− cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.
doi:10.1155/2016/5371050
PMCID: PMC4764743  PMID: 26977417
19.  Associations of Cadmium and Lead Exposure With Leukocyte Telomere Length: Findings From National Health and Nutrition Examination Survey, 1999–2002 
American Journal of Epidemiology  2014;181(2):127-136.
Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999–2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with −5.54% (95% CI: −8.70, −2.37) and −4.50% (95% CI: −8.79, −0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.
doi:10.1093/aje/kwu293
PMCID: PMC4351349  PMID: 25504027
chronic disease; environmental exposures; metals; NHANES; telomeres; United States
20.  Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls – Preliminary findings 
Psychiatry research  2014;224(3):168-174.
Several psychiatric disorders, including major depressive disorder (MDD), are associated with increased blood markers of oxidative stress. The relevance of this to the oxidation-sensitive hippocampus (HC) is unknown. We investigated the relationship between peripheral oxidative stress markers and HC volume in unmedicated individuals with MDD (n=16) and healthy controls (n=19). To conserve power, our primary analysis was carried out in the combined group of subjects, and secondary analyses examined each group separately. Oxidative stress markers (oxidized glutathione) and antioxidants (reduced glutathione, glutathione peroxidase, Vitamin C) were assessed, and a “total net antioxidant score” was calculated. 4-T MRI estimated total HC volume and HC subfield (CA1, CA1-CA2 transition zone, subiculum and CA3/dentate gyrus [CA3&DG]) volumes. Across groups, the antioxidant score was significantly and positively correlated with total HC volume and CA3&DG subfield volume (normalized to total intracranial volume), adjusting for age and sex. Similar relationships were observed in each individual group but missed statistical significance, likely due to type II errors, with the exception of a significant correlation between the antioxidant score and CA3&DG volume in the MDD group. These preliminary data are consistent with oxidative stress being associated with smaller total HC and CA3&DG subfield volumes.
doi:10.1016/j.pscychresns.2014.09.002
PMCID: PMC4254356  PMID: 25266915
oxidative stress; glutathione; Vitamin C; hippocampus; subfields; aging
21.  Associations of Weight Stigma With Cortisol and Oxidative Stress Independent of Adiposity 
Objective
Weight discrimination is associated with increased risk of obesity. The mechanism of this relationship is unknown, but being overweight is a highly stigmatized condition and may be a source of chronic stress that contributes to the development and pathophysiology of obesity. The objective of this study was to test whether weight stigma is associated with physiological risk factors linked to stress and obesity, including hypercortisolism and oxidative stress, independent of adiposity.
Method
We examined the frequency of experiencing situations involving weight stigma and consciousness of weight stigma in relation to hypothalamic–pituitary–adrenal axis activity and oxidative stress (F2-isoprostanes) in 45 healthy overweight to obese women.
Results
Independent of abdominal fat, weight stigma was significantly related to measures of cortisol (including salivary measures of cortisol awakening response and serum morning levels) as well as higher levels of oxidative stress. Perceived stress mediated the relationship between weight stigma consciousness and the cortisol awakening response.
Conclusion
These preliminary findings show that weight stigma is associated with greater biochemical stress, independent of level of adiposity. It is possible that weight stigma may contribute to poor health underlying some forms of obesity.
doi:10.1037/hea0000107
PMCID: PMC4677673  PMID: 25068456
social stigma; weight stigma; oxidative stress; cortisol; stress; obesity; cortisol awakening response
22.  Adverse childhood experiences and leukocyte telomere maintenance in depressed and healthy adults 
BACKGROUND
Adverse childhood experiences (ACEs) are associated with poor physical and mental health outcomes in adulthood. Adverse childhood experiences are also associated with shortened leukocyte telomere length (LTL) in adults, suggesting accelerated cell aging. No studies have yet assessed the relationship of ACEs to LTL in individuals with major depressive disorder (MDD), despite the high incidence of antecedent ACEs in individuals with MDD. Further, no studies in any population have assessed the relationship of ACEs to the activity of telomerase, the major enzyme responsible for maintaining LTL, or the relationship between telomerase and LTL in individuals with ACEs.
METHODS
Twenty healthy, unmedicated adults with MDD and 20 healthy age-, sex- and ethnicity-matched controls had ACEs assessed and had blood drawn for LTL and peripheral blood mononuclear cell (PBMC) resting telomerase activity.
RESULTS
In healthy controls, greater ACE exposure was associated with shorter LTL (p< 0.05) but was unassociated with telomerase activity. In MDD, however, the opposite pattern was seen: Greater ACE exposure was unrelated to LTL but was associated with increased telomerase activity (p< 0.05) and with a higher telomerase: LTL ratio (p= 0.022).
LIMITATIONS
Study limitations include the small sample size, a single timepoint assessment of telomerase activity, and the use of retrospective self-report to assess ACEs.
CONCLUSIONS
These results replicate prior findings of shortened LTL in healthy adults with histories of multiple ACEs. However, in MDD, this relationship was substantially altered, raising the possibility that activation of telomerase in ACE-exposed individuals with MDD could represent a compensatory response to endangered telomeres.
doi:10.1016/j.jad.2014.07.035
PMCID: PMC4172492  PMID: 25173430
Depression; Childhood Adversity; Telomere Length; Telomerase Activity
23.  Effect of restorative yoga vs. stretching on diurnal cortisol dynamics and psychosocial outcomes in individuals with the metabolic syndrome: the PRYSMS randomized controlled trial 
Psychoneuroendocrinology  2014;49:260-271.
Purpose
Chronic stimulation and dysregulation of the neuroendocrine system by stress may cause metabolic abnormalities. We estimated how much cortisol and psychosocial outcomes improved with a restorative yoga (relaxation) versus a low impact stretching intervention for individuals with the metabolic syndrome.
Methods
We conducted a 1-year multi-center randomized controlled trial (6-month intervention and 6-month maintenance phase) of restorative yoga vs. stretching. Participants completed surveys to assess depression, social support, positive affect, and stress at baseline, 6 months and 12 months. For each assessment, we collected saliva at four points daily for three days and collected response to dexamethasone on the fourth day for analysis of diurnal cortisol dynamics. We analyzed our data using multivariate regression models, controlling for study site, medications (antidepressants, hormone therapy), body mass index, and baseline cortisol values.
Results
Psychosocial outcome measures were available for 171 study participants at baseline, 140 at 6 months, and 132 at the 1 year. Complete cortisol data were available for 136 of 171 study participants (72 in restorative yoga and 64 in stretching) and were only available at baseline and 6 months. At 6 months, the stretching group had decreased cortisol at waking and bedtime compared to the restorative yoga group, The pattern of changes in stress mirrored this improvement, with the stretching group showing reductions in chronic stress severity and perseverative thoughts about their stress. Perceived stress decreased by 1.5 points (−0.4; 3.3, p=0.11) at 6 months, and by 2.0 points (0.1; 3.9, p=0.04) at 1 year in the stretching compared to restorative yoga groups. Post hoc analyses suggest that in the stretching group only, perceived increases in social support (particularly feelings of belonging), but not changes in stress were related to improved cortisol dynamics.
Conclusions
We found significant decreases in salivary cortisol, chronic stress severity, and stress perception in the stretching group compared to the restorative yoga group. Group support during the interactive stretch classes may have contributed to these changes.
doi:10.1016/j.psyneuen.2014.07.012
PMCID: PMC4174464  PMID: 25127084
Stress; Metabolic Syndrome; Waking Cortisol; Diurnal Cortisol; Dexamethasone; Social Support
24.  The hypothalamic–pituitary–adrenal–leptin axis and metabolic health: a systems approach to resilience, robustness and control 
Interface Focus  2014;4(5):20140020.
Glucocorticoids contribute to obesity and metabolic syndrome; however, the mechanisms are unclear, and prognostic measures are unavailable. A systems level understanding of the hypothalamic–pituitary–adrenal (HPA)–leptin axis may reveal novel insights. Eighteen obese premenopausal women provided blood samples every 10 min over 24 h, which were assayed for cortisol, adrenocorticotropin releasing hormone (ACTH) and leptin. A published personalized HPA systems model was extended to incorporate leptin, yielding three parameters: (i) cortisol inhibitory feedback signalling, (ii) ACTH–adrenal signalling, and (iii) leptin–cortisol antagonism. We investigated associations between these parameters and metabolic risk profiles: fat and lean body mass (LBM; using dual-energy X-ray absorptiometry), and insulin resistance. Decreased cortisol inhibitory feedback signalling was significantly associated with greater fat (kg; p = 0.01) and insulin resistance (p = 0.03) but not LBM. Leptin significantly antagonized cortisol dynamics in eight women, who exhibited significantly lower 24 h mean leptin levels, LBM and higher ACTH–adrenal signalling nocturnally (all p < 0.05), compared with women without antagonism. Traditional neuroendocrine measures did not predict metabolic health, whereas a dynamic systems approach revealed that lower central inhibitory cortisol feedback signalling was significantly associated with greater metabolic risk. While exploratory, leptin–cortisol antagonism may reflect a ‘neuroendocrine starvation’ response.
doi:10.1098/rsfs.2014.0020
PMCID: PMC4142017  PMID: 25285198
psychological stress; obesity; metabolic syndrome; dynamic systems; stress-eating; robustness
25.  It’s Not What You Think, It’s How You Relate to It: Dispositional Mindfulness Moderates the Relationship Between Psychological Distress and the Cortisol Awakening Response 
Psychoneuroendocrinology  2014;48:11-18.
Objective
The cortisol awakening response (CAR) is a natural metabolic response that can be potentiated by negative cognitive-emotional processes, including stress appraisals, negative affect, and rumination. Psychological distress and the CAR are not consistently related, however. Individual differences in aspects of dispositional mindfulness which reflect how people relate to negative thoughts and emotions may help explain such inconsistencies. We tested whether the tendency to 1) label and describe inner experiences and 2) accept negative thoughts and feelings without judgment moderated the association between psychological distress and the CAR.
Methods
Self-reported dispositional mindfulness, perceived stress, anxiety, negative affect, and rumination, and the CAR were assessed among overweight/obese women. Regression analyses were conducted to examine whether dispositional mindfulness moderated the relationship between indicators of psychological distress and the CAR.
Results
While psychological distress was consistently positively related to the CAR, these associations were qualified by significant interactions with both components of dispositional mindfulness. Psychological distress was associated with the CAR at lower levels of dispositional mindfulness but not at higher levels.
Conclusion
These findings support the idea that the tendency to describe and accept distressing experiences may buffer the impact of psychological distress on physiological arousal. These metacognitive processes may be important moderators in unraveling the complex relationship between psychological distress and physiological stress reactivity. Further research is recommended to replicate this approach in other populations.
doi:10.1016/j.psyneuen.2014.05.012
PMCID: PMC4503930  PMID: 24971591
Dispositional Mindfulness; Meditation; Cortisol; Cortisol Awakening Response; Perceived Stress; Negative Affect; Rumination; Acceptance

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