Elissa S. Epel, Ph.D. - US grants

Chronic stress may lead to abdominal fat deposition, a large risk factor for cardiovascular disease, via dysregulation of the hypothalamic- pituitary-adrenal (HPA) axis. This project is designed to assess whether those with a background of life stress have more abdominal fat deposition, and whether their HPA axis responds differently to a repeated laboratory challenge. The results of this study will contribute to our understanding of the effect of chronic stress on physiological functioning and health outcomes.

DESCRIPTION (provided by applicant): The objective of the proposed Mentored Clinical Scientist Development Award (K08) is to promote the candidate's development as an independent behavioral science researcher, with a focus on neuroendocrine responses to stress, and their effects on mental and physical health. During the five-year career development period, the candidate will engage in formal and informal training in psychoneuroendocrinology and stress and coping, complete three research projects, build collaborations, and address basic questions about relationships between stress, hormones, and risk for depression and cardiovascular disease. Chronic psychological stress contributes strongly to depression and cardiovascular disease, but the mechanisms are unclear. Most research in this area has focused on the deleterious effects of catabolic stress hormones like cortisol. Although hypercortisolemia turned out to be a weak biological marker of depression, it may be more revealing when examined in combination with anabolic hormones, such as dehydroepiandrosterone (DHEA) and growth hormone (GH), which can buffer the damaging effects of cortisol. The long-term goal of the current research program is to examine whether anabolic and catabolic hormones, as well as their levels relative to each other (anabolic balance) serve as a mediating pathway from stress to depression and to risk factors for cardiovascular disease (insulin resistance, visceral fat, and atherosclerosis). Studies 1 and 2 will examine whether history of chronic stress predicts low anabolic balance, depression, and risk for disease in longitudinal cohorts of younger adults (N = 1000) and older adults (N = 1000). Study 3 will assess whether chronic stress alone and with major depression is related to basal and reactive measures of anabolic balance and disease risk in caregivers, who serve as a unique model of chronic stress. If warranted, future research will compare effects of stress reduction and hormonal supplementation on mood and disease risk.

DESCRIPTION (provided by applicant): Understanding factors influencing the aging process is central to reducing morbidity, an increasingly important goal in light of our rapidly aging population. Psychological stress is thought to accelerate biological aging. We found support for this hypothesis using the telomere length/telomerase maintenance system as an index of cell aging in vivo. Leukocyte telomere length (TL), the length of the DNA caps at the ends of chromosomes, shortens with age and predicts mortality. Telomerase is the cellular enzyme that lengthens and protects telomeres. Our preliminary data suggest that chronic psychological stress is associated with cell aging (PBMC TL shortening and decreases in telomerase activity) in two samples of caregivers, and further, prospective increases in stress are associated with decreases in TL over just one year. In vitro research has shown that TL is shortened most in specific cytolytic cells (CD8+CD28- T cells), especially from older donors, which is significant in that CD8+CD28- T cells secrete more proinflammatory cytokines and are a hallmark of immunosenescence. Thus, we will examine prospectively whether chronic stress precedes decreases in telomerase and TL in these cells, as well as in peripheral blood mononuclear cells (PBMCs), in older women. We will investigate putative biochemical mediators of this relationship, focusing on stress hormones and insulin resistance. In our pilot study, we also found that acute psychological stress, in contrast to chronic stress, is associated with acute increases in PBMC telomerase activity ("telomerase reactivity"). The magnitude of this increase was greater in caregivers than in controls. These are novel findings requiring replication with a larger sample. They raise the possibility that exaggerated initial telomerase responses to acute stress may signal unsuccessful attempts at telomere maintenance in chronically stressed individuals. To accomplish these aims, we will examine cell aging in a sample of 150 healthy postmenopausal women, aged 50-75, comparing chronically stressed caregivers (n = 75), to low stress controls (n = 75), matched on age, body fat, ethnicity, and education. We will test for stress-related differences in telomerase and TL in PBMCs, CD8 T cells (CD28+ and CD28-), CD4 T cells, and B cells, at baseline and 2 years later (Aim 1). Secondly, we will examine whether telomerase reactivity after acute lab stress predicts changes in TL over 2 years (Aim 2). Lastly, we will test in vitro whether T cells from high stress caregivers have impaired functional immune responses (greater proinflammatory cytokine response to stimulation, impaired cytotoxic function), and if these differences are mediated by lower basal telomerase and shorter telomeres (Aim 3). Together, these aims will provide a clearer picture of stress-induced immune senescence, elucidating the roles of telomeres and telomerase. Since shorter telomeres predict future disease and earlier mortality, understanding the risk factors for accelerated telomere shortening may facilitate interventions aimed at forestalling such outcomes. PUBLIC HEALTH RELEVANCE: Psychological stress increases risk of disease, and this study examines a potential biological pathway to help explain how. Shorter telomere length (the protective caps at the end of chromosomes) in immune cells, a marker of cell aging, predicts disease and early death. This study tests whether chronic stress accelerates immune cell telomere shortening, and the potential intermediate mechanisms, and could lead to biological targets for protective psychological or pharmacological interventions to mitigate the health risks associated with stress.

DESCRIPTION (provided by applicant): This application brings together a strong interdisciplinary team of scientists at the UCSF Center for Obesity Assessment, Study and Treatment (COAST) with researchers at Kaiser-Permanente to test novel interventions based on the physiology by which stress and reward from palatable food influence eating behaviors and abdominal fat deposition. This type of eating is typically non-homeostatic (not meeting caloric deficit). We plan to reduce this type of intake through proof-of-concept and intervention strategies tailored for obese lower income women prior to pregnancy, a critical period for intervention, which may affect gestational weight gain, postpartum weight retention, and offspring weight. Our translational approach draws from the psychology of eating and behavior change, and neuroscience of stress, appetite and reward, to test whether modulating the reward and stress response systems reduces abdominal obesity and weight. In Phase 1 & 2, we will develop and compare two distinct interventions that target diet, activity, and stress but with different conceptual bases: (1): Developmental Skills Training (DST) designed to curb addictions through promoting self-regulation of emotions and eating behavior. (2); Mindfulness and Diet (MIND) aimed to reduce stress and improve awareness of hunger-satiety cues and automatic eating patterns through mindfulness and mindful eating. Preliminary data on each intervention are promising. We will also test an indirect measure of endogenous opioid tone that may provide insight into mechanisms of weight loss. Pilot research has shown that response to a naltrexone opioid probe is linked to indices of non-homeostatic eating and predicts weight loss. We will test the utility of this opioid probe to determine if it changes during treatment and predicts change in eating and abdominal fat. In Phase 2, we will randomize 80 obese women intending to become pregnant to a 3 month proof-of-concept trial of DST and MIND, to compare relative effects on proposed mechanisms (stress, opioid tone), and feasibility. In Phase 3, we will refine and test the efficacy of the most successful intervention then randomize 120 pre-pregnant obese women to the selected intervention or active control condition (diet and exercise alone). These efforts will produce promising intervention strategies for curbing obesity in women during their reproductive years. All phases will be informed by input from a Scientific Advisory panel and Data Safety and Monitoring Board. Accomplishing the aims of this proposal will expand current understanding of the mechanisms that lead to sustained weight reduction, and will inform further study of alternative strategies for obesity intervention. RELEVANCE: The proposed research develops new obesity interventions based on the science of how stress influences the rewarding value of food, and promotes compulsive eating. We will test promising interventions, with women intending to become pregnant that will result in a new prevention programs that are more effective for sustained weight loss maintenance than what is currently available. This program could have a broad public health impact by improving maternal heath and potentially benefiting the next generation. (End of Abstract)

DESCRIPTION (provided by applicant): A large body of evidence links low socioeconomic status (SES) to the development of age- related diseases and to earlier mortality. The biological mechanisms are not well elucidated, although it appears to be in part through chronic exposure to stressful conditions and stress-mediated damage. The maintenance of telomeres (the DNA caps at the ends of chromosomes) may be mechanistically involved in disease processes and premature mortality. Leukocyte telomere length generally shortens with chronological age and with chronic stress, and predicts mortality independent of age. Further, a recent study found shorter telomeres in people with low socioeconomic status (SES). Leukocyte telomere length thus may link social disadvantage to earlier mortality, and is the focus of this study. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 1999- 2002, the proposed study will be the first to examine telomere length in a nationally representative sample, allowing us to expand on past findings linking SES to shorter telomere length, and telomere length to mortality. We will be able to examine these relationships in a racially and ethnically diverse sample, and examine moderating effects of genetic vulnerabilities, as well as mediating effects of health behaviors and mental health. Our interdisciplinary team represents epidemiology, genetics, biostatistics, psychology, and sociology. We will measure telomere length and polymorphisms in three genes (TERT, TERC, PINX1) that regulate telomere length from archived DNA in approximately 7,200 men and women, aged 20 to 85+, who participated in the NHANES 1999-2002 study. We will examine whether SES predicts telomere length and whether this is mediated by health behaviors and mental health. We will also examine gene-environment interactions, specifically whether low SES interacts with polymorphisms in these 3 genes to predict telomere length. Lastly, in the sample over 50 years of age, we will examine whether telomere length predicts mortality 8 years later, and whether telomere length mediates the well-established relationship between SES and mortality. For all analyses, we will examine whether relationships exist across the entire sample and within three racial/ethnic groups (i.e., Mexican-Americans, African-Americans, and non-Hispanic Whites). Relevance: This study will help determine if social disadvantage is linked to telomere shortening; the behavioral and mental health mediators and genetic moderators of the association between SES and telomere length; and if telomere length mediates the relationship between low SES and early mortality. It will thus help determine whether telomere length might become a useful risk factor to monitor and target of intervention. Understanding the aging process is central to preventing premature morbidity and mortality and to lengthening the healthy lifespan. PUBLIC HEALTH RELEVANCE: This study will inform possible interventions and policies to help the nation to achieve the Healthy People 2010 goal of eliminating health disparities, which necessitates understanding the mechanisms by which disparities develop. Findings from the proposed research will shed light on cellular aging as a biological pathway through which social disadvantage may increase vulnerability to premature mortality. Using a nationally representative sample, it will provide data on the role of socioeconomic status within and across racial/ethnic groups and the interaction with genetic vulnerabilities in determining cell aging, and in turn, how cell aging predicts mortality.

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD), a disease affecting up to 16% of the U.S. population at some point in their lives, has been likened to a state of ?accelerated aging,? with an increased risk of acquiring certain diseases of aging and of premature mortality. Evidence consistent with accelerated aging is reported in the brain as well as in the periphery in MDD. The biological mechanisms underlying this process are beginning to be understood, largely by studying immune cells with shortened telomeres, which is now reported in several studies of MDD. Telomeres cap and protect the cell's DNA, and when telomeres become critically short, cells may undergo apoptosis and die. The body protects telomeres by activating a cellular enzyme, telomerase. Telomerase also has important roles in cell survival, neurogenesis and, in animal models, intrinsic antidepressant effects. These latter effects may be mediated via actions in the hippocampus and other brain regions important in MDD. Our preliminary data suggest that telomerase activity (TA) is important in achieving antidepressant response, and that TA is correlated with volume of the hippocampus and anterior cingulate gyrus, both of which are implicated in MDD. A major Aim is to determine whether cell aging in peripheral cells bespeaks a more generalized process of accelerated cell aging in unmedicated individuals with MDD, focusing on the brain. In particular, we will determine whether peripheral aging markers (leukocyte telomere length [LTL] and TA) are significantly correlated with brain structural and biochemical abnormalities in MDD, as detected by neuroimaging (magnetic resonance imaging [MRI] and magnetic spectroscopic imaging [MRS]); the existence of such relationships would tie peripheral cell aging to neural abnormalities in MDD. Our neuroimaging focuses on the corticolimbic network, which is critical in MDD and which showed strong relationships with cell aging markers in our preliminary data. Our other major Aim is to determine whether the relationship between changes in depression ratings and in cell aging markers during antidepressant treatment is mediated by changes in MRS indices (N-acetyl aspartate, a marker of neuronal integrity, and choline-containing metabolites related to glial metabolism and membrane breakdown). To accomplish this, we will recruit 48 un- medicated individuals with MDD and assess LTL and TA, along with depression ratings and MRI and MRS. Depressed individuals will then be treated with an antidepressant for 8 weeks and baseline procedures will be repeated. We will determine the relationship between cell aging markers, MDD symptoms and corticolimbic network disturbances as well as between their changes with treatment. Controls will be assessed at baseline and 8 weeks to assess natural changes in measures over time. Accomplishing these Aims will aid in developing a new mechanistic understanding of the MDD pathophysiology, which would link neural pathology with the increased somatic illness incidence in MDD. It will also point to novel mechanism-based targets for treatment development, and will foster the development of blood-based biomarkers of MDD neural pathology.

DESCRIPTION (provided by applicant): Abstract Research from animal studies to population based studies supports the importance of immune cellular aging, the telomere/telomerase maintenance system, in human health and longevity. Telomeres, the caps protecting the ends of chromosomes, are important predictors of cardiovascular disease and early mortality. Telomerase is the enzyme that lengthens telomeres and promotes cellular and cardiovascular health. Mouse studies have shown that increasing exercise levels are associated with increased telomerase activity. Given the importance of examining experimentally whether human exercise training can slow cellular aging, we propose an ancillary study to the funded grant "Exercise and Inflammation: Autonomic, Affective &Cellular Mechanisms" (P.I. Richard Sloan) by adding measures of telomerase activity. The parent study is a controlled clinical trial of sedentary, unfit yet healthy young men and women, enrolled in 12 weeks of aerobic exercise training compared to a wait list control condition, to test its impact on inflammation and autonomic activity. Subjects are studied before and after 12 weeks of training, and after 4 weeks of sedentary deconditioning. We aim to test whether increasing aerobic exercise, and in turn fitness levels, of sedentary individuals over a 12-week period will increase in vivo telomerase activity compared to telomerase levels from a wait list control group. We will also examine if telomerase decreases after the 4 weeks of deconditioning. To carry this out, we will compare changes in telomerase activity in 154 participants randomized to the aerobic training intervention or the wait list control group, between baseline and post-intervention (12 weeks), and between post-intervention and deconditioning (4 weeks). As a secondary aim, we will also assess whether these changes are mediated through changes in inflammation, oxidative stress, and insulin resistance. Lastly, this funding would allow us to save cells to test exploratory questions about cell aging. Specifically, if telomerase activity changes as expected, we can examine telomere length, and telomere breakages, in these archived samples. These assays would not be supported by the current mechanism, but would be depend on additional private funding. To carry out these aims, this ancillary study adds the labor-intensive cell collections on 154 subjects remaining to be randomized, and assays of telomerase, oxidative stress, and insulin resistance. Inflammatory cytokines will already be measured as part of the parent study. The necessity of collecting and saving viable cells as subjects are enrolled into the ongoing parent study make this study extremely time sensitive and ideal for this ancillary study funding mechanism. This will be the first randomized controlled exercise intervention with the outcome of telomerase in humans. The proposed study could provide a unique window into how aerobic activity affects fundamental aspects of cell function by testing whether cell aging processes are slowed or reversed through increased aerobic fitness. PUBLIC HEALTH RELEVANCE: Immune cell aging is an important pathway to disease, and Animal studies suggest that exercise can retard cell aging. This will be one of the first intervention studies in humans to test effects of exercise on cell aging. It will provide further insight into mechanisms of cell aging, and whether telomerase can be used as a barometric indicator of health that is partly under people's control. (End of Abstract)

DESCRIPTION (provided by applicant): Stress-induced poor sleep: Sex differences, vulnerability & resilience factors Caring for a child with a neurodevelopmental disorder is a source of chronic stress that can impair sleep, but not for all parents. There is little understanding of the exact psychological or biological mechanisms linking stress and sleep behavior, or the vulnerability and resiliency factors that promote or dampen the stress-sleep relationship. One plausible vulnerability factor is being high in stress sensitivity-certain psychological and biological processes that promote vigilance and arousal. The goal of the proposed project is to unpack the sleep-stress cycle, by examining: 1) stress-sensitivity related psychobiological predictors (emotional and cognitive reactivity and regulation and daily cortisol) of daily sleep (delayed onset, short duration, low efficiency, poor subjective quality); and 2) the ensuing effects of sleep on stress sensitivity variables. Individuals do not exist in a vacuum, and, if partnered, supportive or conflict-laden interactions within a partner dyad can dampen or exacerbate psychological and biological stress responses, further impacting sleep patterns. Therefore, our third goal is to examine if spousal/partner interactions compound or mitigate the effects of stress sensitivity on sleep. To this end, we propose to examine stress and sleep in a sample stratified on chronic stress, with 50 high stress couples (parents of children with Autism Spectrum Disorder or ASD) and 50 low stress couples, demographically similar parents of typically developing children (100 pairs total). We will efficiently piggyback the design and measures onto an already-funded R01 study on stress- induced cell aging that is currently following the sample of mothers. In the proposed project we will recruit their partners and add measures of objective sleep actigraphy, subjective sleep quality, daily psychological stress processes, and diurnal measures of cortisol over 10 consecutive days. The aims of the study are: 1) To assess whether daily stress sensitivity predicts poorer night to night sleep parameters within subjects and across the sample and explains the poorer sleep of the parents of children with ASD compared to control parents; 2) To assess whether supportive vs. strained partner interactions moderate the stress sensitivity-sleep relationship; and 3) To determine whether sex differences exist in the stress-sleep relationships in the above aims. Secondarily, using the R01-funded measures of stress-related biological aging, we will be able to test whether poor sleep, averaged across the 10 days of measurement, is associated with marked changes in biomarkers of chronic stress -- lower vagal tone, dysregulation of the HPA axis negative feedback loop, and shorter leukocyte telomere length. The proposed study answers unique and novel questions about the stress- sleep cycle with remarkable cost savings and efficiency by piggybacking onto the large longitudinal R01 study. Identifying the stress-related influences on nightly sleep within the parent dyads, and the resulting impact of sleep on stress markers, will have implications for both basic research and interventions.

DESCRIPTION (provided by applicant): There is now large-scale epidemiological evidence that aspects of chronic psychological stress, such as early adversity or job strain, and early life stress, predict earlier disease onset and mortality. Despite documentation of the importance of stress to health, there are several critical barriers that prevent progress in the epidemiological study of stress as a risk factor for disease. Measurement of stress is inherently complex and multi-level (e.g., social, psychological, physiological). There are few agreed upon 'gold standard' measures of stress, hence measurement is often inconsistent and superficial where heterogeneous constructs are conflated. There is also little understanding of the conditions under which stress exposure can promote vulnerability vs. resiliency to disease. Meanwhile, there have been rapid advances in the basic science of stress processes, which have helped to unpack the cognitive and affective components, links to brain and peripheral physiological responses, and richer measures of daily stress - e.g., through ecological momentary assessments using technology to obtain detailed profiles of exposures and contexts. Thus, epidemiological stress science can benefit from a more coherent multilevel model that encompasses better measurement of lifespan exposures and responses, including the social, psychological, and physiological indices of stress that have the greatest impact on health. The proposed R24 will recruit excellent scientists with relevant methods to apply their interests to th advancement of stress measurement across human development, with a focus on how lifespan stress affects health in mid to late life. Aims include: 1) Development of a stress measurement taxonomy, including guidelines for best measurement; 2) Development of a 'toolbox' of short measures of stress that can be used in epidemiological studies of adult aging internationally. These will be drawn from innovative measurement from basic experimental and field research, refinement/shortening of existing measures, and results from comparative validation of promising measures; and 3) Promotion of stress research in epidemiological studies of aging, both through harmonizing existing measures and adding new toolbox measures. This in turn will lead to discoveries that refine the taxonomy and research methodologies. Improved stress measurement offers tremendous opportunities for advancing the field of basic research, enhancing the efficacy of health-promotion interventions and policy.

DESCRIPTION (provided by applicant): The growing racial disparity in obesity has reached a critical juncture, particularly among black and white females. Obesity is now being perpetuated across generations. While there is uncertainty about how best to prevent obesity and the related racial disparities, converging lines of evidence support the influence of stress on obesity. We hypothesize that income and race are associated with higher levels of both objective and perceived stress, which in turn are associated with higher rates of dysregulated eating, a behavior posited to result in an increased rate of obesity. Finally, we propose that stress has a direct effect on the level of obesity in the offspring. We propose to model these relationships longitudinally using the National Growth and Healthy Study (NGHS) that enrolled equal numbers of black and white girls and that contains extensive measures of life stress, nonhomeostatic eating, household demographic and socioeconomic indicators and cardiometabolic risk factors for black and white girls initially sampled at age 10 and interviewed annually until age 20. We will extend these data, adding a new wave of data collection for the women who are now 36 and their children. We will interview participants regarding their current levels of stress, household food insecurity, dysregulated eating behaviors such as dietary restraint and overeating, and collect data on dietary intake and physical activity. We will collect measured weight and central adiposity and clinical measures of metabolic syndrome on both the women and their children. Building on the rich source of longitudinal data that NGHS provides, we will model relationships between these factors and weight status from early childhood to adulthood among these women and their children in order to examine the effects of cumulative stress, eating behaviors and obesity on obesity in the next generation. The study aims to test the hypotheses that: 1) stress and dysregulated eating results in an increased rate of obesity, exacerbated by food insecurity; 2) maternal stress and dysregulated eating have a direct effect on the level of obesity and markers of metabolic syndrome in offspring; and, 3) race and income are associated with higher levels of stress and dysregulated eating in women. Our preliminary data suggests that stress leads to excessive weight gain ten years later in the NGHS cohort. We will identify predictors of weight gain trajectories from childhood to adulthood. These constructs have the potential to lead to promising interventions coupled with traditional diet and physical activity components that will help girls and women throughout the life course.

ABSTRACT BACKGROUND: Type 2 diabetes mellitus (T2DM) is the most expensive chronic disease in the U.S. Lifestyle modification is central to T2DM management, but long-term adherence to dietary recommendations is difficult. A key challenge is the difficulty of coping with cravings for high carbohydrate or sugar-laden foods in an environment where these foods are tempting and widely available. One mechanism by which mindfulness may increase long-term dietary adherence is by better equipping individuals with skills to experience food cravings and difficult emotions without eating in response. Such approaches seek to strengthen abilities to be non- judgmentally aware of, tolerate, and respond skillfully to food cravings and difficult emotions without reacting impulsively or maladaptively. We hypothesize that improved ability to manage food cravings and emotional eating is a key mechanism through which mindfulness-enhancements can improve dietary adherence. We will test mindfulness-based intervention (MBI) components for improving dietary adherence based on our group?s recent NCCIH-funded trial testing MBI components for obesity, which showed evidence of improved fasting glucose, lipids, and potentially weight. Although the particular diet employed is not the focus of this study, we plan to use a diet with about 10% of calories from carbohydrate as: (1) it induces a low level of ketone production, which we will use as a biomarker for dietary adherence; (2) prior studies suggest it improves metabolic parameters in T2DM, including glycemic control. METHODS: We will use ecological momentary assessment (EMA) methods to measure eating in response to difficult emotions and/or food cravings. In the R61 phase, we will ensure this measure is appropriate for further testing and assess the impact of the MBI components on our hypothesized behavioral mechanisms in N=45 persons with T2DM. We plan 3 waves of 15 persons each with 12 weekly sessions. All participants will attend an in-person group course providing education on basic behavioral strategies for diet and physical activity. Participants will be randomized to receive this education alone (Ed) or this same material with added MBI components (Ed+MBI). We will also pilot test two levels of intensity of maintenance phase intervention (monthly group meetings alone or supplemented by individualized attention) to prepare them for R33 testing. We plan an R33 phase trial in which 120 persons with T2DM will be randomized (using a 1:2 ratio) to Ed or Ed+MBI conditions and followed for 12 months, including a 9-month maintenance phase. We will test the effects of MBI components on our proposed behavioral mechanisms and dietary adherence, and obtain preliminary data on MBI component effects on weight and glycemic control. We will use an innovative adaptive intervention design to optimize maintenance phase intensity, which we believe may be key to augment the MBI effects. SIGNIFICANCE: Our studies promise to extend our understanding of how MBI components can improve dietary adherence and have broader implications for understanding the mechanisms of MBIs for other conditions such as addiction.

DESCRIPTION (provided by applicant): There is now large-scale epidemiological evidence that aspects of chronic psychological stress, such as early adversity or job strain, and early life stress, predict earlier disease onset and mortality. Despite documentation of the importance of stress to health, there are several critical barriers that prevent progress in the epidemiological study of stress as a risk factor for disease. Measurement of stress is inherently complex and multi-level (e.g., social, psychological, physiological). There are few agreed upon 'gold standard' measures of stress, hence measurement is often inconsistent and superficial where heterogeneous constructs are conflated. There is also little understanding of the conditions under which stress exposure can promote vulnerability vs. resiliency to disease. Meanwhile, there have been rapid advances in the basic science of stress processes, which have helped to unpack the cognitive and affective components, links to brain and peripheral physiological responses, and richer measures of daily stress - e.g., through ecological momentary assessments using technology to obtain detailed profiles of exposures and contexts. Thus, epidemiological stress science can benefit from a more coherent multilevel model that encompasses better measurement of lifespan exposures and responses, including the social, psychological, and physiological indices of stress that have the greatest impact on health. The proposed R24 will recruit excellent scientists with relevant methods to apply their interests to th advancement of stress measurement across human development, with a focus on how lifespan stress affects health in mid to late life. Aims include: 1) Development of a stress measurement taxonomy, including guidelines for best measurement; 2) Development of a 'toolbox' of short measures of stress that can be used in epidemiological studies of adult aging internationally. These will be drawn from innovative measurement from basic experimental and field research, refinement/shortening of existing measures, and results from comparative validation of promising measures; and 3) Promotion of stress research in epidemiological studies of aging, both through harmonizing existing measures and adding new toolbox measures. This in turn will lead to discoveries that refine the taxonomy and research methodologies. Improved stress measurement offers tremendous opportunities for advancing the field of basic research, enhancing the efficacy of health-promotion interventions and policy.

DESCRIPTION (provided by applicant): There is now large-scale epidemiological evidence that aspects of chronic psychological stress, such as early adversity or job strain, and early life stress, predict earlier disease onset and mortality. Despite documentation of the importance of stress to health, there are several critical barriers that prevent progress in the epidemiological study of stress as a risk factor for disease. Measurement of stress is inherently complex and multi-level (e.g., social, psychological, physiological). There are few agreed upon 'gold standard' measures of stress, hence measurement is often inconsistent and superficial where heterogeneous constructs are conflated. There is also little understanding of the conditions under which stress exposure can promote vulnerability vs. resiliency to disease. Meanwhile, there have been rapid advances in the basic science of stress processes, which have helped to unpack the cognitive and affective components, links to brain and peripheral physiological responses, and richer measures of daily stress - e.g., through ecological momentary assessments using technology to obtain detailed profiles of exposures and contexts. Thus, epidemiological stress science can benefit from a more coherent multilevel model that encompasses better measurement of lifespan exposures and responses, including the social, psychological, and physiological indices of stress that have the greatest impact on health. The proposed R24 will recruit excellent scientists with relevant methods to apply their interests to th advancement of stress measurement across human development, with a focus on how lifespan stress affects health in mid to late life. Aims include: 1) Development of a stress measurement taxonomy, including guidelines for best measurement; 2) Development of a 'toolbox' of short measures of stress that can be used in epidemiological studies of adult aging internationally. These will be drawn from innovative measurement from basic experimental and field research, refinement/shortening of existing measures, and results from comparative validation of promising measures; and 3) Promotion of stress research in epidemiological studies of aging, both through harmonizing existing measures and adding new toolbox measures. This in turn will lead to discoveries that refine the taxonomy and research methodologies. Improved stress measurement offers tremendous opportunities for advancing the field of basic research, enhancing the efficacy of health-promotion interventions and policy.

SUMMARY / ABSTRACT This post-doctoral training program trains scientists to conduct interdisciplinary research at the intersection of Psychology and Medicine. Although in its 25th year, the program has evolved over time to reflect new discoveries and approaches. In line with the NIMH strategic plan's emphasis on translational and clinical research, we train fellows to conduct translational research on the interactions among biology, behavioral, and experiential factors that exacerbate illness and mental health. Fellows learn to apply psychological theories and cutting-edge research methodologies to address issues in (1) stress, psychopathology, and psychobiology and (2) health-risk behaviors, related to the prevention and amelioration of diseases including depression, PTSD, and schizophrenia. Within these two research foci fellows receive training and research experience in health disparities, developing and testing interventions, biological underpinnings, precision medicine, and technology using digital health monitoring. During the training course, fellows share a didactic core including seminars Works in Progress, Behavior and Affective Science seminar; Responsible Conduct of Research; and statistics modules. They conduct independent research with the supervision of a mentor, submit papers, present at conferences, and complete a grant application within a highly mentored process. The program benefits from its placement in a leading health science campus, with research programs in the biological, social, behavioral, and clinical sciences. Other strengths include: a top-ranked faculty; ample opportunities for cross-fertilization with interdisciplinary fellows; and access to databases and seed funds for pilot studies. The program has produced outstanding, productive young researchers who have gone on to careers in medical or academic centers. We have increased our focus on depression, PTSD, schizophrenia, and other mental illnesses; enhanced training in psychobiological mechanisms that link psychological/social processes and behavior with mental and physical disorders; and deepened our focus on interventions and health disparities. In this renewal we have retained many successful facets from previous applications, but substantially altered key sections to reflect scientific and conceptual advances. Some of the additions include a focus on precision medicine, training and exposure to dimensional RDOC approaches to understanding mental illness, training in methodology focusing on issues of replication, ethics, and transparency, and digital monitoring. Along with this shift in foci we have reorganized the leadership structure (including a multiple PI team) and our training plan to expand our training focus. We have also added biostatisticians, incorporating new methods for multi-level modeling and big data and established formal ties to the Psychiatry residency research track. Finally, we describe our minority recruitment plan, which has been very successful these past few years.  

? DESCRIPTION (provided by applicant): Population health disparities are evident from the earliest stages of the life, persist over the life span, and are perpetuated across generations. Their most salient determinant is exposure to social disadvantage. Research has elucidated how social disadvantage gets biologically embedded to impact disease risk over the life span, but little is known about how its effects are transmitted across generations. Our application addresses this important gap. We propose to investigate the process of intergenerational (mother-to-child) transmission of social disadvantage, with a focus on newborn and infant telomere biology as the primary outcome, the intrauterine period as the transmission time window, and maternal-placental-fetal (MPF) stress biology as the proximate transmission pathway. Telomere dynamics play a fundamental, causal role in the maintenance of genomic and cellular integrity, and telomere dysfunction represents perhaps the most salient antecedent cellular phenotype of disease risk for common, age-related disorders. Animal and human studies converge to support the critical importance of the initial (early life) setting of telomere length (TL) and telomerase activity (TA) for future health and disease risk, but little is currentl known about the determinants of this initial setting. Published and preliminary data by us and others provides biological plausibility for the novel concept that the initial setting of the telomre system is plastic and substantially influenced by developmental conditions. We hypothesize that, at the cellular level, the origins of health disparities may trace back, in part, to the effets of maternal social disadvantage on the on the initial setting of her child's telomere length and telomerase expression capacity, mediated by the programming actions of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology. We propose to test this hypothesis in a prospective, longitudinal cohort study of N=1,000 child-mother dyads with serial measures across gestation and birth through the first year of life. Because race/ethnicity and socioeconomic status (SES) represent the principal proxy measures of social disadvantage, and because racial/ethnic differences in health are most pronounced between Non-Hispanic Blacks (hereinafter `Black') and Non-Hispanic Whites (hereinafter `White'), our proposed study population will include approximately equal numbers of Black and White mothers and their offspring. A unique strength of this population is the substantial variation in SES not only across but also within the two racial/ethnic groups, which will enable us to extricate their independent and combined (interaction) effects. We also will evaluate whether effects vary by the sex of the child. Specific Aims: A1: To test the hypothesis that maternal social disadvantage is prospectively associated with newborn and infant telomere biology. A2: To test the hypothesis that maternal-placental-fetal (MPF) stress biology mediates the effects of social disadvantage on newborn and infant telomere biology. A3: Identify and quantify the maternal psychological, behavioral and biophysical characteristics that are associated with social disadvantage and may account for its impact on newborn and infant telomere biology. The significance and impact of this study derives from the importance of better understanding the determinants and mechanisms underlying age-related disease risk in minority, disadvantaged populations (NIA Reversibility Initiative 2012) to inform translational research on early identification and intervention.

Early Life Adversity, Cumulative Stress, Race, & Cell Aging in Midlife Women & Offspring BACKGROUND: There is an increasingly recognized role of stress in elevating disease risk, especially among women, minorities and socioeconomically disadvantaged groups. Few prospective studies follow individuals from childhood to adulthood, leaving critical unanswered questions such as which types of adversity, and life periods (childhood, adolescence, adulthood, or cumulative) have the greatest impact on biological aging and can help explain racial differences in health. We have a remarkable opportunity to examine types of lifespan stress in a longitudinal cohort of black and white women who have been followed from 10 years old. We have collected multiple sources of stress, including individual stressors (severe life events, chronic stressors, global perceived stress) and environmental stressors (neighborhood deprivation and violence). Our broad aim is to conduct a novel examination of adversity and links to current epigenomic markers (telomere length, epigenetic aging) in women and their children, and to systemic inflammation in the women. In this re- submission, we have identified archived serum samples from the womens? childhood baseline visit and are thus able to examine change in inflammation as well. These indices of biological aging each serve as a reliable predictor of early disease. METHOD: We are conducting a 30 year follow up of the prospective NHLBI Growth and Health Study (NGHS), a biracial cohort of children to examine intergenerational transmission of obesity (R01 HD073568). Black and white girls were initially followed prospectively from 10 to 20 years old and are now being enrolled at roughly 39 years old. Here we propose to assess indices of cellular aging in 590 NGHS women and their most recent (index) child. Retention of sample and adherence to blood and saliva sampling are excellent and an R56 helped us ensure our target sample size. We will assess whether lifespan stress is associated with indices of accelerated cellular aging at age 39, and for inflammation, change from childhood (Aim 1) and secondarily whether types of stress (severe events, chronic stressors, global perceptions, neighborhood deprivation) or time-periods (childhood, adolescence, adulthood) have differential or cumulative effects. We will assess whether pregnancy stress or lifespan stress is associated with offspring epigenomic markers (Aim 2), and whether race modifies these effects (Aim 3). Lastly, we will explore whether high resilience (support and self- esteem) buffers the effects of adversity. SIGNIFICANCE & INNOVATION: This will be the first prospective study to test lifespan stress predictors of three distinct indices of biological aging, each representing different pathways of aging, in a biracial cohort and to assess stress effects on offspring epigenome. This should advance our understanding of lifespan stress on aging biology. A more granular understanding of the types and timing of stress that impact aging processes is necessary for designing policies and programs that reduce socioeconomic disparities in health and aging.

PROJECT SUMMARY Strong epidemiological evidence demonstrates that chronic psychological stress predicts earlier disease onset and mortality. However, there are several critical barriers that have prevented progress in the epidemiological study of stress as a risk factor for disease. Stress measurement is inherently complex and multi-level (social, psychological, physiological), is typically inconsistent and superficial, and does not capture daily stress processes or include non-self- report measures of stress or stress vulnerability. Meanwhile, there have been advances in the basic science of stress processes, which have helped unpack and define the cognitive, affective, and physiological responses to acute and chronic stress, and advances in granular measures of daily stress through ecological momentary assessments. Thus, stress science could be greatly accelerated by grounding in a multilevel model and enhancing measurement using these novel approaches. In our first cycle of the R24 Stress Measurement Network, we addressed these issues through accomplishing three aims (detailed in Past Accomplishments). 1) We published a transdisciplinary multi-level model of stress and aging that incorporates contextual factors, daily level processes, and physiological responses1; 2) We created a Stress Typology to enhance conceptualization and language of stress; and 3) We developed a Measurement Toolbox for consensus-based best validated measures. Lastly, we completed the harmonization of variables for numerous types of stress experiences across ten national epidemiological studies in partnership with the Gateway to Global Aging data harmonization initiative. We can now support researchers interested in questions related to cross-national associations among stress, aging, and health. With this foundational work, we are ideally poised to improve these products and their use in the field and develop a new set of innovative products. The proposed continuation of the network will rely on our UCSF leadership team, continuing and new scientific advisors who are experts in the area of both stress and aging, and early stage investigators who we will support as they increase their knowledge of best practices in stress measurement. Further, we will reach broadly to recruit excellent scientists to help complete the new aims, which requires deep engagement of interdisciplinary fields of population health. Our new aims will test aspects of the multi-level model. These include: 1) Initiate use of newly available harmonized stress data across 10 epidemiological cohort studies to examine cross-national associations; 2) Develop and test new measures of psychological stress, with a focus on non-self-report measures of stress vulnerability based on basic experimental research; Expand the measurement toolbox to include methods for assessing physiological indices of stress, and disseminate best practices in stress measurement; and 3) Using large scale datasets, validate daily and ecological momentary assessments of stress, and test how various psychological or behavioral manipulations alter daily psychological and autonomic stress responses. Improved stress measurement tools offer tremendous opportunities for discovering and advancing the field of basic research, enhancing the efficacy of health promotion interventions, and policies that impact social stress.

Project Summary/Abstract This R13 conference grant will help further the field of behavioral medicine, lead to novel integration with cutting edge research on aging, and support promising early stage investigators in these areas. The transdisciplinary field of behavioral medicine builds on an understanding of behavioral, biomedical, and psychosocial mechanisms to reduce costly chronic diseases such as cancer, diabetes, cardiovascular and psychiatric disease. However, it has not targeted biological aging as an outcome. Research on biology of aging and geroscience examines common mechanisms of disease, but does not emphasize behavioral and social factors. The integration of these fields holds tremendous promise for understanding disease pathways and improving prevention by slowing biological aging processes. It is imperative to better integrate a geroscience focus into behavioral medicine research. The Academy of Behavioral Medicine Research (AMBR) annual meeting provides a highly interactive forum for thought leaders to exchange transdisciplinary ideas often with a high impact on research programs and collaborations. In June 2020, the focus will be on ?Optimal Longevity: Mechanisms, health disparities, and increasing healthspan.? Confirmed keynote speakers include Elizabeth Blackburn (cell aging mechanisms), Eileen Crimmins (socio- and biodemography of aging), Terrie Moffitt (early life, mental health, aging trajectories), Daniel Belsky (social disadvantage and biological indices of aging), and Bonnie Kaplan (nutrition, aging, and mental health). Drawing on the deep expertise of ABMR members, symposium and discussion topics focus on mechanisms of disease and aging such as stress and discrimination, vagal regulation, personality, mindfulness, and self-regulation in understanding trajectories of aging. We will address questions such as how to best measure healthspan, biological aging trajectories, biobehavioral risk factors, and interventions to slow aging and target cancer and other diseases of aging. The program will be overseen by ABMR President Elissa Epel, council members, and the planning committee. Dr. Epel has experience in chairing conferences and a strong commitment to mentoring the next generation of researchers. Our aims are: To introduce behavioral medicine researchers to critical topics in healthy longevity; 2) To support Early Stage Investigators, particularly URM, interested in integrating behavioral medicine and aging research to attend the conference and receive a mentored experience; 3) To implement a mentored experience, strategies for sustaining and strengthening investigator independence and leadership. This includes a leadership workshop, NIH led roundtable, process group, and mentor assignments. We had 21% URM faculty in 2019 and we aim to grow representation in 2020. This R13 will increase the success of future generations of diverse behavioral medicine researchers, as well as help integrate cutting edge issues in healthy longevity into behavioral medicine research programs widely. Dissemination of the conference proceedings will include a special issue in Psychosomatic Medicine.

Advancing Psychosocial & Biobehavioral Approaches to Improving Emotional Well-Being PROJECT SUMMARY/ABSTRACT Given rising levels of global stress, exacerbated by the pandemic, loneliness and mental health problems are on the rise, adding to the burden of chronic diseases. Most health-oriented research takes a harm-reduction approach, identifying and mitigating problems to reduce disease burden. Recent research has demonstrated that a greater focus on emotional well-being may provide another critical strategy for reducing disease burden and lead to significant improvements in population health. To advance the science and provide the strongest evidence base for practice, greater development of research capacity for studying emotional well- being (EWB) is needed. Core elements of emotional well-being (EWB)--hedonic, evaluative, and eudaimonic-- are associated with better healthspan and are hypothesized to play a causal role. Our overall aim is to create a cohesive transdisciplinary network of scientists engaged in mechanistic intervention-relevant research on EWB, with a specific focus on eudaimonia, and pathways by which EWB leads to healthy longevity, including social connection, positive physiology, and healthy behaviors. We bring together three leading institutions in EWB science, uniting UCSF (Epel, Mendes), Lee Kum Sheung Center for Health and Happiness at Harvard (Kubzansky) and UC Berkeley (Keltner, Simon-Thomas) and its interdisciplinary Greater Good Science Center (GGSC), whose digital platforms reach several millions annually (researchers, educators, health professionals). We will catalyze innovation and progress of mechanistic research on EWB by fostering a scientific community focused on measurement and intervention. Our aims include Aim 1) Facilitating analysis of EWB and healthspan across national cohort studies in 30 nations that are part of the Health and Retirement Study Family of Studies by harmonizing existing measures of EWB (e.g., life satisfaction, eudaimonic well-being, positive affect) and supporting causal- inference analyses; Aim 2) Promoting early stage intervention research by developing sensitive EWB measures, and interventions that can increase EWB and drive change in relevant biobehavioral mediators including positive physiology profiles, leveraging existing technology and validated biosensors that measure autonomic nervous system and sleep; and Aim 3) Creating and disseminating valuable research resources for studies of EWB and physical health, including a) making the harmonized EWB data across countries publicly available and providing pilot funding and senior scientist expertise to support investigator time to use the data; b) creating an expert consensus toolbox of EWB measures and methodology; and c) developing a library of empirically-validated EWB interventions (building on UCB's repository). After 4 years, the EWB network will have built strong research capacity and catapulted the field forward with innovative unifying models, consensus measurement and intervention resources, and mechanistic pilot data. Transdisciplinary collaborations will continue to generate key findings well beyond the network's input.