Social Relations and Health
SOCIAL REGULATION OF PRO-INFLAMMATORY MONOCYTES
PI: Steve Cole, PhD
The proposed research seeks to determine how adverse social environments influence the risk of inflammation-related disease by up-regulating the expression of pro-inflammatory genes. These studies test the hypothesis that adverse social environments stimulate the hematopoietic production of immature pro-inflammatory monocytes (CD16- in humans, Ly-6c-high in mice) via threat-induced activation of beta-adrenergic receptors in bone marrow myelopoietic cells. Specific aims will: (Aim 1) Define the neural and endocrine pathways by which chronic threat up-regulates pro-inflammatory monocytes; (Aim 2) Define the specific beta-adrenergic receptors and target cell types mediating threat-induced expansion of pro- inflammatory monocytes; and (Aim 3) Define the myelopoietic molecules mediating beta-adrenergic expansion of pro-inflammatory monocytes (including GM-CSF, TGF-beta, and the CXCL12/CXCR4 chemokine signaling axis). When complete, these studies will provide an integrated mechanistic model of the neural / hematopoietic pathway by which chronic adversity can up-regulate inflammatory gene expression in circulating immune cells. The overarching goal of these studies is to develop a comprehensive theory that explains how common social risk factors can influence multiple inflammation-related diseases. In addition to clarifying the basic physiologic mechanisms involved in "defensive programming" of the immune system transcriptome, these studies will identify specific CNS mechanisms (e.g., Crf gene activation in central nucleus of the amygdala), pharmacologic intervention strategies (e.g., beta-2 and beta-3 adrenergic antagonists, and antagonists of GM-CSF, TGF-beta, and/or CXCR4), and mechanistic biomarkers (e.g., myelopoietic molecules and circulating monocyte phenotypes) that can be applied in future studies to clarify how stress-induced up- regulation of pro-inflammatory monocytes impacts specific inflammation-related diseases such as atherosclerosis, Type II diabetes, Alzheimer's disease, and cancer.
CHILDHOOD ORIGINS OF CHD DISPARITIES: NEURAL & IMMUNE PATHWAYS
PI: Greg Miller / Steve Cole, PhD, UCLA Co-I
In recent decades there has been a marked decline in morbidity and mortality from coronary heart disease (CHD) in the US. But the strength of this trend varies across demographic groups. Those of low socioeconomic status (SES) continue to develop, and die from, CHD at rates more typical of the 1970's. Most research on the origins of these disparities focuses on middle stages of the lifespan, when CHD manifests clinically. While this research has been fruitful, shifting the focus towards earlier life stages could yield valuabl insights. Many pathogenic mechanisms that give rise to CHD begin in childhood, and by adolescence increasing numbers of American youth display risk factors for and preclinical signs of CHD, which themselves pattern by SES. Despite these findings, relatively little attention has been directed towards early CHD disparities. We know little about why they emerge and how they unfold developmentally. To address these questions, we propose a prospective, multilevel study of 250 youth from economically diverse backgrounds. Subjects will be enrolled during eighth grade and reassessed in tenth grade. Drawing on hypotheses from a recently developed conceptual framework, the study poses three questions about SES disparities in immunologic, neural, and psychosocial development, and the implications for early CHD risk. First, we ask whether SES relates to maturation patterns in the immune system, with a focus on inflammatory processes that underlie CHD. We expect low-SES youth to display a multilayer inflammatory phenotype, which manifests at the genomic, cellular, and systemic levels of analyses. Second, we ask whether SES relates to maturation patterns in the brain's corticolimbic and corticostriatal circuitries, and thereby give rise to behavioral proclivities that heighten CHD risk. Using high-dimensional structural imaging and diffusion tensor imaging, we expect low SES to be associated with disparities in grey- and white-matter development in these circuitries. These disparities should, in turn, presage CHD-relevant behavioral proclivities, including threat vigilance, social turmoil, poor self-regulation, and unhealthy lifestyles. Finally, noting that som low-SES youth have positive health outcomes, we explore characteristics and experiences that "bend" the normative demographic curve. We expect that lower-SES youth who encounter positive social influences - specifically role models and high maternal warmth - will develop a suite of personal resources - trust, emotion regulation skills, and self-esteem - that help them navigate the challenges of high school and low-SES life more broadly. Those resources will shift low-SES youth off their expected risk trajectory, resulting in immune and neural patterns similar to higher-SES youth.
MULTI-LEVEL UNDERSTANDING OF SOCIAL CONTRIBUTORS TO SESDISPARITIES IN ASTHMA
PI: Edith Chen / Steve Cole, PhD, UCLA Co-I
Disparities in health outcomes by socioeconomic status (SES) are one of the most pressing public health problems our society faces today. in line with PAR-10-136's interest in Multi-Level approaches to Understanding health Disparities, we focus on childhood Asthma and investigate factors simultaneously across neighborhood, family, and Individual levels; we consider both physical environment and Social environment exposures together; and we examine various levels of biological processes (organ systems, cellular, genomic) that drive Asthma pathophysiology, all within a single project that seeks to develop a more comprehensive Understanding of the causes of Asthma Disparities. The first aim is to understand how neighborhood, family, and individual-level Social factors both shape and are shaped by one another, and how they collectively affect Asthma Disparities. The second aim is to measure Social and physical exposures concurrently in order toexplain how they interact to affect Asthma Disparities. The third aim is to create biologically plausible models for how Social contexts contribute to health Disparities by characterizing pathways at multiple levels biologicall (organ systems, cellular, genomic) that can explain how Social contexts come to affect Asthma Disparities. This study will recruit a sample of 300 families from varying SES backgrounds who have a child ages 10-18 with persistent Asthma. Families will participate in laboratory assessmentsof individual- and family-level Social processes as well as child biological measures. Information on neighborhood characteristics will be linked from geographic information system maps of pollution exposures and maps of the Social characteristics of communities created by a research consortium locally. in order to establish the temporal precedence of each of the 'levels' of factors, Clinical outcomes will be tracked across a 1 year follow up period via monthly monitoring of Symptoms as well as from hospitalization data obtained from provincial health records. Creating models that explain how neighborhood, family, and Individual factors simultaneously contribute toAsthma Disparities is critical for developing a more holistic picture of how Social contexts affect disease progression. These models will in turn shape our approaches tointerventions. For example, interventions to improve medication adherence may not be effective if they do not acknowledge the broader Social factors (e.g., neighborhood and family stress) that affect families' abilities to keep up with medication regimens. Assessing interactive effects between factors will also allow us to identify specific conditions under which potential targets of Intervention would make the biggest differences in mitigating the pathophysiological processes underlying Asthma. The overall goal of this project is to develop a more sophisticated Understanding of why Asthma Disparities by SES exist and to identify the constellation of factors that would need to be targeted simultaneously in order to effectively alleviate these Disparities.
FEELING NEEDED: EFFECTS OF GENERATIVITY ON HEALTH IN LONELY OLDER ADULTS
PI: Naomi Eisenberger, PhD
The proportion of the world's population over age 60 is increasing at an unprecedented rate. Given this trend, it is imperative to study the mental and physical health of older adults. Psychosocial factors, such as loneliness, are critical in understanding the overall health of older adults, given that increased feelings of loneliness have been linked to functional decline and increased risk of mortality in older adults. Loneliness in older adults may be partially driven by disruptions in meaningful social engagement. In fact, generativity defined as concern and activity dedicated to the well-being of others, especially younger generations and its related components, such as feeling socially useful or needed, are often included in models of successful aging. Furthermore, greater perceptions of generativity have been linked to better health outcomes and longevity in older adults. Thus, lonely older adults may especially benefit from a targeted psychological intervention aimed at increasing perceptions of generativity, which may improve feelings of social connection through increased feelings of social usefulness, as well as improve health outcomes. The objective of this NIA R03 application is to investigate the relationships between social psychological processes and pro-inflammatory responses in the context of health and aging. To do so, the proposed study will investigate the effect of an intervention aimed at increasing perceptions of generativity in lonely older adults on physical and mental health outcomes. Given that pro-inflammatory activity has been linked to both loneliness and poor health outcomes, the study will also examine the effect of the intervention on biological markers of inflammation (i.e., circulating and stimulated pro-inflammatory cytokines and pro-inflammatory gene expression). Participants (n=70) will be randomly assigned to a 6-week intervention aimed at increasing perceptions of generativity or a control condition. During pre- and post-intervention sessions, all participants will complete self-report measures of physical and mental health and have blood drawn (in order to assess biological markers of inflammation). It is hypothesized that participants in the generativity intervention, compared to those in the control condition, will show: 1) improved physical and mental health outcomes and 2) decreased pro-inflammatory activity from pre- to post-intervention. Furthermore, it is hypothesized that decreases in biological pro-inflammatory activity will mediate improvements in health outcomes. The present study will help advance the understanding of the impact of generativity on the lives of older adults, including its effects on health and inflammatory activity. This may inform a low-cost and low-effort way to improve health outcomes in older adults, especially those who may be most vulnerable to poor health outcomes, such as those who are lonely.
USC/UCLA CENTER ON BIODEMOGRAPHY AND POPULATION HEALTH
PI: Eileen Crimmins, PhD, USC PI; Steve Cole, PhD, UCLA Co-I
USC/UCLA Center on Biodemography and Population Health (CBPH) Direct Core D / UCLA Social Genomics Core Laboratory is part of a broader effort to understand biological pathways through which socio-demographic factors affect health risks across the life-course. The Center provides support for research in and the development of the field of Biodemography to clarify how biology mediates between social and economic factors to affect physical and mental health of the population. The integration of biological, epidemiologic and medical risk information into demographic models is fundamental to understanding and projecting demographic trends and population sub group differences in health in order to inform policy. In this application, we request continued funding for the USC/UCLA CBPH in order to: 1) support the development of cutting-edge biodemographic research among CBPH affiliates through support of pilot projects and research infrastructure; 2) to support development of approaches to biodemographic data collection and valdation for demographic research through the use of pilot projects and research infrastructure 3) to further develop an active biodemographic research community both within our two universities and more broadly in the field of popualtion studies; 4) to implement a new External Research Support and Dissemination Core to support development and validation of new research methodologies, including genetic factors, for use in biodemographic research and population surveys more generally; 5) to disseminate broadly information on biodemographic methods. The research supported by the CBPH and the developmnet of infrastructure for measurement and integration of genetic factors will continue to improve our understanding of how individual biological risk factors, combinations of biological risk factors, and interactions of risk factors affect the total length of life, the length of life with health problems, and the population prevalence of specific chronic conditions and disabilities.
SOCIAL REGULATION OF GENE EXPRESSION
PI: John T. Cacioppo, PhD / Steve Cole, PhD, UCLA PI
Research has repeatedly shown that a lack of social ties increases risk for poor health. Recent research has demonstrated that poor mental and physical health outcomes are distally associated with social isolation, are more proximally associated with perceived social isolation, and are not explicable in terms of differences in health behaviors. Recent studies have identified alterations in hypothalamic-pituitary-adrenal (HPA) axis regulation of inflammatory biology in leukocytes as a potential mechanism of isolation-related health risks. Individuals reporting chronically high levels of subjective social isolation have shown a heightened rise in morning cortisol levels (Adams et al. 2006), and alterations in genome-wide transcription of glucocorticoid target genes andNF-:B target genes (Cole et al. 2007). These isolation-related alterations in leukocyte biology might stem from a functional desensitization of the glucocorticoid receptor (GR) in isolated people (Cole 2008), which in turn, is reciprocally related toNF-:B expression, a key factor in regulation of cellular responses to infection, cancer, and inflammation. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of perceived social isolation. Initial genomics analyses tested a relatively small sample and provided preliminary support for this hypothesis. This revised application seeks to extend those initial findings by (1) expanding the range of genomic analyses, (2) identifying the specific aspect of glucocorticoid-mediated transcriptional control driving those effects, (3) determining the plausibility of a causal role for subjective social isolation in predicting transcriptional control in longitudinal studies, and (4) establishing an animal model of subjective social isolation that can provide a platform for experimental studies. Utilizing participants from the Chicago Health, Aging and social Relations longitudinal study, a population-based sample of middle-aged and older adults, we investigate whether transcriptional alterations occur only in those who show chronically high levels of subjective isolation, or whether similar effects occur even at minimal or variable levels of subjective isolation. Differential expression of GR and/orNF-:B proteins, and/or post-translational modifications of the GR (e.g., GR phosphorylation) will be examined as potential molecular mechanisms of altered glucocorticoid transcriptional control. The plausibility of a causal role for social isolation will be evaluated by examining the extent to which naturally occurring changes in subjective isolation over a two-year period predict changes in transcriptional control. Finally, a non-human primate model will be evaluated by conducting social behavioral assays to distinguish among and determine stability of "sociability" phenotypes in adult male rhesus monkeys, and biological assays will be done to determine relationships between social phenotypes and measures of HPA activity, GR- mediated signal transduction, and genome-wide transcriptional profiles. PUBLIC HEALTH RELEVANCE: Research has repeatedly shown that social isolation increases risk for poor health. We previously found functional genomic differences between individuals high and low in social isolation which could contribute to differences in risk of disease. The proposed research therefore is designed to identify the specific biological mechanisms mediating these genomic effects.
DAILY EXPERIENCE IN ADOLESCENCE AND BIOMARKERS OF EARLY RISK FOR ADULT HEALTH
PI: Andrew Fuligni, PhD / Michael R. Irwin, MD, Co-I
Despite calls for the identification of early risk factors for the development of chronic health conditions, there has been little longitudinal research on biomarkers of health that has been conducted in persons younger than 25 years of age. In addition, there is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European Americans. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts. We propose a 3-wave longitudinal study of adolescents and their caregivers from Mexican, Chinese and European backgrounds in order to assess the impact of daily experience on biological indicators of early risk for adult health. Our focus on daily experience stems from the need to identify the mechanisms by which global social factors identified in demographic surveys, such as lower education and income, play themselves out in individuals' daily lives. Daily experiences such as social conflict, excessive demands, emotional distress, threat, and sleep behaviors have been shown to be linked to both global risk factors and multiple biological indices of health risk among adults. The project will include both intensive behavioral assessments and detailed biological markers of health risk from both adolescents and their parents in order to address the following specific aims: (1) describe the development during adolescence of biological indices of early risk for adult health; (2) assess the role of daily experience in the development of early health risk; (3) examine the existence of ethnic disparities in early health risk; and (4) explore the role of potential protective factors in the development of early health risk. Approximately 540 pairs of adolescents and primary caregivers (180 from each ethnic group) will be assessed when the adolescents are approximately 15-16, 17-18, and 19-20 years of age. Each year, both adolescents and caregivers will participate in interviews that include measures of global social factors such as socioeconomic background and potential protective factors such as social connectedness. Participants will report daily experiences using a nightly diary checklist for 9 consecutive days. Salivary cortisol will be obtained at 4 time points each day for 4 of these days in order to analyze HPA activity, and participants will wear wrist actigraphs for the same 4 days to measure objective sleep behaviors. Blood pressure, BMI, and waist/hip ratio will be assessed, and dried blood spots will be obtained for the assessment of c-reactive-protein (CRP), cholesterol, and high density lipoproteins (HDL). Finally, peripheral blood samples will be provided by a subsample of 120 families for the assessment of plasma interleukin-6 (IL-6), a pro-inflammatory cytokine, and for gene expression analyses of molecular signaling pathways driving inflammatory biology. PUBLIC HEALTH RELEVANCE: There is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European American. More in-depth examinations of the daily lives of adolescents from these populations could identify both the sources of these disparities as well as unique risk and protective factors. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts.
BRAIN AND BEHAVIOR IN INDIVIDUALS WITH INTERSEX CONDITIONS
PI: Eileen Lueders, PhD, UCLA PI
Studies of non-human mammals show that androgens, particularly testosterone (T), during early development play a major role in sexual differentiation of the brain, with long-term consequences for behavior. Research on clinical populations suggests that prenatal T exposure has similar effects in humans, increasing male-typical behavior and reducing female-typical behavior. Almost nothing is known, however, about the impact of early T exposure on the structure of the human brain. In addition, the brain mechanisms underlying T-related behavioral changes are unknown. This project will study brain structure and behavior in individuals with one of two disorders of sex development (DSD, also called intersex conditions) that are characterized by androgen abnormality beginning prenatally: 1. Congenital adrenal hyperplasia (CAH), which causes overproduction of adrenal androgens; and 2. Complete androgen insensitivity syndrome (CAIS), which involves an inability to respond to androgens, and so an effective lack of androgen exposure. CAH affects both males and females, and 35 men and 35 women with CAH will be compared to 35 male and 35 female controls. Individuals with CAIS are XY females, and 35 females with CAIS will be compared to 35 male and 35 female controls. State-of- the-art imaging technology will be used to map brain structure. Also, aspects of behavior, known to show substantial sex differences, and for which there is evidence of a relationship to prenatal T exposure, will be assessed. Specifically, these are mental rotation ability, targeting ability, and propensities to physical aggression (where men score higher than women), and verbal fluency, fine motor ability and empathy (where women score higher than men). The information obtained will provide convergent evidence regarding the influence of T on human brain and behavior. Convergent evidence is important because ethical considerations preclude experimental manipulations of T during early human development. Instead, naturally occurring conditions that involve T excess or deficiency will be studied. Each condition involves consequences in addition to T abnormality. Therefore, confidence that testosterone caused any brain or behavior differences is strengthened when data from both conditions suggest this conclusion. For instance, prior research indicates that, with respect to physical aggression, men score higher than women, and females with CAH score higher than other females. If XY females with CAIS resemble women rather than men in regard to physical aggression, confidence that T is the responsible agent will be increased. The information obtained will enhance understanding of the neural mechanisms involved in sexual differentiation of human brain and behavior, and so will be relevant to the many psychological disorders that differ by sex. It will also be relevant to clinical management of individuals who have experienced T abnormality before birth, for any of several reasons, including genetic disorders, such as CAH or CAIS, or other disorders of sex development, maternal treatment with hormones during pregnancy, or contact with environmental endocrine disruptors.