This project is in response to the US-Ireland R&D Partnership Programme. The project will support the analysis of existing social and epigenetic data for three countries and the development of longitudinal epigenetic data for the three countries. The NIH proposal requests support for the US aspect of the project; the same proposal has been submitted to the Republic of Ireland and Northern Ireland for support of their parts of the project. The project will answer basic questions about how life circumstances in both childhood and adulthood affect epigenetic change and how that change in turn is associated with health after age 50. The three countries have a set of integrated aims and analyses that will be done using data from three national studies of aging in the family of Health and Retirement Studies: the US Health and Retirement Study (HRS), the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA), and the Irish Longitudinal Study of Aging (TILDA). The project will examine the links between lifetime social, economic, psychological, environmental and behavioral circumstances, and epigenetic markers related to aging and health, and subsequent health. Epigenetic modification is one of the ?hallmarks? of aging, i.e. an underlying physiological change that can speedup or delay aging-related health outcomes. Faster aging is characteristic of people in adverse social circumstances. Epigenetic change, particularly DNA methylation (DNAm), appears to be especially influenced by adverse social circumstances, both at early ages and at later ages. This project will be unique in evaluating how a variety of social circumstances, i.e. low levels of education and income, minority group membership, adverse childhood experiences, adult traumas, risky health behaviors, psychological states, and chronic stress, are associated with epigenetic markers in three different countries, with somewhat different historical, social and behavioral characteristics which are operating in different health policy regimes ? allowing for both replication where effects are hypothesized to be similar and differentiation where they are hypothesized to differ (e.g., where risk characteristics are differentially patterned by SES). The applicants are uniquely placed with their collaborative resources to explore how socioeconomic experiences across the life course alter epigenetic profiles to influence health outcomes such as frailty, disability, chronic disease, and premature mortality. The three data sets have been highly harmonized for information collection from the beginning of the studies and were designed to encourage comparative analysis. They have been harmonized in the survey information and the development of the epigenetic data in the three countries. Each country has strong independent research teams who bring unique expertise and resources and a history of collaboration to this collaborative proposal.