PROJECT SUMMARY Age-related declines in physical function are predictive of downstream declines such as extended hospital or nursing home care, declines in cognitive function, an increased risk of disability, and a higher risk for mortality. It is therefore imperative to understand the possible mechanisms for these declines among older individuals, with a goal to develop effective prevention strategies and maintaining their quality of life. Dietary quality and dietary patterns are proven to be critical for overall health and well-being, including age-related declines in physical function. However, the biological mechanisms for these associations remains an understudied area. Metabolomics, the comprehensive analysis of metabolites in biological specimens, provides researchers an opportunity to characterize metabolic phenotypes, examine the metabolic changes responsible for disease, and discover new therapeutic targets. Increasingly, metabolomics is being used to study chronic diseases, including examining the associations of metabolites with specific phenotypes, characterizing the role of metabolites as predictors of disease, and studying the causal role of metabolites in interventional studies. It is important to note that environmental factors such as diet, a modifiable lifestyle behavior, is an important determinant of metabolite profiles. Chronic disease epidemiology is now focused on identifying the key circulating metabolites critical to the development or progression of disease that can be modified using behavioral or other therapeutic interventions. However, significantly less is known about the role of diet- associated plasma metabolites and their relationship in mediating the associations of dietary predictors and measures of age-associated declines in physical function. We therefore propose to address this gap in knowledge, by conducting a study to: (a) determine the associations between measures of dietary quality and dietary patterns with plasma metabolites, (b) examine the associations between diet-related plasma metabolite biomarkers with age-related declines in physical function, frailty and disability, and (c) characterize the mediating effects of diet-related plasma metabolite biomarkers on the associations between dietary predictors with measures of physical function, frailty, and disability. This study will be conducted in the NIA-supported Baltimore Longitudinal Study of Aging (BLSA). The BLSA provides us the opportunity for prospective analyses and includes dietary data collected using valid methods, assessment of plasma metabolites, measures of physical function and a wealth of data on potential covariates and confounders to examine our research questions. Additional replication will be conducted in a second NIA-supported cohort, the Health, Aging and Body Composition study.