Age-related declines in physical function are common and lead to increased health care costs, institutionalization and mortality. As a traditional epidemiologist with unique expertise in skeletal muscle aging and physical function, I have researched lifestyle interventions (weight loss, aerobic and resistance training) to prevent age-related declines in physical function. However, lifestyle changes are difficult to adopt, especially for those at the highest risk for functional decline. To extend the benefits of these interventions, it is imperative to understand biological processes underlying changes in function with aging and following intervention. As such, the current proposal will provide the candidate with advanced training in molecular epidemiology and biology of aging, yield novel insight on the genetic and biological basis of physical function among older adults and lay the foundation for future research. Specially, Aim 1 will identify genes and genetic variants for physical function and changes in physical function with aging. Aim 2 will examine blood RNA expression for components of the transforming growth factor beta (TGF-β) pathway, which is implicated in muscle dysfunction and pathogenic fibrosis, with physical function and its change with aging. Aim 3 will test if serum levels of TGF-β and procollagen type 3 N- terminal propeptide (P3NP - a biomarker of pathogenic fibrosis) are related physical function among older adults. I will leverage robustly collected physical function measures, biological samples, and an ultra-high-density genome-wide polymorphism map from the NIA-funded Long Life Family Study (LLFS), a multi-center study of exceptional aging and longevity in families and from The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium . The proposed research and training is very innovative. First, despite being implicated in several age-related conditions there have been no human studies that have examined the relationship between TGF-β or P3NP and physical function. Further, LLFS has a large number of “oldest old”, who are understudied and at the highest risk for functional decline. There has also been limited research on the genetics of physical function. The proposed career development award will provide the applicant with essential new mentorship, knowledge and skills in human genetics and molecular epidemiology including but not limited to blood RNA expression and protein biomarker development (Aim 2 and 3), genome wide association (GWA) and linkage analyses (Aim 1 ), meta-analysis (Aim 1) and bioinformatics (Aim 1) approaches to follow-up association and linkage analyses. Finally, this award will be critical for facilitating my transition to an independent research career in aging and molecular epidemiology with a focus on physical function. As an epidemiologist with expertise in both traditional and molecular methods, I will be well-positioned to contribute to the advancement of the evolving ...