ABSTRACT The overarching objectives of the PRIME Collaborative (Physical Resilience: Indicators and Mechanisms in the Elderly) are to characterize specific resilience phenotypes, elucidate biological mechanisms, and validate clinically valuable predictive tools and measures of physical resilience. The application focuses on resilience in three systems that are central to older adults' overall health: musculoskeletal, cognitive, and immune. The central hypothesis of this application is that resilience to physical stressors is influenced by biological mechanisms at the molecular level. We will examine whether mechanisms associated with one or more of the seven “Pillars of Aging,” which have been described by the trans-NIH Geroscience Interest Group, underlie a more generalized capacity for recovery that applies across multiple stressor/response scenarios. An inter- professional team of aging researchers from has been assembled to accomplish these objectives; the team represents expertise from six NIA-funded Older American Independence Centers (OAICs) and leverages other existing resources. The PRIME Collaborative team will use a two-phased approach. In Phase 1, workgroups will define specific resilience phenotypes in existing datasets using latent class trajectory analysis of sequential outcome measures following a stressor. The three resilience phenotypes, selected for their over-arching relevance to late life health as well as our team's expertise, are: musculoskeletal recovery after orthopedic surgery, immune recovery after infection, and cognitive recovery after surgery/anesthesia. We will conduct pilot studies to identify novel clinical tests and biomarkers associated with each of these resiliencies. Feasibility and response data from pilot studies will inform the design of a larger cohort study in Phase 2. In the final 6 months of Phase 1, the most promising predictive tests and markers will be selected and will inform two parallel activities in Phase 2. First, a longitudinal cohort study of older patients undergoing elective surgery will be conducted to validate predictors in a more diverse population. The Phase 2 cohort study will also allow us to assess synergy and interactions between different types of predictors (provocative tests, physiologic output measures, biomarkers) and different types of resilience (musculoskeletal, cognitive, immune). Second, biological mechanisms underpinning resilience will be identified using newly developed mouse resilience models, and in vitro human and mouse myotubule systems. These model systems are suitable for intervention studies. The Phase 2 biological studies will be designed to identify pathways related to one or more Pillars of Aging so that they are likely to underpin multiple types of resilience, and suggest therapeutic targets and novel, resilience-bolstering interventions.