Project Summary When confronted with a major physical stressor, some older adults are able to recover, with minimal decline, their physical and cognitive function, while others suffer precipitous, irreversible declines in function. This is the central notion behind resiliency. Little is known about the intrinsic (e.g., physiologic and molecular processes) and extrinsic (e.g., health behaviors) factors that impact resiliency. A two-phase study is proposed here to address this gap in our understanding. In phase 1, data will be generated to characterize age-related changes in physical resiliencies, their determinants, and their outcomes. Phase 2 will involve construction and validation of measures of resiliency; assessment of their predictive and clinical value; and investigation of age-related biological mechanisms determining specific resiliencies. Phase 1 Specific Aims: 1. To define, develop and refine phenotypic measures of resiliency responses to three pre-defined physical stressors: hip replacement surgery, initiation of hemodialysis, and bone marrow transplantation for hematologic malignancy. 2. To develop and pilot test candidate indicators of physical resiliency to include static and dynamic, as well as global and stressor-specific, measures. 3. To identify pre-stressor determinants of resilience, including measures of disease states, psychosocial factors, and molecular measures, and to characterize their measurement and statistical properties. 4. To synthesize data developed in Aims 1-3 to inform the design of Phase 2 studies. Phase 2 Specific Aims: 1. For each of clinical stressor to be studied: To build and evaluate assessments of resiliency incorporating measures identified in phase 1. Promising candidate measures will be cross-validated and their accuracy in predicting short- and long-term resilient stressor response rigorously characterized. The relative predictive value of global vs. specific, static vs. dynamic, and solely EHR-based versus broader resiliency measures will be assessed. 2. To characterize and assess age-related biological mechanisms that contribute to resilience or lack thereof that are specific to each clinical stressor, as well as mechanisms that are common across three specific physical stressors in older adults. 3. In preparation for the conduct of intervention studies: to cross-validate measures of resiliency at an external institution and to design pilot studies of strategies to bolster resiliencies based on clinical findings and biological mechanisms identified in Phase 1.