The goal of this revised competing renewal for the Cardiovascular Health Study (CHS) All Stars Study is to determine how aging unfolds across systems and predicts disability-free survival. Based on observations made between 1992/93 and 1998/99 and relating changes within and across systems to disability-free survival over the subsequent 15 years, we will seek to determine whether observed changes are upstream predictors of disease events, are concurrent with disease changes, or are adaptive responses that maintain homeostasis. The proposed approach will allow the design of prevention intervention strategies aimed at pivotal morbidities and tracked by associated biomarkers in a window of time where age related functional decline is modifiable. The specific aims are: 1. To continue to follow the remaining 1260 men and women in CHS cohort to characterize their long term survival and disability-free survival. This will provide an accurate assessment of rates and predictors of very long active and disabled life span overall and by sex, race and birth cohort. 2. To determine the levels and changes in subclinical disease measures and aging biomarkers that are associated with long term survival and disability free survival. We will evaluate whether changes in aging biomarkers are explained by existing disease, change concurrently with subclinical disease markers, and/or predict future mortality and disability, independently of subclinical disease. 3. To examine the correspondence between changes across multiple systems, using repeated measures of subclinical disease and biomarkers of aging. We hypothesize that measures of subclinical disease and biomarkers of aging significantly cluster in the individuals with the longest term disability free survival. We will explore novel metabolic factors to further address the hypothesis that energy homeostasis is key to survival. PUBLIC HEALTH RELEVANCE: This study will provide a novel multisystem, longitudinal perspective on the processes that are key to aging well and identify quantifiable goals for successful aging. The determination of changes in biomarkers as consequences of or adaptations to subclinical accumulation of disease could shift thinking about interventions towards the promotion of adaptation rather than replacement or reversal of aging processes. The CHS cohort is uniquely and ideally suited to achieve these goals, which are major goals of the National Institute on Aging.