This is a competitive renewal application for the Women’s Health Initiative (WHI) Strong & Healthy (WHISH) trial. America’s 65-and-older population is projected to double in size from 49 million today to 95 million by 2060, with women far outnumbering men, particularly among adults aged 85-and-older. Compelling evidence supports the hypothesis that physical activity (PA) reduces cardiovascular (CV) disease (CVD), preserves physical function (PF) and promotes other aspects of CV health in older adults. WHISH is a landmark, pragmatic randomized controlled trial testing whether a centralized, public health intervention designed to increase and/or maintain PA levels and reduce sedentary behavior will reduce major CVD (MI, stroke, CV death) in older women. Using a randomized consent design to simulate real-world programmatic implementation, WHISH randomized 49,333 eligible participants in the WHI Extension Study to a behavioral intervention versus usual follow-up in May 2015. A passive consent process in the Intervention group (n=24,663) resulted in <4% of women “opting out” of receiving intervention materials. WHISH delivers a targeted, adaptive, instructional intervention, based on 2008 and 2018 DHHS PA guidelines and designed to complement the National Institute on Aging’s (NIA) Go4Life® campaign, using seasonal newsletters, manuals, pedometers, resistance bands, telephone and e-mail motivational messages, and a website designed for older women. The intervention adapts to participant feedback from annual surveys and other input regarding activity preferences and is customized and targeted to their current PF and PA levels. Primary effectiveness and safety outcomes (CVD, fracture) are evaluated using intention-to-treat in the entire randomized cohort. By the end of the current grant period (Feb. 2020), 4 years of follow-up will be available. Based on WHISH observed CVD event rates, intervention effects on PA and sedentary behavior, and new WHI data relating PA behaviors to CVD endpoints, revised power calculations suggest we will have only 65% power to evaluate the impact of the WHISH intervention on CVD events. We estimate that 4 additional years of follow-up (8 years overall) will yield 85-89% power to provide a definitive test of the primary WHISH hypothesis. This application proposes to extend the WHISH intervention and follow-up of outcomes for 4 additional years so that the trial can reach a definitive conclusion on the benefits and risks of the PA intervention. We also propose to leverage data and biospecimen collections in a planned WHI Extension Study home visit to enable evaluation of key markers of healthy CVD aging including physical performance, sleep duration and insomnia symptoms, and depressive symptoms. Pilot studies will be executed to explore long-term effects of the WHISH intervention on changes in established and novel biomarkers known or postulated to be influenced by PA levels and indicative of various underlying mechanisms re...