Project Summary/Abstract Aging is associated with significant declines in muscle mass, strength, and physical performance, which often lead to disability, loss of independence, and adverse clinical outcomes including multimorbidity and mortality. At present, health care providers have no therapeutic options to offer their patients to slow aging-related declines in physical function. Importantly, evidence is emerging that statins could be an effective treatment for preserving physical function by preventing disabling events such as stroke, heart failure, or myocardial infarction. In addition, statins have pleiotropic properties including anti-inflammatory, anti-oxidant, and immuno- modulatory effects, which may slow or prevent aging-related declines in physical function. However, reports of muscle pain and weakness in patients on statins has led to a significant number of patients discontinuing statins. Thus, the proposed study is critical to establish whether statins may help to preserve physical function and independence in older adults, or whether statin-associated muscle symptoms portend a statin-related decline in physical function. The PREVENTABLE trial (U19 AG065188) provides an ideal opportunity to definitively determine the effect of statins as a treatment for aging-related declines in physical function. PREVENTABLE is a placebo-controlled pragmatic clinical trial designed to investigate whether randomization to a statin can prevent dementia and prolong disability-free survival in 20,000 participants aged 75+ years without clinically evident coronary heart disease. While the PREVENTABLE trial will help clarify the effects of statins on self-reported disability, the proposed ancillary study will extend and validate the physical disability data by investigating the effects of statins on changes in physical performance, which are typically observed earlier in the trajectory of functional decline and may be a more sensitive marker for the effects of statin. To determine if statins affect longitudinal change in physical performance, the proposed ancillary will add the Short Physical Performance Battery (SPPB), a validated measure of lower-extremity performance comprised of balance tasks, a 4-m walk, and repeated chair stand test, over 3 years of follow-up in 2,500 PREVENTABLE participants (1,250 per intervention arm). Self-reported information on patient-centered outcomes relevant to physical function including statin-associated muscle symptoms, fatigue, and pain will also be collected. The specific aims of this ancillary study are to: 1) determine whether randomization to statin slows the aging- related decline in usual gait speed; 2) determine whether randomization to statin slows aging-related declines in lower-extremity function (SPPB score) and strength (chair rise time); and 3) explore whether randomization to statin is associated with self-reported statin-associated muscle symptoms, fatigue, and pain. By leveraging the rich resources an...