ABSTRACT Frailty is a state of depleted physiologic reserve that is common in older adults. To date there are no proven therapies to prevent frailty beyond recommendations to adhere to a healthy lifestyle. Frailty is associated with chronic diseases, such as cardiovascular disease (CVD), through shared pathophysiology mediated in part by inflammation. Statins are the mainstay of CVD prevention and have effects beyond lipid lowering, including reducing inflammation. Yet, many adults aged 75 and older are not taking statins due to a lack of evidence in this age group. The ongoing PREVENTABLE trial will test the effect of atorvastatin 40mg vs placebo in 20,000 adults aged 75 and older free of CVD for the primary outcomes of survival free of dementia and disability, and secondarily for incident CVD. However, whether statins can slow frailty has not been previously tested and is not in the parent trial’s protocol. Thus, the proposed study is critical to establish whether statins may prevent or slow the progression of frailty. PREVENTABLE provides a unique opportunity to test the effect of statins on frailty using the two leading prevalent conceptual frameworks for quantifying frailty: the Rockwood cumulative deficit frailty index (Rockwood FI) and Fried physical phenotype. As part of the parent trial, participants will have a Short Physical Performance Battery (SPPB) performed at baseline and assessment of weight loss. A funded Physical Performance ancillary study will support the administration of the SPPB at annual follow-up in 2500 participants and annual questionnaires will quantify other domains of frailty, including fatigue and physical activity. The proposed PREVENTABLE Frailty Ancillary Study will complement the main trial by cleaning and harmonizing EHR, claims, and trial data to calculate a Rockwood FI for all trial participants (n=20,000), and in the Physical Performance subset (n=2,000), add annual grip strength and weight loss assessments to complete the Fried phenotype. Finally, an annual blood sample will be collected in the same 2,000 participants to measure markers of inflammation, neurodegeneration, and other measures to augment the Rockwood FI with systematically collected routine labs, calculate a lab-FI, and examine Geroscience pathways to determine the effect of statins on markers of inflammation and biologic aging. The frailty ancillary study will augment the parent trial and existing ancillary study to determine whether statins: 1) lower the risk of incident frailty defined according to the Rockwood FI in the entire trial population and Fried physical phenotype in a subset, and 2) slow the progression of frailty over time according to the Rockwood FI in the entire trial population and Fried phenotype in a subset. Finally, in the subset with annual blood samples, we will determine the effect of statins on an FI augmented with labs and a lab-only FI. We will also explore the effect of statins on inflammation and other hallmarks of aging. Leveraging the infrastructure of the PREVENTABLE trial and its Physical Performance ancillary study, this timely and cost-effective proposal represents an exceptional opportunity to test the possibility of statins as a treatment for frailty and biologic aging in a randomized setting.

PROJECT NARRATIVE Frailty is a syndrome increasingly common in older adults that makes it difficult to recover from a stressful event, such as an infection or fall, and increases the need for more help at home or long-term institutionalization. We believe that statins, one of the most common medications to lower cholesterol and prevent heart disease and strokes, may have a role in lowering frailty by lowering inflammation. In this study we will test whether statins can lower the risk of frailty, measured according to several physical function parameters such as walk speed and grip strength, common blood tests, and other health variables.