Abstract A hallmark of aging is an impaired ability to adequately recover following a stressor, such as muscle disuse, resulting in muscle fibrosis and weakness thereby increasing the risk for falls and loss of independence. Mechanistic-based therapeutic strategies to enhance muscle recovery in older adults do not exist. Synchronized muscle interstitial cellular events involving immune cells (e.g., macrophages), fibro-adipogenic progenitor (FAP) cells and satellite cells are critical to promote myogenesis, extracellular matrix (ECM) remodeling, and ultimately, restore muscle size and function. However, in aging, senescence cells exceed the rate of removal during recovery from injury resulting in excessive senescence associated secretory phenotype (SASP; secretion of factors such as pro-inflammatory and pro-fibrotic mediators) thereby amplifying dysfunction in macrophages, FAPs and satellite cells and resulting in poor ECM remodeling. Metformin has been implicated to have positive effects on muscle size and function through non-glycemic mechanisms. Of interest to the current proposal, metformin has been shown to enhance macrophage function and lessen cellular senescence burden by targeting SASP in a variety of muscle interstitial cell. However, the role of metformin to improve ECM remodeling and muscle recovery in older adults following disuse atrophy through immunomodulating and senomorphic mechanisms have not been examined. We provide compelling data in older adult skeletal muscle that a clinical dose of metformin can potentially improve muscle macrophage, FAP and satellite cell function while also decrease muscle fibrosis and cellular senescence and SASP. Therefore, the purpose of this application is to conduct a randomized, double blind, placebo-controlled clinical trial in older adults to determine if short-term metformin delivery (vs placebo) during the recovery phase following disuse atrophy can improve macrophage function, reduce cellular senescence and SASP, and enhance ECM remodeling thereby facilitating muscle regrowth. We will use state-of-the-art methodologies and elegant in vivo and vitro approaches to identify the impact metformin treatment on macrophage, FAP and satellite cell senescence and SASP, collagen organization, and muscle regrowth in aging. We anticipate that the findings will aid in the repurposing of metformin to be timely delivered to accelerate the recovery of aged muscle following disuse related events (e.g., surgery, illness).