Aging is associated with a loss of body weight, often referred to as the anorexia of aging, which is accompanied by loss of muscle mass (sarcopenia) and bone loss (osteoporosis). The cytokine-like hormone leptin is secreted from peripheral fissues including fat and skeletal muscle, and leptin deficiency is associated with decreased bone mass as well as loss of muscle mass and strength. We have identified an animal model, the aged C57BL/6 mouse, that shares a number of key features in common with the aging human musculoskeletal system: an age-related decline in serum lepfin, decline in serum IGF-1, decreased muscle mass, and loss of bone density. We have also found that leptin treatment increases serum IGF-1 and muscle mass in aged mice. Our preliminary studies therefore suggest that the decline in musculoskeletal funcfion that occurs with aging is due in part to alterations in the lepfin-IGFI axis. We also show for the first time that musculoskeletal tissues from aged mice show increased expression of microRNAs (miRNAs) targefing leptin. The central hypothesis of our proposal is that leptin is a key factor linking nutrient intake with normal musculoskeletal funcfion, but leptin signaling in musculoskeletal tissues is altered with age, contributing direcfiy to age-related loss of muscle and bone. Specific Aim 1 will identify cell- and tissue-specific alterations in leptin expression with age, and will define the role of circulating leptin in regulating age-associated changes in the local and systemic secretion of IGF-1. Aim 2 will determine how aging and nutrient intake alter leptin sensitivity and the expression of functional leptin receptors in muscle and bone cells. Aim 3 will identify fissue-specific microRNAs that are altered with age and leptin treatment, and functional in vitro studies will be used to define the role of these small molecules in the proliferation and differentiation of myogenic and osteogenic cells. The proposed studies will therefore define new therapeutic targets and diagnostic biomarkers related to sarcopenia and fall risk that can be developed to improve upon exisfing fracture treatment and prevention strategies.