Project Summary/Abstract Aging-related sarcopenia includes the loss of muscle mass and strength/function, which impairs mobility, increases falls, decreases independence and quality of life, and increases mortality. Alcohol use is among the lifestyle factors that may influence the development and progression of aging-related sarcopenia, as it promotes skeletal muscle myopathy in adults at high doses, and at low doses may improve mitochondrial function. Cross-sectional and prospective cohort studies indicate that high doses of alcohol are associated with greater incidence of sarcopenia while low to moderate intake is associated with maintenance of physical function and grip strength, as well as decreased frailty. As this dose dependent relationship has never been investigated experimentally in a well-controlled setting, the objective of this proposal is to develop and characterize a pre-clinical mouse model of aging to determine the dose- and sex-dependent effects of alcohol on aging-related sarcopenia. Relatedly, our long-term goal is to then investigate the potential paradoxical properties of alcohol on aging muscle while focusing on mechanisms that can be targeted pharmacologically to either limit or mimic the effects of each dose of alcohol. Specific Aim 1 will determine the dose-dependent effects of alcohol on the development and progression of aging related losses in skeletal muscle strength and performance, while Specific Aim 2 will investigate the effects of alcohol on aging related changes in skeletal muscle size and composition. These research questions will be addressed using middle aged (12 mo. old) male and female mice consuming either a high (15%v/v) or low (3.5%v/v) dose of alcohol in their water daily until reaching old age (~30 mo. old). Every 3 months performance tests and measurements of frailty, metabolic rate and cage activity will be completed. At 12 (baseline), 18, 24 and ~30 months of age, in-situ and ex vivo skeletal muscle force production and fatigability will be quantified on muscles of the lower leg. Follow-up assessments will include measurement of myofiber cross sectional area per fiber type and deposition of collagen and fat in the muscle. This will be the first investigation of the dose-dependent effects of alcohol on sarcopenia and will lay the foundation for future mechanistic investigations to determine how alcohol influences sarcopenia risk and aging associated changes to skeletal muscle in a sex-specific manner.