Project Summary/Abstract Sarcopenia, the progressive loss of muscle mass and function, universally impacts the aging population, contributing to loss of mobility and independence in older adults. With the rapid growth of the aging population, there is an urgent need for effective strategies against sarcopenia. Exercise is the most effective intervention that increases muscle mass and function in younger adults, but its benefits are attenuated in older adults due to diminished responses to exercise training. Over the years, several candidate molecules, including metformin, antioxidants, and resveratrol were combined with endurance exercise (EE) in an attempt to increase training- induced benefits; however, these interventions failed to enhance training responses and, in some cases, reduced the positive effects of exercise. Given metformin’s inhibitory effects on mitochondrial respiration and the ability of antioxidants to scavenge signaling molecules in response to exercise, a logical next step is to combine EE with a candidate molecule that specifically enhances mitochondrial bioenergetics and its downstream pathways. A strong such candidate is unacylated ghrelin (UnAG), whose circulating levels are significantly decreased in older adults and mice. Our pilot data provides evidence that UnAG combined with endurance exercise (UnAG+EE) additively increases mitochondrial bioenergetics, while synergistically improving motor coordination, muscle mass and contractile function. Our data also revealed that UnAG activated both shared (i.e., PGC-1α) and distinct (i.e., mTORC2) pathways compared to those triggered by EE alone, suggesting that UnAG+EE may provide synergistic and complementary benefits. Building on our compelling preliminary data, we hypothesized that the combination of UnAG+EE will enhance mitochondrial bioenergetics and preserve NMJ integrity in older mice, providing synergistic protection for sarcopenia. Our specific aims will focus on the effects of UnAG, EE,