Project Summary Endurance exercise is a highly effective intervention for ensuring healthy metabolism and maintaining healthy function during aging, but is unavailable to patients with illnesses or injuries that restrict their movement. Here, we follow up on previous discoveries from the fruit fly model system showing that stimulation of octopamine secretion from the brain acts through receptors in muscle and fat to coordinate benefits of exercise in sedentary animals. Here, we propose to identify genetic factors that mediate increased neuronal branching in the exercising brain (Aim 1), elucidate the pathway regulating the response to octopamine in exercising muscle (Aim 2), and by extending these results into humans for the first time using virtual reality stimulation to produce some benefits of exercise in sedentary humans (Aim 3).