PROJECT SUMMARY Aging is a primary risk factor for development of cardiovascular dysfunction and disease. The hallmarks of vascular aging are endothelial dysfunction, development of a synthetic, atherosclerotic phenotype in smooth muscle, and arterial inflammation and stiffening. We have shown that aerobic exercise training can mitigate or reverse age-induced vascular dysfunction and adverse arterial remodeling; however, the cellular signals that contribute to age-induced vascular dysfunction and its reversal by aerobic exercise training remain unknown. Reduced circulating adiponectin has been associated with all of the adverse vascular changes that occur with advancing age; however, a direct role for adiponectin signaling in age-induced vascular dysfunction has not been demonstrated. Similarly, although we have reported that circulating adiponectin levels increase in response to late-life exercise training, a direct role for adiponectin signaling in reversal of age-induced vascular dysfunction by exercise training has not been shown. We now propose to test a central hypothesis that 1) loss of adiponectin signaling is a critical contributor to age-related vascular dysfunction and adverse arterial remodeling, and 2) upregulation of adiponectin signaling is necessary for exercise training-induced reversal of age-related vascular dysfunction and adverse vascular remodeling. We propose to study sedentary and exercise trained mice, across the murine lifespan, to determine 1) the impact of loss- and gain-of-function of adiponectin on ceramide/sphingosine-1-phosphate signaling in the endothelium of the resistance vasculature, 2) the impact of loss- and gain-of-function of adiponectin on development of a senescence- associated synthetic phenotype in vascular smooth muscle of the resistance vasculature, and 3) the impact of loss- and gain-of-function of adiponectin on inflammation and fibrosis within the arterial wall. Results from the proposed work will increase our understanding of the role of adiponectin signaling in age- and exercise training-induced adaptations of the vasculature. A top biomedical research priority is to identify strategies that prevent or reverse vascular dysfunction with advancing age. The proposed work could identify 1) components of the adiponectin signaling pathway that could be targeted for prevention of age-related vascular dysfunction, and 2) novel exercise mimetics that could be employed in reversal of age-related vascular dysfunction.