Advancing age is associated with the development of arterial dysfunction and disease. Two major contributors to arterial disease with aging are endothelial dysfunction and stiffening of the large elastic arteries. However, the mechanisms involved and the ability of lifestyle behaviors to prevent these changes are incompletely understood. One novel and largely unexplored hypothesis is that "physiological resistance" to the adverse effects of common environmental factors to which we are chronically exposed decreases with aging, thus exacerbating the resulting dysfunction and increased risk of disease. One such factor may be a "western", i.e., high-fat, diet (WD). WD generally is associated with development of vascular inflammation linked to oxidative stress, a reduction in nitric oxide (NO) bioavailability and an increased risk of vascular dysfunction/disease. In contrast to WD, habitual aerobic exercise is associated with enhanced arterial function and reduced risk of vascular diseases. It is unknown if the potentially adverse effects of short-term or lifelong exposure to WD become greater with aging, if these effects can be prevented by habitual aerobic exercise (or an agent with potential "exercise-like" vascular effects), and the mechanisms that may be involved. Initial critical proof of concept evidence can be obtained from a mouse model of age-associated arterial dysfunction. Working Hypotheses 1. Older age is associated with progressively greater reductions in vascular endothelial function and increases in large elastic artery stiffness in response to both short-term and lifelong ingestion of WD. 2. The greater impairments in endothelial function and large elastic artery stiffness in response to WD with increasing age will be mediated by vascular inflammation, which will, in turn, be associated with oxidative stress, increased superoxide and reduced NO production, and altered protein expression. 3. Habitual aerobic exercise will prevent the greater reductions in vascular endothelial function and increases in large elastic artery stiffness in response to short-term and lifelong WD with older age. 4. This protective effect of habitual aerobic exercise will be mediated by preventing the exacerbation of arterial inflammation (and its associated effects on oxidative stress and NO) in response to WD. 5. Increased arterial expression and/or activity of adenosine monophosphate activated protein kinase (AMPK) will contribute to these protective effects of exercise. Importantly, chronic pharmacological activation of AMPK will prevent the adverse effects of WD in the absence of physical activity. Impact. The results will provide novel insight into the mechanisms by which aging increases vulnerability to the development of arterial dysfunction and disease, and if this might be prevented by lifestyle or "lifestyle mimicking" pharmacological interventions. New, clinically relevant knowledge will be gained as to how both short-term and lifelong exposure to a high fat diet interacts with aging to produce arterial dysfunction. PUBLIC HEALTH RELEVANCE: The goal of this research is to determine if the dysfunction of arteries that occurs in response to both short- term and lifelong ingestion of a "western" (high-fat) diet worsens with aging. We also will determine if regular exercise and a pharmacological compound with presumed exercise-like effects "protect" arteries from both short-term and lifelong exposure to a western diet. Finally, we will gain insight into why aging has an adverse influence on arteries exposed to a western diet, and how exercise and the exercise-like agent prevent this effect. We will study mice as a first step in investigating these issues.