The candidate, Susan J. Zieman, M.D., is an Assistant Professor of Medicine in the Cardiology Division at Johns Hopkins. She is trained and certified in Geriatric Medicine and Cardiology and is pursuing a Ph.D. in Clinical Investigation at the Johns Hopkins School of Hygiene and Public Health. Her long-term goal is to become a clinical investigator focusing on age-associated changes in vascular function and how they relate to the development, manifestations and treatment of cardiovascular disease in older adults. To realize this goal, she has developed a mentor-based research career development plan which provides training in 3 realms: 1) clinical trial design, management and analysis 2) vascular assessment techniques and 3) professional skills needed to launch a career as an independent investigator. This didactic and structured training program complements the following research proposal focused on the study of vascular stiffness. The physiologic changes that render age the most significant risk factor for cardiovascular (CV) disease are unclear. Although increased arterial stiffness and endothelial dysfunction accompany aging and are associated with increased CV risk, the mechanisms by which they impart increased CV risk and the causal nature of their relationship are unknown. The recent development of novel agents which increase vascular distensibility (VD) by altering structural components of the vessel wall now allows exploration of these relationships. The guiding hypothesis of this proposal is that decreased vascular distensibility itself impairs endothelial function. Specific Aim 1 tests whether decreased VD is associated with impaired endothelial flow-mediated vasodilation (FMD) in the brachial arteries of healthy young and older volunteers. Specific Aim 2 tests whether the endothelial vasoactive response to increased pulsatility following lower limb exercise is diminished in arteries with reduced distensibility. Specific Aim 3 tests the hypothesis that increasing arterial distensibility improves FMD and exercise-induced pulse perfusion-mediated vasodilation (PPMV) in older adults with increased vascular stiffness. A novel advanced glycation end-product crosslink breaker will be tested in a prospective, randomized, double-blind, placebo-controlled two-month trial investigating the effect of increased vascular distensibility on endothelial function (FMD at rest and exercise-induced PPMV). The overall goal is to identify a novel, important mechanism whereby vascular stiffening contributes to atherosclerotic risk, and thereby target efforts to treat such risks by enhancing vascular distensibility. These projects and career development plans will provide the resources, collaborative relationships, and academic foundation on which Dr. Zieman will build a successful career as an independent clinical investigator.