Inflammatory suppression of endothelial function with aging and habitual exercise

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DESCRIPTION (provided by applicant): This predoctoral NRSA proposal seeks support for research career development in the emerging, biomedically important field of "vascular aging". The career goal of the candidate, Ms. Walker, is to become an independent investigator in translational research focusing on the mechanisms mediating vascular aging in humans and interventions that prevent or reverse vascular aging. The proposed research project has important clinical implications for the prevention of cardiovascular disease (CVD) because vascular aging is now accepted as a major risk factor CVD. This project will focus on the reduction in vascular endothelial function, a key expression of vascular aging, as determined by measurement of endothelium-dependent dilation (EDO). EDD is markedly reduced with aging, even in healthy older adults, but the underlying mechanisms are incompletely understood. Chronic low-grade inflammation (with associated oxidative stress) is one possible mechanism that has not been directly investigated. In contrast to their sedentary peers, older adults who regularly perform aerobic exercise demonstrate largely preserved EDD. It is unknown if an absence of inflammation and associated oxidative stress-mediated suppression of EDD contributes to the preserved function in habitually exercising older adults. The influence of inflammation and oxidative stress on aging and age-associated diseases is a major research goal of the National Institute on Aging. To investigate these topics, groups of young and older healthy sedentary and habitually exercising men and women will be studied. The influence of inflammation on EDD (brachial artery flow-mediated dilation) will be determined by short-term inhibition of nuclear factor kappa B signaling with orally administered Salsalate, an aspirin-like compound. Intravenous infusion of vitamin C, a potent antioxidant, will be used to determine the effects of oxidative stress on EDD. Additional insight into the cellular and molecular mechanisms involved in age- and exercise-related effects on EDD will be obtained by measurement of circulating markers of inflammation and oxidative stress and gene and/or protein expression of inflammatory molecules, oxidatively modified proteins, and oxidant and antioxidant enzymes in peripheral blood mononuclear cells and vascular endothelial cells from human subjects. The proposed research project has important public health relevance as CVD remains a leading cause of illness and death in the US.