IS DHEA REPLACMENT THERAPY BENEFICIAL?

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The maor emphasis of our researh on the prevention of physical frailty and loss of independence has been on the adaptatations to exercise. However, because most Americans are not motivated to exercise, we have started to evaluate other approaches to maintenance of health and prevention of frailty. Of these, the most powerful appears to be DHEA replacement therapy. In tis context, the overall goals of this study are to determine whether long term dehydroepiandrosterone (DHEA) replacement therapy has beneficial effects that could (a) delay the development of frailty and disability, (b) protect against development of type 2 diabetes and coronary artery disease, (c) improve quality of life, and (d) obtain information on the mechanisms of DHEA action. DHEA and DHEA sulfate (DHEAS) plasma concentration peak at ~20 yrs of age and decline rapidly ad markedly after age 25 yr DHEA is a PPARa activator. PPARa play major roles in regulatinglipid metabolism and controlling inflammation. DHEA also appears to have anabolic effects on muscle and bone. The study proposed here is a randomized, double blind, placebo-controlled trial of DHEA replacement. It is designed to determine the effects of 12 mo of DHEA replacement in 65-75 yr old women adn men on (a) truncal and visceral (b) insulin resistance and serum triglycerides, (c) muscle mass and strength, (d) bone mineral density, (e) chronic inflammation, (f) arterial-endothelium-dependent vasodilation, adn (g) sense of well being. The specific aims of this study are to test the hypothesis that 12 mo of DHEA replacement will (a) result in significant decreases in truncal and visceral fat by shifting metabolism to fat oxidation and increasing energy wastage; (b) decrease insulin resistance and decrease serum triglycerides; (c) increase muscle mass and strength, by decreasing catabolic stimuli an increasing anaolic stimuli; (d) increase bone mineral density by increasing anabolic stimuli an decreasing catabolic stimuli; (e) Reduce chronic inflammation and decrease pro-inflammatory cytokine production by peripheral blood mononuclear cells; (f) improve arterial endothelium dependent vasodilation; and (g) improve general sense of well being. A major emphasis of his research is on the mechanisms responsible for the biological effects of DHEA replacement.