This is a competitive supplemental application to R01 AG019339, 'Testosterone Supplementation and Exercise in Elderly Men"""""""". The long-term goal of the parent award (5/1/04 start date) is to understand the physiological significance of the age-related decline in serum testosterone (T) levels and the role of T supplementation, with and without progressive resistance exercise (PRT), in attenuating the reduced physical function and frailty found in aging men. Additionally, the parent grant will determine whether low- dose T has beneficial effects (i.e., body composition, physical function) with fewer adverse effects (i.e., erythrocytosis, and prostate growth). In the present amended supplemental proposal, we propose to continue along this theme by examining the effects of the age-related decline of T and supplementation of T on vascular aging. Vascular aging, including an increase in large elastic arterial stiffness, has been emphasized recently as a major risk factor for the development of cardiovascular disease (CVD), which when expressed, is a significant contributor to reduced physical function and frailty. The purpose of this supplemental application is to obtain the necessary funds to acquire measurements of large elastic artery stiffness in response to low-dose T [25 mg/d], usual-dose T [50 mg/d]) crossed with PRT (some versus none), in healthy older men with low-normal to slightly low serum T levels. The general hypothesis is that both low-dose and usual dose T will decrease arterial stiffness which will, in turn, result in functional benefits (e.g., decreased left ventricular [LV] mass), and that these favorable adaptations will be mediated, in part, by an increased local vasodilatory state (increased brachial artery flow-mediated vasodilation). Additionally, because resistance training has been shown to be associated with increases in arterial stiffness and LV mass, we hypothesize that T supplementation with PRT will prevent this. The proposed supplement will have no significant impact on the research design of the parent award, but will address two key areas identified for future research: understanding the mechanisms involved and strategies that attenuate or prevent the age- related increase in large elastic arterial stiffness. Additionally, like the parent grant, these measurements will provide important new information regarding the risk/benefit profile of low-dose T supplementation compared to conventional T replacement doses. Collectively, these studies will influence future development of androgen formulations and guide intervention trials to assess the benefits and risks of T treatment, in both healthy and frail elderly men, to possibly prevent the development of CVD and frailty, and help restore physical function. ? ? ?
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