The progressive decline in muscle mass, strength, and maximal aerobic capacity and increased fatiguability in the aging population is a major public health problem of our society. An important question in the investigation of this aging-related problem is what is the pathogenesis of this aging-related sarcopenia and whether it is partially or completely reversible by therapeutic interventions. Previous studies using whole body measurements failed to elucidate the biochemical basis of age-related sarcopenia, although, measurements of mixed muscle protein synthesis indicated that a decline in synthesis rate of muscle protein is a factor in the pathogenesis of sarcopenia. Recent development of techniques to measure synthetic rates of specific proteins such as myosin heavy chain and mitochondrial protein demonstrated that a decline in synthesis rate of these proteins could cause a decline in muscle strength and V02 max. The current proposal will determine whether interventions such as testosterone replacement in the elderly men and DHEA replacement in elderly men and women will positively affect changes in muscle mass, muscle function and V02 max in the elderly population. It is hypothesized that while androgens increase synthetic rates of myosin heavy chain, which is a major contractile protein resulting in increased muscle mass and muscle strength only combined aerobic and resistance training increase synthesis rate of both myosin heavy chain and mitochondrial protein, thereby enhancing not only muscle strength and mass but also V02 max. Studies will be performed in 80 elderly men with low testosterone and DHEA and 60 elderly women with low DHEA. Studies will be performed at baseline t a 3 month interval (to determine the immediate effects) and then after one year of the interventions. The results will be compared with 20 young men and women 18-30 years old. It is anticipated that the proposed studies will not only help in defining the effects of androgen replacement on the quantity and quality of muscle, but also provide insight into the biochemical basis of their action and their potential benefits and risks as future hormone replacements approach in the elderly population. A unique aspect of this study is the ability to compare these results from studies on muscle with that of insulin action substrate metabolism and bone turnover.
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