Rhesus-Human Adrenal Comparisons During Aging

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The factors that regulate the production of adrenal androgens in the human during health and disease are ill defined. Much of the problem in this regard results from a lack of correspondence in the profile of androgens that the human secretes from its adrenal cortex among the commonly utilized experimental animal models. Consequently, the causes for the dramatic deficiency that develops during aging in adrenal secretion of DHEA and DHEA sulfate, the principal secretory products of the human adrenal along with cortisol, remains an unexplained problem in human physiology. It seems quite likely that this deficiency, which in some individuals is equivalent to a 90% reduction in DHEA/DHEA sulfate production compared to that seen in the average young adult, has serious health consequences. In view of the fact that several aspects of the development of the adrenal in the human and other primates are similar, and that adrenal androgen production during fetal development and in adulthood of human and rhesus macaque appear to be quite similar, we propose to investigate the possibility that this animal might be a useful model for study of the regulation of adrenal androgen production in the human and particularly, that the rhesus might be utilized for meaningful studies on the mechanisms of adrenal androgen deficit that occurs during aging as well as providing a model system for evaluation of methods to ameliorate or reverse such changes. DHEA and DHEA sulfate likely arise from the zona reticularis of both the human and rhesus, providing a common focus for hypothesis development and testing. The studies that we propose will involve morphological comparisons of the adrenocortical zones of the young adult rhesus and human, quantitative and qualitative evaluations of the distribution in young adults of both species of key enzymes and co-factors that play important roles in androgen synthesis or that might shunt steroid substrate into alternative biosynthetic pathways, and finally quantitative and qualitative comparisons of aging effects on the morphology and biochemical phenotype of adrenocortical zones of the rhesus compared to that of the human. We hypothesize that there will be found to be sufficient similarities in the rhesus and human to justify the proposal of in-depth studies in the future to address important issues about the mechanisms of adrenal androgen regulation during aging.