Rhesus-Human Adrenal Comparisons During Aging

人类在健康和疾病期间调节肾上腺雄激素产生的因素尚未明确。这方面的许多问题是由于在常用的实验动物模型中，人类肾上腺皮质分泌的雄激素的轮廓缺乏对应。因此，脱氢表雄酮和硫酸脱氢表雄酮（人类肾上腺与皮质醇的主要分泌产物）在衰老过程中肾上腺分泌显著不足的原因，在人类生理学中仍然是一个无法解释的问题。与普通年轻人相比，某些人体内的脱氢表雄酮/脱氢表雄酮硫酸盐含量减少了90%，这种缺乏似乎很可能会对健康产生严重影响。鉴于人类和其他灵长类动物肾上腺发育的几个方面是相似的，并且人类和恒河猴在胎儿发育和成年期的肾上腺雄激素分泌似乎非常相似，我们建议研究这种动物可能成为研究人类肾上腺雄激素分泌调节的有用模型，特别是，该恒河猴可用于有意义的研究衰老过程中肾上腺雄激素缺乏的机制，并为改善或逆转这种变化的方法的评估提供模型系统。脱氢表雄酮和硫酸脱氢表雄酮可能来自人类和恒河猴的网状带，这为假设的发展和检验提供了一个共同的焦点。我们提出的研究将包括对年轻成年恒河猴和人类肾上腺皮质区的形态学比较，定量和定性评估这两种物种的关键酶和辅助因子在年轻人中的分布，这些酶和辅助因子在雄激素合成中起重要作用，或者可能将类固醇底物转移到其他生物合成途径中。最后定量和定性比较了衰老对恒河猴和人类肾上腺皮质区形态和生化表型的影响。我们假设在恒河猴和人类身上会发现足够的相似性，以证明未来有必要进行深入研究，以解决衰老过程中肾上腺雄激素调节机制的重要问题。

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.