ACTH SENSITIVITY/RESPONSIVITY IN AGING

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Aging in humans is associated with a striking deficiency in adrenal production of dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulfate (DS). Reductions in DHA and DS have been correlated with increased incidence of many sequelae of aging such as cardiovascular disease, cancer, insulin resistance, hyperlipidemia and impaired immune competence. The mechanism(s) responsible for reduced adrenal production of DHA and DS is unknown and the impact of aging on adrenal production of other androgens is not clearly defined. It also is unclear whether adrenal function in men and women is similarly affected with aging. Based on the results of prior studies, several enzymatic activities in the adrenal may be altered during aging: 17-hydroxylase, 17, 20-lyase, 3'-hydroxysteroid dehydrogenase, and steroid sulfotransferase. We propose to determine the impact of aging on each of the above elements of the adrenal steroid biosynthetic pathway by means of functional testing of adrenal responses to graded doses of ACTH in young and aged men and women. We also propose to quantify the amount of cytochrome P450-176, 3'hydroxysteroid dehydrogenase, and steroid sulfotransferase and their mRNA's in adrenal specimens obtained at autopsy of young and aged men and women. By use of the proposed approaches, we expect to be able to characterize the changes due to aging in men and women, to determine whether changes are due to alterations in enzyme levels within particular adrenal zones, and to establish whether such changes are likely to be due to altered gene transcription. The results of these studies should provide a sound basis for further studies directed toward prevention or amelioration of the effects of aging on the human adrenal.