Dehydroepiandrosterone (DHEA) and its sulfoconjugate DHEAS, represent important biomarkers for the aging process in humans. Both steroids undergo dramatic decreases in secretion in association with aging such that by the 7th decade of life the levels drop to 20 percent of those seen in young adulthood. Not only does the decrease in DHEA act as a biomarker for aging, there is considerable evidence that this steroid may indeed hinder progression of a variety of diseases associated with aging. Therefore an understanding of the mechanisms that control DHEA synthesis and cause the loss of synthesis seen in aging is of paramount importance. To date the adrenocortical alterations which occur in the reticularis zone of the aging adrenal have not been documented. Our laboratory has recently demonstrated that the adrenal reticularis undergoes specific alterations in the expression of the enzyme 3 beta- hydroxysteriod dehydrogenase (3 betaHSD) at the time of adrenarche which occurs prior to puberty. These data support our hypothesis that defining the mechanisms which inhibit expression 3betaHSD in the adrenal reticularis are key to defining the regulation of DHEA synthesis. Herein, we propose to determine if, as seen in adrenarche, that aging of the adrenal and the loss of DHEA synthesis is associated with changes in the expression of steroid-metabolizing enzymes. Specifically, we will utilize adrenal glands collected at autopsy to examine the expression of cholesterol side-chain cleavage (CYP11A) and 17 alpha- hydrolase (CYP17), the enzymes needed for DHEA synthesis, as well as 3betaHSD. The proposed studies will provide much needed information on the effects of aging on the enzymes involved in DHEA biosynthesis. In addition, we will develop viral reporter constructs which will allow us to proceed with screening for the factors that differentially regulate the transcription of the genes involved in promoting adrenal DHEA synthesis. Using a human adrenal cell line developed in our laboratory these viral constructs will be used to gather preliminary information for the submission of an R0-1 application directed at defining the factors regulating DHEA synthesis and what role they play in aging.
| Suzuki, T; Sasano, H; Takeyama, J et al. (2000) Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf) 53:739-47 |
