Studies from our laboratory and others have indicated that the adrenal cortex of aging rats accumulates cholesterol esters with diminished cholesterol utilization for steroidogenesis and decreased steroid production. These changes are associated with dramatic morphologic changes in the adrenal cell involving increases in lipofuscin granules and degeneration of mitochondria. The importance of mitochondria and lysosomes in the steroidogenic process points to an association between the observed morphological and functional changes in aging rat adrenal cells. We have demonstrated that primary cultures of adrenocortical cells from young and old rats retain the morphologic and functional characteristics observed in vivo. The young rat predominantly utilizes circulating high density lipoprotein (HDL)-cholesterol as a precursor for steroidogenesis by a lysosome-independent process. However, the presence of LDL receptors in rat adrenal cells and the ability of rat adrenal glands to utilize LDL-cholesterol for steroidogenesis suggests that these cells can serve as a model for studying mechanisms of cellular aging in humans and other species.
The aims of the proposed research are to understand how aging affects cholesterol processing and steroidogenic function in the adrenal cortex of the laboratory rat, and to elucidate an association between lipofuscin accumulation and lysosomal processing of cholesterol in aging adrenal cells. Initially, young and aging rats will be studied in vivo to determine: 1. plasma lipoprotein composition; 2. adrenal lipid content and metabolism; 3. adrenal lipid peroxidation activity; 4. adrenal steroidogenic function and mitochondrial enzyme levels. Primary cultures of young and old rat adrenal cells will be used to evaluate: 1. mitochondrial steroidogenic enzyme turnover and steroidogenic responsiveness to ACTH, cAMP and other agonists; 2. the effects of aging on HDL and LDL pathways of cholesterol uptake and metabolism to cholesterol esters and steroid; 3. possible enzyme sites of altered activity; 4. the intracellular uptake of cholesterol by lipofuscin granules, and the effects of ACTH and steroids on lipofuscin accumulation. The feasibility of using 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an agent which induces lipofuscin accumulation, as a model for studying aging will also be determined. The aging adrenal gland can provide a system for obtaining a more generalized understanding of how lipid oxidation may affect physiologic function in aging cells.
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