The broad objective of this renewal application for a Program Grant is to gain further insight into the biochemistry of aging by investigating the integrity of a diverse and select group of regulatory mechanisms. Project 1 concerns the relative contribution by beta cells and by other cell types within the isolated pancreatic islet of Langerhans to the previously reported inability of isolated islets from aged Sprague-Dawley rats to secrete insulin in response to glucose. Availability and/or action of glucagon, somatostatin and other islet secretory products will be examined with respect to the glucose-stimulated secretion of insulin. Project 2 concerns the changing heterogeneity of immunoreactive insulin-like species detected in Sprague-Dawley rats of different ages. Specific molecular species will be characterized with respect to occurrence, insulin-like potency and chemical identification. Project 3 concerns the capacity of cultured fibroblasts from mammalian species of different life spans to activate polycyclic hydrocarbon carcinogens. The regulatory role of mixed-function oxidases, the relationship to general drug-metabolizing activity, and the binding of active metabolites to DNA will be examined in several cellular systems. Project 4 concerns the role of dehydroepiandrosterone (DHEA) in apparently delaying the rate of aging, as well as inhibiting spontaneous breast cancer in female mice. Long term effects of DHEA will be studied with respect to development of autoimmunity and such related processes as the appearance of Coombs positive hemolytic anemia, DNA antibodies, and renal histopathology.