The activity of hormone-sensitive adenylate cyclases of rat liver is age-dependent. Catecholamine- and glucagon-stimulated adenylate cyclase activities increase during post-maturational aging. This proposal has two specific aims: I. to examine the biochemical alterations, or mechanisms, underlying the age-related changes of rat liver adenylate cyclase activities, and II. to define whether these biochemical determinants of enzyme activity play a physiological role in the regulation of cyclic AMP-mediated glycogen mobilization during aging. In vitro studies addressing the first specific aim will examine age-related changes of individual components of the adenylate cyclase enzyme complex, including hormone receptors, guanine nucleotide regulatory components, and catalytic component. Other plasma membrane-bound enzymes (ATPases, 5'-nucleotidase) as well as plasma membrane lipid composition and fluidity will also be studied during the post-maturational life span to determine if aging changes of adenylate cyclases reflect alterations of the plasma membrane. To address the second specific aim, in vitro studies will examine whether age-related alterations of catecholamine- and glucagon-sensitive adenylate cyclases of rat liver are associated with altered control of glycogenolysis by these agents. Furthermore, since changes of liver adenylate cyclase activities occurring during early development of the rat do appear to regulate glycogenolysis, the mechanisms underlying these developmental changes of enzyme activity will also be investigated to determine if related molecular events regulate cyclic AMP-mediated glycogenolysis throughout the life span. The studies of this proposal should provide important insights into 1) age-related alteration of hormone action at the plasma membrane and 2) hormonal regulation of physiological changes of glucose metabolism occurring during aging.
