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A number of studies clearly suggest that a general decline in signal transduction and, specifically, a decline in growth hormone signal transduction, are critical aspects of biological aging but the specific etiology of these changes are unknown. Preliminary data from this laboratory and others suggest that pro-inflammatory cytokines e.g. tumor necrosis factor alpha (TNFa), actively suppress both signal transduction and growth hormone secretory dynamics. Enhanced secretion of TNFa has been detected in abdominal adipose tissue of older animals and moderate caloric restriction, which decreases adipose tissue mass and potentially decreases plasma TNFa, restores both the decrease in growth hormone secretion and tissue response to growth hormone. These studies as well as results from other laboratories raise the possibility that secretion of TNFa from adipose tissue has a critical role in regulating the growth hormone/IGF-1 axis at multiple sites and therefore has an important role in biological aging. The Specific Aims proposed in this application address the hypothesis: TNFa, a pro-inflammatory cytokine secreted by abdominal adipose tissue, is responsible, in part, for the decrease in growth hormone signal transduction and growth hormone secretory dynamics with age. This application is designed to: 1) Determine whether TNFa suppresses growth hormone signal transduction and if hepatic response to TNFa increases with age. Studies will investigate whether: a) TNFa inhibits growth hormone signal transduction in young animals, b) deficiencies in signal transduction induced by TNFa are comparable to those observed in aged animals, c) hepatic response to TNFa increases with age, and d) passive immunization with TNFa antiserum restores growth hormone signal transduction; 2) Assess the sources (subcutaneous versus abdominal), regulation and expression of TNFa from adipose tissue. Experiments will detail: a) age-related changes in basal and LPS stimulate TNFa expression, b) effects of short-term caloric restriction on the regulation of TNFa levels, and c) the regulation of TNFa levels by growth hormone; 3) Establish whether TNFa regulates growth hormone pulse amplitude. Studies will investigate whether administration of TNFa suppresses growth hormone secretory dynamics in young animals and whether inhibition of TNFa levels in old animals restores growth hormone secretory dynamics. Results from these studies will be the first to specifically detail the potential mechanisms responsible for the decline in growth hormone secretory dynamics and signal transduction with age. If successful, the results of these studies will have important implications for the decline in signal transduction and tissue function in general and provide important insight into the etiology of aging and age-related diseases.
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