Our long-term objectives are to study the effect of aging on the metabolism and actions of gastrointestinal (GI) hormones. The significance of the proposed research is that, we intend to enlarge upon our observations of age-related changes in gut function, as well as in the mechanisms responsible for these changes, that we have documented during the first phase of studies. These changes may be manifest in the metabolic processes of gut hormones, or in the interaction between GI hormones and their target tissues, at the levels of both the ligand-receptor interface and the post- receptor mechanisms. Clarification of the mechanisms that underlie these age-related changes may contribute to better understanding of the aging process. The specific objectives for this project are: 1) To document age-related changes in the mechanisms for stimulation of release of GI hormones, including profiles of molecular heterogeneity of released hormones, peptide-receptor interactions, defects in transmembrane signal- transduction and abnormalities of intracellular mobilization of calcium. We plan to investigate the changes in transcription,post-translational processing (prepro-hormonal forms), and synthesis of GI hormones. 2) To study standard models of injury in order to determine the manner in which age-related changes in gut function may be related to development of disease. We will study models of gastric, duodenal, pancreatic and colon injury for age-related differences. 3) To explore the mechanisms that are responsible for age-related changes in growth responses of the gut and pancreas to trophic agents. We plan to examine the in role of autocrine growth-factors (transforming growth factor [TGF]alpha and beta), polyamine metabolism (including luminal uptake,polyamine content and regulation of enzymes in the polyamine pathway), and protooncogene expression. These studies will address two issues, first, whether there is a breakdown in the normal tight-coupling between cellular proliferation and differentiation in the villus and crypt compartments of the gut, and second, whether these changes predispose to the increased incidence of carcinoma with aging. We will perform similar experiments with the pancreas. 4) To determine whether the prolongation of lifespan achieved by diet-restriction in rodents affects those changes in GI hormone metabolism and mucosal growth of the gut and pancreas that are seen normally with aging. This study will be in collaboration with ongoing studies in San Antonio (Dr. Yu). We anticipate that the studies proposed will allow better understanding of age-related changes in the gut, and we hope that his may lead to improved care for aged patients.
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