DIETARY REGULATION OF NUTRIENT ABSORPTION IN AGING

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The long-term objective of this application is to understand how intestinal nutrient absorption and its regulation change during the process of aging. Aging is associated with intestinal malabsorption, and the first specific aim is to assess the effects of age on intestinal nutrient absorption and to determine the mechanisms underlying these effects. The absorption rates of various monosaccharides, amino acids and vitamins will be compared between pair-fed aged and young adult mice. To determine whether age-related changes in absorption involve a specific change in number of transporters, the site density of brushborder Na+/D- glucose (SGLT1) and basolateral facilitated D-glucose (GLUT2) transporters will be estimated using specific phlorizin and cytochalasin B binding, respectively, and Western blot analysis. To assess the influence of age on transcription of genes coding for these transporters, levels of SGLT1 and GLUT2 mRNA will be estimated by Northern blot analysis. To evaluate the effects of age-related changes in enterocyte proliferation, immunocytochemistry, autoradiography and ligand-binding techniques will be used to examine the distribution of SGLT1 and GLUT2 along the crypt/villus axis. To determine whether a change in intestinal mass alters nutrient absorption, various indices of mucosal proliferation will be measured. To ascertain whether aging involves a nonspecific change in membrane structure, mucosal permeability or Na + gradient, the lipid composition of, microvilli structure of, passive Permeability of and Na + uptake by the intestinal mucosa will be determined. Aging is associated with impaired adaptive responses, and the second specific aim is to evaluate the effect of age on the dietary regulation of intestinal nutrient transport. Young and aged mice will be fed diets designed to elicit adaptation in nutrient absorption. Changes in nutrient transport rates and certain indices of transporter number, levels of transporter mRNA, mucosal mass and tissue permeability will each be monitored in order to (1) assess the amplitude and pace of adaptation of nutrient transport in aged mice to shifts in diet, and (2) understand the mechanisms for compensation of impaired regulatory processes. This study is significant for the following reasons. First, it will elucidate the mechanisms underlying intestinal malabsorption in the aged, and demonstrate whether dietary manipulations can prevent its onset and/or reduce its severity. Second, it will increase our understanding of how regulatory mechanisms in the small intestine respond to dietary manipulations. Because dietary restriction retards the aging process in rodents, dietary manipulation is increasingly becoming a powerful tool for studying the nature of the aging process. Third, it will demonstrate that aging alters the rate and site of intestinal glucose absorption, factors which determine post-prandial plasma glucose concentrations, thereby contributing to age-related changes in glucose tolerance. Finally, it will yield an important data base for use during development of nutritional interventions in human aging.