DIETARY REGULATION OF NUTRIENT ABSORPTION IN AGING

这个应用程序的长期目标是了解如何 大鼠肠道养分吸收及其调控变化 衰老的过程。衰老与肠道吸收不良有关，而且 第一个具体目标是评估年龄对肠道的影响。 并确定营养吸收的机制。 效果。不同单糖、氨基酸和蛋白质的吸收速率 维生素将在成对喂养的老年和年轻成年小鼠之间进行比较。至 确定与年龄相关的吸收变化是否涉及特定的 转运体的数目、刷状边界Na+/D-的位置密度的变化 葡萄糖(SGLT1)和基底外侧促进的D-葡萄糖(GLUT2)转运体 将使用特定的根茎苷和细胞松弛素B结合来估计， 分别进行蛋白质印迹分析。评估年龄对…的影响 编码这些转运蛋白的基因转录、SGLT1和 GLUT2的mRNA将通过Northern印迹分析进行估计。要评估 年龄相关变化对肠细胞增殖的影响， 免疫细胞化学、放射自显影和配体结合技术将 用于检测SGLT1和GLUT2沿隐窝/绒毛的分布 轴心。确定肠道质量的变化是否会改变营养物质 吸收后，将测量粘膜增殖的各种指数。至 确定衰老是否涉及细胞膜的非特异性变化 结构、粘膜通透性或钠离子梯度、脂质成分 、微绒毛结构、被动通透性和Na+吸收 将对肠粘膜进行测定。衰老与以下因素有关 受损的适应性反应，第二个特定目标是评估 年龄对肠道营养素膳食调节的影响 运输。幼年和老年小鼠将被喂食旨在诱导 养分吸收中的适应。营养物质运移速率和 转运蛋白数量、转运蛋白mRNA水平、粘膜的某些指标 将分别监测质量和组织渗透性，以便(1)评估 老年小鼠营养物质转运适应的幅度和速度 饮食的变化，以及(2)了解 监管程序受损。本研究对以下几个方面具有重要意义 理由。首先，它将阐明肠道潜在的机制 老年人的吸收不良，并证明饮食控制是否 可以预防其发病和/或减轻其严重程度。第二，它将增加 我们对小肠调节机制的理解 对饮食控制做出反应。因为饮食限制会延缓 在啮齿动物的衰老过程中，饮食控制正日益成为一种 是研究衰老过程本质的有力工具。第三，它将 证明衰老改变了肠道葡萄糖的速率和位置 吸收，决定餐后血糖的因素 浓度，从而导致与年龄相关的血糖变化 宽容。最后，它将产生一个重要的数据库，供在 人类衰老的营养干预研究进展。

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.