DIETARY REGULATION OF NUTRIENT ABSORPTION IN AGING

衰老过程中营养吸收的饮食调节

基本信息

批准号：
2667621
负责人：
RONALDO PARAOAN FERRARIS
金额：
$ 10.36万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-04-01 至 2000-02-29
项目状态：
已结题

项目摘要

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.

该应用程序的长期目标是了解如何肠道营养吸收及其调节在此期间的变化衰老过程。衰老与肠道吸收不良有关，并且第一个具体目的是评估年龄对肠道的影响营养吸收并确定这些机制效果。各种单糖，氨基酸和将比较成对的老年小鼠和年轻小鼠之间的维生素。到确定吸收年龄相关的变化是否涉及特定转运蛋白数量的变化，刷子Na+/d-的位点密度葡萄糖（SGLT1）和基底外侧促进的D-葡萄糖（GLUT2）转运蛋白将使用特定的菲洛依蛋白和细胞切拉蛋白B结合来估计分别和Western印迹分析。评估年龄对编码这些转运蛋白的基因的转录，SGLT1和 GLUT2 mRNA将通过Northern印迹分析估算。评估与年龄相关的肠细胞增殖变化的影响，免疫细胞化学，放射自显影和配体结合技术将是用于检查沿着地下/绒毛的SGLT1和GLUT2的分布轴。确定肠道质量的变化是否改变了营养吸收，将测量各种粘膜增殖指标。到确定衰老是否涉及膜的非特异性变化结构，粘膜渗透性或Na +梯度，脂质组成，由，被动渗透性的微绒毛结构和Na +的摄取。将确定肠粘膜。衰老与自适应反应受损，第二个特定目的是评估年龄对肠道营养饮食调节的影响运输。年轻小鼠和老年小鼠将被喂养旨在引起的饮食营养吸收的适应性。营养运输率的变化和转运蛋白数量的某些指标，转运蛋白mRNA的水平，粘膜为了（1）评估，将监测质量和组织渗透率老年小鼠养分转运的适应幅度和速度饮食转移，（2）了解补偿机制监管过程受损。这项研究对于以下非常重要原因。首先，它将阐明肠道基础的机制老年人的吸收不良，并证明是否饮食操纵可以防止其发作和/或减少其严重性。其次，它将增加我们对小肠中的监管机制如何理解应对饮食操纵。因为饮食限制降低了啮齿动物的衰老过程，饮食的操纵越来越多地成为研究衰老过程的性质的强大工具。第三，它将证明衰老会改变肠葡萄糖的速率和部位吸收，确定餐后血糖的因素浓度，从而导致与年龄相关的葡萄糖变化宽容。最后，它将产生重要的数据库发展人类衰老中的营养干预措施。