Project Details


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.
Effective start/end date4/1/942/29/00


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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