Transgenic and Other Approaches to Probe the Role of Glucocorticoids in the Anti-Aging Action of Calorie Restriction.
James F. Nelson
Department of Physiology, University of Texas Health Science Center at San Antonio, TX
The best evidence that hormones are involved in mammalian aging is that manipulations in mammals that have broad anti-aging actions are associated with profound changes in hormone levels and actions. Both the calorie-restricted rodent and the dwarf mouse exhibit marked changes in a number of endocrine systems. In the calorie-restricted rodent, these changes occur during adulthood—the time frame of calorie restriction. In the mutant dwarf mouse, the changes occur during adulthood, but may also be present during development. Both models exhibit reduced circulating levels of insulin, IGF-1, growth hormone, triiodothyronine, and prolactin. Calorie-restricted rodents also exhibit marked elevations in the diurnal peak of corticosterone—not yet documented in the dwarf mouse. One important caveat is whether these changes in plasma hormone concentration are reflected in altered hormone action intracellularly. For example, insulin-sensitivity measured by glucoregulation is markedly elevated in calorie-restricted rodents. An even greater caveat is that all data relating hormones to the retarded aging of these models are correlative.
Current research, focused on moving beyond mere correlation to more direct testing of the hypothesized role of glucocorticoids in aging, will be presented. We are using classical endocrine as well as transgenic approaches to manipulate components of the endocrine systems of mice and rats. Emphasis is on the glucocorticoids, because they are elevated in calorie-restricted rodents and are plausible candidates for contributing to the enhanced stress-resistance of this animal model. Results from these studies, as well as other data suggesting the hypothesis that glucocorticoids might be important integrators of the calorie-restricted phenotype, will be presented.
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