The rate of growth in the first tenth of the life span has a strong influence on the risks of late life disease in a variety of animal models, whether the growth retardation is produced by dietary manipulation (e.g. calorie or methionine restriction) or by genetic changes (such as the Pit-1 mutants or by selective breeding for slow growth rate). This project will attempt to discriminate among several hypotheses that might explain the linkages between slow early life growth rates and increased disease resistance in old age.
Aim 1 will measure lifespan of dw/dw mutant mice treated with growth hormone (GH), thyroid hormone, both, or neither, to determine if the exceptionally long lifespan of these mutants is due to hormonal deficiencies or to some unknown concomitant of small body size per se.
Aim 2 will measure lifespan in another mouse life, the Atchley LS2 stock, which has been selected for diminished weight gain in early life, to see if the exceptional longevity of the LS2 mice is maintained when these mice are subjected to a brief course of GH injections sufficient to restore them to normal size.
Aim 3 will determine whether lifespan of the LS2 mice can be extended still further by constructing a congenic line carrying the dw allele on a background 97% identical to the LS2 stock. Lifespan data on these congenic mice will show whether the dw allele and the genes that lead to LS2 longevity are at least partly complementary.
Aim 4 will test whether a dietary protocol involving low methionine levels, shown previously to extend lifespan in one inbred rat strain, will also promote longevity and disease resistance in a long-lived genetically heterogeneous mouse stock, and show further whether the intervention works when first imposed in mid-adult life.
Aim 5 will determine whether each of these long-lived populations-dw/dw, LS2, and methionine deprivation-is accompanied by a parallel retardation in immune senescence, as an indication of whether the effect is mediated by a deceleration of aging per se. Lastly, Aim 6 will provide measures of key metabolic and hormonal endpoints-leptin, IGF-1, corticosterone-glucose and insulin, body temperature, and fat/lean rations and cause of death-to support or refute a series of mechanistic theories about the way in which retardation of aging, with concomitant delay in late-life illness, is linked to trajectories of weight gain in early life. By sorting among various explanations for the association of small adult body size and disease-free lifespan, the results should set the stage for intervention protocols to develop new ways to prevent the premature onset of late-life illness.
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