The general objective of this application is to test the hypothesis that tissue protein synthesis and the endocrine and paracrine factors that regulate tissue protein synthesis are potential biomarkers of mammalian aging. The particular focus of these experiments will be an integrated study of growth hormone secretory dynamics, plasma IGF-1, tissue IGF-1 and IGF-1 receptors, and protein synthesis (using tissue, age, strain, species, sex, and dietary condition as independent variables). Our working hypothesis, for which there is now substantial data, is that a) decreases in the amplitude of growth hormone pulses in ad libitum fed animals result in a decrement in IGF-1 levels and a decline in tissue protein synthesis and function, b) moderate dietary restriction acts to prolong lifespan by increasing the amplitude of growth hormone pulses and increasing paracrine activity of tissue IGF-1 or the levels of type 1 IGF receptors within specific tissues thereby contributing to increased protein synthesis and tissue function, and c) age-related decreases in the amplitude of growth hormone pulses and tissue IGF-1 mRNA concentrations are part of the mechanism(s) for the decrease in protein synthesis with age, are correlated with lifespan, and can be used to measure biological aging. The studies described in this proposal will test these hypotheses by: 1) Assessing the age-related decrease in protein synthesis in heart, kidney, liver, skeletal muscle, and brain in 3 strains of rats and 4 strains of mice at 8 month intervals throughout the lifespan of ad libitum or dietary restricted animals; Analyzing tissue protein synthesis after returning dietary restricted animals to an ad libitum fed feeding regimen to determine whether the age-related decline in the rate of protein synthesis has been altered by dietary restriction, 2) Analyzing paracrine regulation of protein synthesis by measuring tissue IGF-1 and type 1 IGF receptor mRNA in liver, kidney, brain, heart and skeletal muscle. Levels of growth hormone receptor mRNA will be examined as well as plasma levels of IGF-1 to test the hypothesis that growth hormone regulates tissue IGF-1 levels and/or type 1 IGF receptors, 3) Assessing endocrine regulation of protein synthesis by measuring age-related changes in the amplitude of growth hormone pulses in 3 strains of ad libitum fed and dietary restricted rats and pituitary growth hormone concentrations and mRNA levels in mice. Results will be correlated with plasma IGF-1 levels, tissue IGF-1 and type 1 IGF receptor mRNA concentrations, and relative rates of protein synthesis. Additional studies will assess these measures after returning dietary restricted animals to the ad libitum feeding regimen. The integrated and comprehensive approach of this application should provide data of high reliability and validity on the usefulness of these measures as an indicator of biological aging. The results of this research will be critical in understanding the relationships between growth hormone/IGF-1 and aging and testing the hypothesis that a decline in factors regulating tissue protein synthesis can be used as a non-invasive biomarker of aging.
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