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The primary objective of this application is to determine the causes for the age-related reduction in amplitude of growth hormone pulses. Our working hypothesis is that increased sensitivity of the hypothalamus of aging rats to the negative feedback effects of growth hormone and/or somatomedin-C results in diminished amplitude of growth hormone pulses. We proposes that these changes are manifest by increased release of, or alterations in the molecular processing of, somatostatin by hypothalamic neurons of aged animals, and in vitro responsiveness of young and old pituitaries to hpGRF(1-44) indirectly support this hypothesis. This hypothesis will be tested directly by 1) stimulating the release of somatostatin from superfused hypothalamic fragments of young, middle-aged, and old male rats in response to growth hormone, somatomedin-C, and 55 mM K+, and 2) fractionating the samples to determine absolute and relative concentrations of somatostatin-14 and -28 by RIA using affinity purified antibodies developed in our laboratory. Alternative hypotheses for the decline in growth hormone pulse amplitude have been developed which will also be evaluated. These include 1) assessing age-related changes in the autocrine/paracrine effects of intraventricularly administered somatostatin-14 or -28 in vivo and in vitro, 2) assessing age-related alterations in the mechanism of hypothalamic hormone action on pituitary somototrophs by testing the ability of somatostatin-14 and -28 to inhibit and rhGRF to increase growth hormone release in vivo and in vitro, 3) comparing the ability of young and old rats to synthesize growth hormone in vitro (incorporation of 3H-leucine into growth hormone, separation by polyacrylamide gel electrophoresis, and analysis of growth hormone and free leucine specific activity), 4) determining the biological activity of growth hormone in young and old animals using the calssical tibial bioassay.

These results have potential clinical relevance since the decline in growth hormone pulse amplitude with age may be resoponsible for the reduced capacity of both animals and man to synthesize protein and may be responsible for the decline in function of many tissues and organs.
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