Aging, characterized by changes in body composition and a parallel decline of somatotropic function, is due to a decrease in growth hormone (GH) release, which is regulated by a dual mechanism involving growth hormone-releasing hormone (GHRH) for stimulation and somatostatin (SS) for inhibition. The objective of this proposal is to investigate the hypothesis that the decline of somatotropic function with aging is due to a decrease in GHRH, and that administration of GHRH is effective in ameliorating the decreased physical function associated with again in primates. The rhesus monkey will be used as a model for aging in humans, since characteristics of the aging process are very similar. In the first Aim, we will determine the release pattern of GH, GHRH, and SS in the stalk-median eminence (S-ME) of the aged and young female monkeys using a push-pull perfusion method, and will test the hypothesis that GHRH release decreases with aging in the rhesus monkey. Since no data from the direct measurement of GHRH and SS in the S-ME in primates are available, it is essential to examine how GHRH release and SS release correlate with GH release in aged and young non-human primates. In the second Aim, we will investigate the hypothesis that an increase in relative inhibitory tone of SS results in a decrease in GHRH release in aging. This will be accomplished by disrupting SS synthesis using an antisense oligodeoxynucleotide for SS messenger RNA (mRNA), while measuring GHRH release in the S-ME in vivo. In the third Aim, we will determine whether changes in GHRH release during aging are due to the alteration of GHRH neurons themselves or due to changes in the regulatory input to GHRH neurons, such as altered input from catecholamine neurons. The age-related changes in releasability of GHRH neurons will be tested with electrical stimulation, and release of GHRH, norepinephrine and dopamine in the S-ME will be compared in the two age groups. We will also examine the changes in the gene expression of GHRH neurons during aging. Collectively, the proposed studies will increase current knowledge on aging of the neuroendocrine hypothalamus, and will provide useful information for treatments to repair the physical decline in aged humans.
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