GRANT=6446813;P01AG Biological aging is a process of progressive loss of function with time leads to a decreased capacity of the organism to maintain homeostasis in the face of stress initially and under baseline condition subsequently. The aging process results from multiple changes, which have both a genetic and environmental basis resulting in a reduction in the number and/or functional reserve capacity of various types of differentiated cells. This is clearly exemplified by the endocrine organs and their regulatory centers. Thus, the aging phenotype resembles various states of hormone deficiency or excess. A major and significant example is the hypothalamus-pituitary-liver axis. Aging is characterized by loss fo lean body mass, especially muscle, increased percentage of body fat, more centripetal distribution of body fat, and reduce rates of protein synthesis and tissue healing. This is due in part, to a decline in growth hormone (GH) and growth hormone releasing factors (GHRH). This proposal will shown that the restoration of low GH levels with GHRH not only prevents further decline in these processes, but they are, in fact, improved or corrected. Furthermore, this proposal will establish that GH can be restored endogenously through the GHRH pathway, which preserves feedback regulation as well as maintaining a physiological pulsatile pattern of GH release.
The specific aims are to demonstrate that in GH-deficient volunteers greater than or equal too 65 years (1) GHRH induced rise in endogenous GH is accompanied by a reduction in total percentage of body fat as well as a significant reduction in visceral fat, (2) an increase in lean body mass will occur both in bone mineral density and muscle tissue. The latter is initially due to increased protein synthesis until a new baseline has been achieved. Increase in lean body mass will offset the well known antagonisms of GH on insulin action, (3) GH replacement therapy is more efficacious in restoration of body habitus and its sequela in males than in females due to a greater preponderance of visceral fat in females. The restoration of endogenously secreted GH will be achieved by twice daily administration of GHRH. Determinations of body composition will be assessed by DXA and CT scans. Metabolic profiles will be evaluated with the glucose clamp technique coupled to tracer methodology. GHRH induced increase in GH replacement in the elderly in hypothesized to become as routine a therapy as thyroid replacement therapy in hypothyroidism.
