Loss of physiological adaptability is one of the hallmarks of old age. As neuroendocrine and circadian systems are intimately involved with adaptation, the declining functional integrity of these systems with increasing age may play an important role in the development of physical frailty, disrupted sleep pattern, a shift from balanced anabolism/catabolism toward a catabolic state and a decreased circadian amplitude of core body temperature (BT(c)). Evidence can be marshalled that attenuation of the GH-IGF-I axis (growth hormone-insulin-like growth factor-1) and nocturnal melatonin secretion in aging men and women contribute to these changes. GH and its peripheral tissue mediator, IGF-I, are important promoters of increased bone and muscle mass and reduced body fat. Nocturnal melatonin levels are inversely coupled with the nadir of BT(c) and melatonin appears to be responsible for 40% of BT(c) decline at night. Both melatonin and BT(c) are robust circadian markers and are physiologically important as they monitor the environmental cue (melatonin) and internal cue (BT(c)). Thus, melatonin may function to augment circadian stability. In the present proposal, experiments have been designed to test the hypothesis that in aging men and women activation of the GH-IGF-I axis by nightly administration (sc) of GHRH will induce anabolism and that melatonin administration will improve the circadian amplitude of BT(c), the quality of sleep and well-being and possibly augment nocturnal GH secretion. Finally, the potential of a synergistic effect of melatonin and GHRH on the above variables will be determined. The proposed studies consist of two phases with the overall aim being the restoration of the relative deficient GH-IGF-I axis and melatonin rhythm. Phase 1 will be conducted in a double-blind placebo-controlled randomized factorial design with 30 subjects in each of the 4 cells (melatonin, GHRH, GHRH + melatonin, placebo) and with equal numbers of men and women to discern gender differences; phase II constitutes an open trial of the most effective agent(s) derived from phase I studies to determine the long-term (1 year) benefits and to insure safety sufficient for clinical application in the aging population.
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