Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Abstract

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P Ͻ 0.01 and P Ͻ 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P Ͻ 0.001) and SS mRNA (P Ͻ 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P Ͻ 0.01 and P Ͻ 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment. growth hormone; ghrelin; growth hormone-releasing peptide-6; growth hormone secretagogue; aging; growth hormone decline GROWTH HORMONE (GH) secretion in humans and rats declines progressively with aging (17, 41) and results in lower serum insulin-like growth factor-I (IGF-I) levels.Early studies in elderly humans showed an age-associated attenuation of GH pulse amplitude and GH secretion in response to several stimuli, including insulin-induced hypoglycemia and arginine administration (32,43). Subsequent studies revealed a decrease in plasma IGF-I parallel to the decline in GH pulses (51). The studies in humans have been confirmed in experimental animals, and it is now evident that the decline in high-amplitude pulsatile GH release and plasma IGF-I concentrations is one of the best characterized events that occur with aging in humans and rats (61). Thus the aging rat is a model of relative or partial GH deficiency and consequently is suitable for studying the mechanisms of this alteration.GH has a broad range of actions and therefore its diminished secretion rate has clinical significance and may be responsible for the generalized catabolic state, functional alterations, cognitive impairment, and decreased neuroprotection associated with normal aging. In elderly adults, with or without GH defect, GH increases IGF-I, the lean-to-fat ratio, muscle strength, and skin thickness and reduces total body fat cont...

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