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-month) and old (24-month). Hypothalamic growth hormone releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P<0.01 and P<0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS) (P<0.001) and SS mRNA (P<0.01), and median eminence IR-SS were found in old rats as were GH secretagogue receptor (GHS-R) and IGF-I mRNA (P<0.01 and P<0.05). Hypothalamic IGF-I receptor (IGF-I-R) mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or co-cultured 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, GHRP-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.