A NEUROENDOCRINOLOGICAL APPROACH TO EVIDENCE AN IMPAIRMENT OF CENTRAL CHOLINERGIC FUNCTION IN AGING

A hypothalamic pathogenesis for the reduced GH secretion in aging has been reported for both animal and man. To further address this issue we studied in 31 elderly normal subjects (6 males and 25 females, aged 66-90 yr) and in 22 young healthy controls (13 males and 9 females, aged 20-35 yr) the GH responses to GHRH test (GHRH29, 1 mug/kg iv as a bolus at 0 min) alone and combined with pyridostigmine, a cholinesterase inhibitor (PD, 120 mg po 60 min before GHRH), or with arginine (ARG, 30 g in 100 ml infused from 0 to 30 min). Serum IGF-I levels were lower in elderly than in young subjects (mean+/-SE : 86.9+/-7.2 vs 288.7+/-22.1 mug/L, p<0.01). The GHRH-induced GH increase was lower in elderly than in young subjects (p<0.01). PD increased the GH response to GHRH in both groups (p<0.001), but in elderly subjects this response persisted lower (p<0.0001) than that observed in young adults. Also ARG coadministration potentiated the GHRH-induced GH release in both groups (p<0.0001) but in this case the elderly's responses overlapped with the young's. The GH increase observed after combined administration of ARG and GHRH was higher (p<0.0001) than that elicited by PD plus GHRH in elderly but not in young subjects. Analyzing individual GH responses, a GH peak below the limit of normality for young adults was observed in 19 (61.3%) elderly subjects after PD plus GHRH administration while ARG plus GHRH test elicited a normal GH peak in all but one. Taking into account that the GH-releasing effect of both PD and ARG is likely mediated by inhibition of hypothalamic somatostatin release, our data show that in elderly subjects the acutely releasable GH pool is preserved and give support to the hypothesis that a somatostatin hypertone underlies the reduced GH secretion of aged individuals. PD but not ARG fails to potentiate the GH response to GHRH in about 60% of aged subjects. These findings are suggestive for an impairment of the hypothalamic cholinergic system which, in turn, would be responsible for somatostatin hyperactivity and GH hyposecretion.