Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats

Aging is frequently associated with changes in physiological and cognitive processes. Among these changes is a distinct dysregulation of the hypothalamic-pituitary-adrenal axis. In the current experiments, aspects of hypothalamic-pituitary-adrenal axis function were compared in young (3- to 4-month-old) and aged (21- to 24-month-old) Fisher 344/N male rats. Basal ACTH and corticosterone levels during the circadian trough were elevated in aged compared to young rats. During the evening peak of the circadian cycle, plasma ACTH levels in the young and aged rats were comparable; however, aged rats had significantly lower corticosterone levels than young rats. Stimulus-induced secretion of pituitary-adrenal hormones was attenuated in aged rats. The ACTH response to hemorrhage in the aged group was only 45 +/- 3% of the hemorrhage response in young rats. Pituitary responsiveness to an iv CRF challenge was 58 +/- 6% of that in the young population. These changes were associated with a 38 +/- 5% loss of anterior pituitary CRF receptor number in the aged population. Changes in the hypothalamic regulation of pituitary-adrenal function were also evident in the aged rats. Hypophysial-portal blood concentrations of CRF were significantly greater in aged (56 +/- 6 pM) compared to young rats (37 +/- 4 pM; P < 0.02, by two-tailed unpaired t test; n = 8/group), whereas portal levels of arginine vasopressin were significantly reduced in aged (0.56 +/- 0.01 nM) compared to young rats (0.89 +/- 0.01 nM; P < 0.01, by two-tailed unpaired t test; mean +/- SEM; n = 8/group). Portal CRF responses to hemorrhage were significantly (P < 0.01) greater in aged rats, whereas hemorrhage-stimulated increases in portal AVP levels were significantly (P < 0.01) reduced in the aged group compared to those in the young rats. Finally, regional assay of CRF content demonstrated significant reductions in the median eminence and frontal cortex of aged rats compared to young rats, whereas in situ hybridization analysis failed to reveal age-related differences in paraventricular CRF mRNA levels. Overall, these observations are consonant with the hypothesis that senescence is associated with hypothalamic CRF hypersecretion and a consequent down-regulation of corticotrope CRF receptor.