Cizza G, Calogero A E, Brady L S, Bagdy G, Bergamini E, Blackman M R, Chrousos G P, Gold P W
Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892.
Endocrinology. 1994 Apr;134(4):1611-20. doi: 10.1210/endo.134.4.8137722.
We investigated the effects of aging on the regulation of hypothalamic-pituitary-adrenal function and hippocampal steroid receptors in a series of in vivo and in vitro studies conducted in healthy intact 2-, 8-, 18-, and 24-month-old male Fischer 344/N rats. Basal plasma ACTH levels were similar among age groups, and basal plasma corticosterone levels showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. In contrast, the i.v. injection of a muscarinic agonist, arecoline, elicited similar ACTH and corticosterone responses in all age groups. An i.v. injection of ACTH-(1-24) evoked lower corticosterone responses in the older (18- and 24-month-old) than in the younger (2- and 8-month-old) groups of rats, consistent with an impairment of hypothalamic-pituitary-adrenal axis function in older animals. Steady state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational, rather than senescent, changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, CRF content, and in vitro secretion by whole explanted hypothalami were progressively and significantly reduced with age, whereas the steady state levels of arginine vasopressin mRNA were significantly increased with age. Steady state levels of POMC mRNA were decreased, and ACTH content and in vitro secretion by corticotrophs were increased with age in the anterior pituitary. We conclude that male Fischer 344/N rats show a progressive hypothalamic CRH deficiency with advancing age, which appears to be associated with elevated production of arginine vasopressin in the hypothalamus.
我们在一系列针对健康、未阉割的2月龄、8月龄、18月龄和24月龄雄性Fischer 344/N大鼠进行的体内和体外研究中，探究了衰老对下丘脑 - 垂体 - 肾上腺功能调节及海马体类固醇受体的影响。各年龄组的基础血浆促肾上腺皮质激素（ACTH）水平相似，但基础血浆皮质酮水平呈现出与衰老相关的显著下降。静脉注射两剂（2和20微克/千克体重）大鼠促肾上腺皮质激素释放因子（CRF）后，老年大鼠的ACTH反应显著增强且延迟，皮质酮反应也更强，这与下丘脑CRF缺乏时的情况一致。相比之下，静脉注射毒蕈碱激动剂槟榔碱后，所有年龄组的ACTH和皮质酮反应相似。静脉注射促肾上腺皮质激素（1 - 24）后老年（18月龄和24月龄）大鼠的皮质酮反应低于年轻（2月龄和8月龄）大鼠组，这与老年动物下丘脑 - 垂体 - 肾上腺轴功能受损一致。8月龄、18月龄和24月龄大鼠海马体中盐皮质激素和糖皮质激素受体的稳态mRNA水平显著降低，这与成熟而非衰老变化相符。下丘脑室旁核中的CRF mRNA水平、CRF含量以及整个离体下丘脑的体外分泌量均随年龄增长而逐渐显著降低，而精氨酸加压素mRNA的稳态水平则随年龄显著升高。垂体前叶中阿黑皮素原（POMC）mRNA的稳态水平降低，促肾上腺皮质激素细胞的ACTH含量和体外分泌量随年龄增加。我们得出结论，雄性Fischer 344/N大鼠随着年龄增长呈现出渐进性的下丘脑促肾上腺皮质激素释放激素（CRH）缺乏，这似乎与下丘脑中精氨酸加压素的产生增加有关。
