Girard N, Ferland G, Boulanger L, Gaudreau P
Neuroendocrinology Laboratory, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada.
Neuroendocrinology. 1998 Jul;68(1):21-9. doi: 10.1159/000054346.
In mammals, middle age and late adulthood is characterized by a decrease of growth hormone (GH) secretion and insulin-like growth factor 1 (IGF-1) serum levels, contributing to tissue and organ atrophy. This condition is related, at least in part, to alterations of pituitary GH-releasing hormone (GHRH) receptor-binding sites. Prevention of age-related deterioration of tissues and organs, retardation of the onset or progression of a wide range of age-related diseases and extension of both mean and maximum life span can be achieved through life-long moderate calorie restriction (CR). Because CR has been reported to positively modulate the somatotropic axis resulting in the maintenance of a youthful GH secretory pattern in aged rats, we investigated whether or not benefits of a long-term (10 months) 40% CR, started in 8-month-old male Sprague-Dawley rats, was accomplished by preventing age-related alterations of pituitary GHRH receptor binding sites. We also studied whether or not a short-term (50 days) 40% CR, started in 16-month-old rats, could revert them. Potential hormonal and metabolic modulators of the GHRH receptors were investigated as well. GHRH binding parameters were derived from saturation studies performed in pituitary homogenates with [125I-Tyr10]hGHRH (1-44)NH2. As previously reported, the high affinity GHRH receptor-binding sites were blunted in 18-month-old ad libitum-fed rats and the apparent concentration of total binding sites was reduced. Short-term CR neither restored high affinity GHRH binding sites nor increased the apparent concentration of total binding sites. On the contrary, long-term calorie-restricted 18-month-old rats exhibited high and low affinity GHRH binding sites (Kd1: 1.73 +/- 0.35 nM; Kd2: 310 +/- 41 nM; Bmax1: 183 +/- 55 fmol/mg protein; Bmax2: 30 +/- 3 pmol/mg protein) as found in 2-month-old rats (Kd1: 0.68 +/- 0.15 nM; Kd2: 350 +/- 47 nM; Bmax1: 219 +/- 53 fmol/mg protein; Bmax2: 84 +/- 9 pmol/mg protein). Our results imply that CR must be implemented before age-related alterations of GHRH receptor-binding sites become too severe or that CR has to be carried out for a long period of time, independently from the age at which it begins. Protection of pituitary GHRH binding sites from age-related alterations could not be attributed to changes in circulating levels of total or free T4 or free fatty acids. Finally, the anti-aging effect of a long-term CR observed at the level of pituitary GHRH receptors does not result in a significant increase of total IGF-1 circulating levels. Identification of molecular and cellular mechanisms responsible for these actions will deserve attention in order to identify centrally and/or peripherally active classes of molecules that could preserve, in aging mammals, the functionality of the somatotropic axis through selective regulation of pituitary GHRH receptors.
在哺乳动物中，中年和成年后期的特征是生长激素（GH）分泌减少以及胰岛素样生长因子1（IGF-1）血清水平降低，这会导致组织和器官萎缩。这种情况至少部分与垂体生长激素释放激素（GHRH）受体结合位点的改变有关。通过终生适度热量限制（CR），可以预防与年龄相关的组织和器官退化，延缓多种与年龄相关疾病的发病或进展，并延长平均寿命和最大寿命。由于据报道CR能正向调节生长激素轴，从而在老年大鼠中维持年轻的GH分泌模式，我们研究了从8月龄雄性Sprague-Dawley大鼠开始的长期（10个月）40%热量限制是否通过预防垂体GHRH受体结合位点的年龄相关改变而实现。我们还研究了从16月龄大鼠开始的短期（50天）40%热量限制是否能使其恢复。同时也研究了GHRH受体潜在的激素和代谢调节因子。GHRH结合参数来自于用[125I-Tyr10]hGHRH（1-44）NH2在垂体匀浆中进行的饱和研究。如先前报道，18月龄自由摄食大鼠中高亲和力GHRH受体结合位点减弱，总结合位点的表观浓度降低。短期热量限制既未恢复高亲和力GHRH结合位点，也未增加总结合位点的表观浓度。相反，长期热量限制的18月龄大鼠表现出与2月龄大鼠（Kd1：0.68±0.15 nM；Kd2：350±47 nM；Bmax1：219±53 fmol/mg蛋白；Bmax2：84±9 pmol/mg蛋白）中相似的高亲和力和低亲和力GHRH结合位点（Kd1：1.73±0.35 nM；Kd2：310±41 nM；Bmax1：183±55 fmol/mg蛋白；Bmax2：30±3 pmol/mg蛋白）。我们的结果表明，必须在GHRH受体结合位点的年龄相关改变变得过于严重之前实施热量限制，或者热量限制必须长期进行，与开始的年龄无关。垂体GHRH结合位点免受年龄相关改变的保护不能归因于总T4或游离T4或游离脂肪酸循环水平上的变化。最后，在垂体GHRH受体水平观察到的长期热量限制抗衰老作用并未导致循环中总IGF-1水平显著升高。为了确定在衰老哺乳动物中通过选择性调节垂体GHRH受体来维持生长激素轴功能的中枢和/或外周活性分子类别，负责这些作用的分子和细胞机制的鉴定将值得关注。
