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.

Tannenbaum GS, Ling N: The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm and GH secretion. Endocrinology 1984;115:1952–1957.
Mayo KE: Molecular cloning and expression of a pituitary specific receptor for growth hormone-releasing factor. Mol Endocrinol 1992;6:1734–1744.
Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino S: Cloning and functional characterization of a family of human and mouse somatosatin receptors expressed in brain, gastrointestinal tract and kidney. Proc Natl Acad Sci USA 1992;89:251–255.
Frohman LA, Jasson JO: Growth hormone-releasing hormone. Endocr Rev 1986;7:223–253.
Deslauriers N, Gaudreau P, Abribat T, Renier G, Petitclerc D, Brazeau P: Dynamics of growth hormone responsiveness to growth hormone releasing factor in aging rats: peripheral and central influences. Neuroendocrinology 1991;53:439–446.
Sonntag WE, Steger RW, Forman LJ, Meites J: Decreased pulsatile release of growth hormone in old male rats. Endocrinology 1980;107:1875–1879.
Takahashi S, Gottschall PE, Quigley KL, Goya RG, Meites J: Growth hormone secretory pattern in young, middle-aged and old female rats. Neuroendocrinology 1987;46:137–142.
Corpas E, Harman M, Blackman MR: Human growth hormone and human aging. Endocr Rev 1993;14:20–39.
Rudman D: Growth hormone, body composition and aging. J Am Geriatr Soc 1985;33:800–807.
Borst SE, Millard WJ, Lowenthal DT: Growth hormone, exercise and aging: The future of therapy for the frail elderly. J Am Geriatr Soc 1994;42:528–435.
Meites J, Goya RG, Takahashi S: Why the neuroendocrine system is important in aging processes. Exp Gerontol 1987;22:1–15.
Morimoto N, Kawakami F, Makino S, Chibara K, Hasegawa M, Ibata Y: Age-related changes in growth hormone-releasing factor and somatostatin in rat hypothalamus. Neuroendocrinology 1988;47:459–464.
De Gennaro Colonna V, Zoli M, Cocchi D, Maggi A, Marrama P, Agnati F, Müller EE: Reduced growth hormone-releasing factor (GHRF)-like immunoreactivity and GHRF gene expression in the hypothalamus of aged rats. Peptides 1989;10:705–708.
Ge F, Tsagarakis LH, Rees LH, Besser GM, Grossman A: Relationship between growth hormone-releasing hormone and somatostatin in the rat: Effects of age and sex on content and in vitro release from hypothalamic explants. J Endocrinol 1989;123:53–58.
Martinoli MG, Ouellet J, Rhéaume J, Pelletier G: Growth-hormone and somatostatin gene expression in adult and aging rats as measured by quantitative in situ hybridization. Neuroendocrinology 1991;54:607–615.
Sonntag WE, Boyd RL, Boozee RM: Somatostatin gene expression in hypothalamus and cortex of aging male rats. Neurobiol Aging 1990;11:409–416.
Sonntag WE, Gottschall PE, Meites J: Increased secretion of somatostatin 28 from hypothalamic neurones of aged rats in vitro. Brain Res 1986;380:229–234.
Walker RF, Yang SW, Bercu BB: Robust growth hormone secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and growth hormone-releasing factor. Life Sci 1991;49:1499–1504.
Gregerman RI: Mechanisms of age-related alteration of hormone secretions and actions: An overview of 30 years of progress. Exp Gerontology 1986;21:345–365.
Abribat T, Deslauriers N, Brazeau P, Gaudreau P: Alterations of pituitary growth hormone-releasing factor binding sites in aging rats. Endocrinology 1991;128:633–635.
Lefrançois L, Boulanger L, Gaudreau P: Effects of aging on pituitary growth hormone-releasing factor receptor binding sites: In vitro mimicry by guanyl nucleotides and reducing agents. Brain Res 1995;673:39–46.
Spik K, Sonntag WE: Increased pituitary response to somatostatin in aging male rats: Relationship to somatostatin receptor number and affinity. Neuroendocrinology 1988;50:489–494.
Robberecht P, Gillard M, Waelbroeck M, Camus JC, DeNeff P, Christophe J: Decreased stimulation of adenylate cyclase by growth hormone-releasing factor in the anterior pituitary of old rats. Neuroendocrinology 1986;44:429–432.
Parenti M, Cocchi D, Ceresoli G, Marcozzi C, Müller EE: Age-related changes of growth hormone secretory mechanisms in the rat pituitary gland. J Endocrinol 1991;131:251–257.
Schlienger JL, Pradignac A, Grunenberger F: Nutrition of the elderly: a challenge between facts and needs. Hormone Res 1995;43:46–51.
Weindruch R, Walford RL: The Retardation of Aging and Disease by Dietary Restriction. Springfield, Thomas, 1988, pp 7–215.
Poe B, Lynch C, Cooney P, Brunso-Bechtold JK, Sonntag WE, Huntchins PM: Caloric restriction increases cortical microvasculature in aged animals. Abstract program of Society for Neuroscience, Washington, 1996, vol 22, No 492.14.
D’Costa AP, Ingram RL, Lenham JE, Sonntag WE: The regulation and mechanisms of action of growth hormone and insulin-like growth factor 1 during aging. J Reprod Fert 1993;46:87–98.
Lowry DH, Rosebrough NJ, Farr AL, Randall OH: Protein measurement with Folin phenol reagent. J Biol Chem 1951;193:265–275.
Gaudreau P, Boulanger L, Abribat T: Affinity of human growth hormone-releasing factor (1–29)NH2 analogues for GRF binding sites in rat adenopituitary. J Biol Chem 1992;35:1864–1869.
Tam S-P, Lam KSL, Srivastava G: Gene expression of hypothalamic somatostatin, growth hormone-releasing factor, and their pituitary receptors in hypothyroidism. Endocrinology 1996;137:418–424.
Dole VP, Meinertz H: Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem 1960;235:2595–2599.
Munson PJ, Rodbard D: LIGAND: A versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 1980;107:220–239.
Ricketts WG, Birchenall-Sparks MC, Hardwick JP, Richardson A: Effect of age and dietary restriction on protein synthesis by isolated kidney cells. J Cell Physiol 1985;125:492–498.
Ward WF: Enhancement by food restriction of liver protein synthesis in the aging Fisher 344 rat. J Gerontol Biol Sci 1988;43:B50–B53.
Lane MA, Baer DJ, Rumpler WV, Weindruch R, Ingram DK, Tilmont EM, Cutler RG, Roth GS: Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proc Natl Acad Sci USA 1996;93:4159–4164.
Kalu DN, Hardin RH, Coockerham R, Yu BP: Aging and dietary modulation of rat skeleton and parathyroid hormone. Endocrinology 1984;115:1239–1247.
Sonntag WE, Xu X, Ingram RL, D’Costa A: Moderate caloric restriction alters the subcellular distribution of somatostatin mRNA and increases growth hormone pulse amplitude in aged animals. Neuroendocrinology 1995;81:601–608.
Yu BP: How diet influences the aging process of the rat. Proc Soc Exp Biol Med 1994;205:97–104.
Miki N, Ono M, Murata Y, Ohsaki E, Tamitsu K, Ri T, Denmura H, Yamada M: Thyroid hormone regulation of gene expression of the pituitary growth hormone-releasing factor receptor. Biochem Biophys Res Commun 1995;217:1087–1093.
Godfery PA, Mayo K: Structure of the rat GHRH receptor gene and characterization of two receptor isoforms. Abstract program of the 77th Annual Meeting of the Endocrine Society, Washington, 1995, No P3–129.
Quigley K, Goya R, Nachreiner R, Meites J: Effects of underfeeding and refeeding on GH and thyroid secretion in young, middle-aged and old rats. Exp Gerontol 1990;25:447–457.
Renier G, Abribat A, Brazeau P, Deslauriers N, Gaudreau P: Cellular mechanism of caprylic acid-induced growth hormone suppression. Metabolism 1990;39:1108–1112.
Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL: Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 1981;212:1279–1281.
Harel Z, Tannenbaum GS: Synergistic interaction between insulin-like growth factors I and II in cerebral regulation of pulsatile growth hormone secretion. Endocrinology 1992;131:758–764.
Thissen JP, Ketelslegers J-M, Underwood LE: Nutritional regulation of the insulin-like growth factors. Endocr Rev 1994;15:80–101.
D’Costa AP, Lenham JE, Ingram RL, Sonntag WE: Comparison of protein synthesis in brain and peripheral tissue during aging: Relationship to insulin-like growth factor-1 and type 1 IGF receptors. Ann NY Acad Sci 1993;692:253–255.
Horikawa R, Hellmann P, Cella SG, Torsello A, Day RN, Müller EE, Thorner MO: Growth hormone-releasing factor (GRF) regulates the expression of its own receptor. Endocrinology 1996;137:2642–2645.
Mehls O, Tönshoff B, Kovàcs G, Mayer C, Schurek J, Oh J: Interaction between glucocorticoids and growth hormone. Acta Paediatr 1993;388(suppl):76–82.
Seifert H, Perrin M, Rivier J, Vale W: Binding sites for growth hormone-releasing factor on rat anterior pituitary cells. Nature 1985;313:487–489.
Tamaki M, Sato M, Matsubara S, Wada Y, Takahara J: Dexamethaxone increases growth-hormone (GH)-releasing hormone (GRH) receptor mRNA levels in cultured rat anterior pituitary cells. J Neuroendocrinol 1996;8:475–480.
Sabatino F, Masoro EJ, McMahan A, Kuhn RW: Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 1991;46:B171–B179.
Korytko A, Zeitler P, Cuttler L: Developmental regulation of pituitary growth hormone-releasing hormone receptor gene expression in the rat. Endocrinology 1996;137:1326–1331.
Lin C, Lin S-C, Chang C-P, Rosenfeld MG: Pit-1-dependent expression of the receptor for growth hormone-releasing factor mediates pituitary cell growth. Nature 1992;360:375–378.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.