A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth.

1.
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD: Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011;3:70ra13.
2.
McCay CM, Crowell MF, Maynard LA: The effect of retarded growth upon the length of the life span and upon the ultimate body size. J Nutrition 1935;10.
3.
Bartke A, Coschigano K, Kopchick J, Chandrashekar V, Mattison J, Kinney B, Hauck S: Genes that prolong life: relationships of growth hormone and growth to aging and life span. J Gerontol A Biol Sci Med Sci 2001;56:B340–349.
4.
Samaras TT, Elrick H, Storms LH: Height, health and growth hormone. Acta Paediatr 1999;88:602–609.
5.
Silberberg R: Articular aging and osteoarthrosis in dwarf mice. Pathol Microbiol (Basel) 1972;38:417–430.
6.
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A: Dwarf mice and the ageing process. Nature 1996;384:33.
7.
Tatar M, Bartke A, Antebi A: The endocrine regulation of aging by insulin-like signals. Science 2003;299:1346–1351.
8.
Kenyon CJ: The genetics of ageing. Nature 2010;464:504–512.
9.
Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G: daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997;277:942–946.
10.
Tissenbaum H, Ruvkun G: An insulin-like signaling pathway affect both longevity and reproduction in Caenorhabditis elegans. Genetics 1998;148:703–717.
11.
Longo VD, Finch CE: Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 2003;299:1342–1346.
12.
Russell SJ, Kahn CR: Endocrine regulation of ageing. Nat Rev Mol Cell Biol 2007;8:681–691.
13.
Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ: Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 2003;144:3799–3810.
14.
Bartke A, Peluso MR, Moretz N, Wright C, Bonkowski M, Winters TA, Shanahan MF, Kopchick JJ, Banz WJ: Effects of soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice. Horm Metab Res 2004;36:550–558.
15.
Bonkowski MS, Rocha JS, Masternak MM, Al-Regaiey KA, Bartke A: Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 2006;103:7901–7905.
16.
Flurkey K, Papaconstantinou J, Miller RA, Harrison DE: Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 2001;98:6736–6741.
17.
Kinney BA, Coschigano KT, Kopchick JJ, Bartke A: Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 2001;72:653–660.
18.
Miller RA, Harper JM, Galecki A, Burke DT: Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice. Aging Cell 2002;1:22–29.
19.
Yuan R, Tsaih SW, Petkova SB, Marin de Evsikova C, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B: Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 2009;8:277–287.
20.
Rollo CD: Growth negatively impacts the life span of mammals. Evol Dev 2002;4:55–61.
21.
Patronek GJ, Waters DJ, Glickman LT: Comparative longevity of pet dogs and humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci 1997;52A:B171–B178.
22.
Paradis MR: Demographics of health and disease in the geriatric horse. Vet Clin North Am Equine Pract 2002;18:391–401.
23.
Eigenmann JE, Amador A, Patterson DF: Insulin-like growth factor I levels in proportionate dogs, chondrodystrophic dogs and in giant dogs. Acta Endocrinol (Copenh) 1988;118:105–108.
24.
Samaras TT: Human Body Size and the Laws of Scaling: Physiological, Performance, Growth, Longevity and Ecological Ramifications, ed 1. New York, Nova Science, 2007.
25.
Batty GD, Barzi F, Woodward M, Jamrozik K, Woo J, Kim HC, Ueshima H, Huxley RR: Adult height and cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration. Ann Oncol 2010;21:646–654.
26.
Sung J, Song YM, Lawlor DA, Smith GD, Ebrahim S: Height and site-specific cancer risk: a cohort study of a Korean adult population. Am J Epidemiol 2009;170:53–64.
27.
Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS, Mullis PE: Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab 2003;88:3664–3667.
28.
Oliveira JL, Aguiar-Oliveira MH, D’Oliveira A Jr, Pereira RM, Oliveira CR, Farias CT, Barreto-Filho JA, Anjos-Andrade FD, Marques-Santos C, Nascimento-Junior AC, Alves EO, Oliveira FT, Campos VC, Ximenes R, Blackford A, Parmigiani G, Salvatori R: Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults. J Clin Endocrinol Metab 2007;92:4664–4670.
29.
Shechter M, Ginsberg S, Scheinowitz M, Feinberg MS, Laron Z: Obese adults with primary growth hormone resistance (Laron syndrome) have normal endothelial function. Growth Horm IGF Res 2007;17:165–170.
30.
Steuerman R, Shevah O, Laron Z: Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 2011;164:485–489.
31.
Jadresic A, Banks LM, Child DF, Diamant L, Doyle FH, Fraser TR, Joplin GF: The acromegaly syndrome. Quart J Med 1982;202:189–204.
32.
Bartke A: Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 2003;78:210–216.
33.
Krzisnik C, Kolacio Z, Battelino T, Brown M, Parks JS, Laron Z: The ‘little people’ of the island of Krk – revisited. Etiology of hypopituitarism revealed. J Endocr Genet 1999;1:9–19.
34.
Van Heemst D, Beekman M, Mooijaart SP, Heijmans BT, Brandt BW, Zwaan BJ, Slagboom PE, Westendorp RG: Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 2005;4:79–85.
35.
Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P: Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 2008;105:3438–3442.
36.
Brown-Borg HM, Rakoczy SG, Sharma S, Bartke A: Long-living growth hormone receptor knockout mice: potential mechanisms of altered stress resistance. Exp Gerontol 2009;44:10–19.
37.
Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM: Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J 2010;24:5073–5079.
38.
Bokov AF, Lindsey ML, Khodr C, Sabia MR, Richardson A: Long-lived Ames dwarf mice are resistant to chemical stressors. J Gerontol A Biol Sci Med Sci 2009;64:819–827.
39.
Bonkowski MS, Dominici FP, Arum O, Rocha JS, Al Regaiey KA, Westbrook R, Spong A, Panici J, Masternak MM, Kopchick JJ, Bartke A: Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS One 2009;4:e4567.
40.
Berryman DE, List EO, Palmer AJ, Chung MY, Wright-Piekarski J, Lubbers E, O’Con-nor P, Okada S, Kopchick JJ: Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci 2010; 65:31–40.
41.
Atzmon G, Pollin TI, Crandall J, Tanner K, Schechter CB, Scherer PE, Rincon M, Siegel G, Katz M, Lipton RB, Shuldiner AR, Barzilai N: Adiponectin levels and genotype: a potential regulator of life span in humans. J Gerontol A Biol Sci Med Sci 2008;63:447–453.
42.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–395.
43.
Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ: Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009;326:140–144.
44.
Sharp ZD, Bartke A: Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci 2005;60:293–300.
45.
Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Webb CR, Berryman DE, List EO, Kopchick JJ, Bartke A: Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 2009;64:522–529.
46.
Westbrook R, Bonkowski MS, Strader AD, Bartke A: Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice. J Gerontol A Biol Sci Med Sci 2009;64A:443–451.
47.
Hauck SJ, Hunter WS, Danilovich N, Kopchick JJ, Bartke A: Reduced levels of thyroid hormones, insulin, and glucose, and lower body core temperature in the growth hormone receptor/binding protein knockout mouse. Exp Biol Med 2001;226:552–558.
48.
Ratajczak J, Shin DM, Wan W, Liu R, Masternak MM, Piotrowska K, Wiszniewska B, Kucia M, Bartke A, Ratajczak MZ: Higher number of stem cells in the bone marrow of circulating low IGF-1 level Laron dwarf mice – novel view on IGF-1, stem cells and aging. Leukemia 2011;25:729–733.
49.
Garcia AM, Busuttil RA, Calder RB, Dollé MET, Diaz V, McMahan CA, Bartke A, Nelson J, Reddick R, Vijg J: Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. Mech Ageing Dev 2008;129:528–533.
50.
Amador-Noguez D, Dean A, Huang W, Setchell K, Moore D, Darlington G: Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell 2007;6:453–470.
51.
Sun L, Sadighi Akha AA, Miller RA, Harper JM: Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J Gerontol A Biol Sci Med Sci 2009;64:711–722.
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.