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Biogerontology

, Volume 4, Issue 1, pp 1–8 | Cite as

Insulin-like growth factor 1 (IGF-1) and aging: Controversies and new insights

  • A. BartkeEmail author
  • F. Dominici
  • D. Turyn
  • B. Kinney
  • R. Steger
  • J.J. Kopchick
Article

Abstract

Insulin/insulin-like growth factor(IGF) signaling plays a major role in thecontrol of aging and life span ininvertebrates. Major extension of life span ingrowth hormone receptor knock out (GHR-KO) micethat are GH resistant, and subsequently, IGF-I-deficient indicates that similar mechanisms mayoperate in mammals. This conclusion issupported by association of reduced IGF-Ilevels and delayed aging in three different GH-deficient mutant mice and in animals subjectedto caloric restriction, but is difficult toreconcile with neuroprotective effects of IGF-Iand with the suspected role of declining GHlevels during aging. We suggest that the roleof IGF in the regulation of growth and adultbody size is important in mediating the effectsof longevity genes on aging and life span. Suspected mechanisms of IGF-I action in agingalso include reduced insulin signaling,enhanced sensitivity to insulin, and reducedthermogenesis with diminished oxidative damageof macromolecules being the likely final commonpathway of these effects. We suspect thatIGF-I is important in evolutionarily conservedmechanisms that link life history, includingdevelopment, reproduction, and aging withavailability of energy resources.

body size growth growth hormone insulin-like growth factor 1 insulin signaling long-lived mice 

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References

  1. Adashi EY, Resnick CE, D'Ercole AJ, Svoboda ME and Van Wyk JJ (1985) Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev 6: 400–418Google Scholar
  2. Bartke A, Brown-Borg H, Kinney B, Mattison J, Wright C, Hauck S, Coschigano K and Kopchick J (2000) Growth hormone and aging. J Am Aging Assoc 23: 219–225Google Scholar
  3. Bartke A, Wright JC, Mattison J, Ingram DK, Miller RA and Roth GS (2001) Extending the lifespan of long-lived mice. Nature 414: 412Google Scholar
  4. Bartke A, Chandrashekar V, Bailey B, Zaczek D and Turyn D (2002) Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides 36: 201–208Google Scholar
  5. Baum HBA, Katznelson L, Sherman JC, Biller BMK, Hayden DL, Schoenfeld JC, Cannistraro KE and Klibanski A (1998) Effects of a physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83: 3184–3189Google Scholar
  6. Baynes JW and Monnier VM (1989) The Maillard Reaction in Aging, Diabetes and Nutrition. Alan R. Liss, New York.Google Scholar
  7. Brown-Borg HM, Borg KE, Meliska CJ and Bartke A (1996) Dwarf mice and the ageing process. Nature 384: 33Google Scholar
  8. Butler AA, Yakar S and LeRoith D (2002) Insulin-like growth factor-I: compartmentalization within the somatotropic axis? News Physiol Sci 17: 82–85Google Scholar
  9. Chan J, Stampfer M, Giovannucci E, Gann P, Ma J, Wilkinson P, Hennekens C and Pollak M (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563–571Google Scholar
  10. Chandrashekar V, Bartke A, Coschigano KT and Kopchick JJ (1999) Pituitary and testicular function in growth hormone receptor gene knockout mice. Endocrinology 140: 1082–1088Google Scholar
  11. Chandrashekar V, Bartke A, Awoniyi CA, Tsai-Morris CH, Dufau ML, Russell LD and Kopchick JJ (2001) Testicular endocrine function in growth hormone receptor gene disrupted mice. Endocrinology 142: 3443–3450Google Scholar
  12. Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ and Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292: 104–106Google Scholar
  13. Clemmons DR (2001) Insulin-like growth factor-1 and its binding proteins. In: DeGroot LJ and Jameson JL (eds) Endocrinology 4th ed, Vol 1, Chapter 33, pp 439–460, WB Saunders, PhiladelphiaGoogle Scholar
  14. Coschigano KT, Riders ME, Bellush LL and Kopchick JJ (1999) Glucose Metabolism in Growth Hormone Receptor/Binding Protein Gene Disrupted Mice. Annual Meeting, The Endocrine Society, San Diego, California, Abstract P3-537, p 553Google Scholar
  15. Coschigano KT, Clemmons D, Bellush LL and Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP genedisrupted mice. Endocrinology 141: 2608–2613Google Scholar
  16. Danilovich N, Wernsing D, Coschigano KT, Kopchick JJ and Bartke A (1999) Deficits in female reproductive function in GH-R-KO mice: role of IGF-I. Endocrinology 140: 2637–2640Google Scholar
  17. D'Costa AP, Lenham JE, Ingram RL and Sonntag WE (1993) Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats. Mech Ageing Dev 71(1-2): 59-71Google Scholar
  18. Dominici FP, Arostegui Diaz G, Bartke A, Kopchick JJ and Turyn D (2000) Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice. J Endocrinol 166: 579–590Google Scholar
  19. Dupont J, Khan J, Qu B-H, Metzler P, Helman L and LaRoith D (2001) Insulin and IGF-I induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. Endocrinology 142: 4969–4975Google Scholar
  20. Eigenmann JE, Amador A and Patterson DF (1988) Insulin-like growth factor I levels in proportionate dogs, chondrodystrophic dogs and in giant dogs. Acta Endocrinol 118: 105–108Google Scholar
  21. Eklund J and Bradford CE (1977) Longevity and lifetime body weight in mice selected for rapid growth. Nature 265: 48–49Google Scholar
  22. Esquifino AI, VillanÚa MA, Szary A, Yau J and Bartke A (1991) Ectopic pituitary transplants restore immunocompetence in Ames dwarf mice. Acta Endocrinol 125: 67–72Google Scholar
  23. Facchini FS, Hua N, Abbasi F and Reaven GM (2001) Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 86: 3574–3578Google Scholar
  24. Flurkey K, Papaconstantinou J, Miller RA and Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 98: 6736–6741Google Scholar
  25. Forster MJ, Sumien N, Morris P and Sohal RS (2002) Genotype and age influence the effect of caloric restriction on mortality. In: Aging from Molecules to Humans; 31st Annual Meeting of the American Aging Association; 16th Annual Meeting of the American College of Clinical Gerontology, San Diego, CaliforniaGoogle Scholar
  26. French RA, Broussard SR, Meier WA, Minshall C, Arkins S, Zachary JF, Dantzer R and Kelley KW (2002) Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology 143: 690–699Google Scholar
  27. Friedlander AL, Butterfield GE, Moynihan S, Grillo J, Pollack M, Holloway L, Friedman L, Yesavage J, Matthias D, Lee S, Marcus R and Hoffman AR (2001) One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. J Clin Endocrinol Metab 86: 1496–1503Google Scholar
  28. Gala RR and Shevach EM (1993) Influence of prolactin and growth hormone on the activation of dwarf mouse lymphocytes in vivo. Proc Soc Exp Biol Med 204: 224–230Google Scholar
  29. Garcia-Segura LM, Cardona-Gomez GP, Chowen JA and Azcoitia I (2000) Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and nuroprotection. J Neurocytol 29(5-6): 425–437Google Scholar
  30. Gnessi L, Fabbri A and Spera G (1997) Gonadal peptides as mediators of development and functional control of the testis: an integrated system with hormones and local environment. Endocr Rev 18: 541–590Google Scholar
  31. Groesbeck MD, Parlow AF and Daughaday WH (1987) Stimulation of supranormal growth in pubertal, adult plateaued, and hypophysectomized female rats by large doses of rat growth hormone: physiological effects and adverse consequences. Endocrinology 120: 1963–1975Google Scholar
  32. Hall MA, Bartke A and Martinko JM (2002) Humoral immune response in mice overexpressing or deficient in growth hormone. Exp Biol Med 227: 535–544Google Scholar
  33. Hauck SJ, Hunter WS, Danilovich N, Kopchick JJ and Bartke A (2001) 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 226: 552–558Google Scholar
  34. Hebert PR, Ajani U, Cook NR, Lee IM, Chan KS and Hennekens CH (1997) Adult height and incidence of cancer in male physicians. (United States). Cancer Causes Control 8: 591–597Google Scholar
  35. Heck S, Lezoualch F, Engert S and Bahl C (1999) Insulin-like growth factor-I mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB. J Biol Chem 274: 9823–9835Google Scholar
  36. Hiney JK, Srivastava V, Nyberg CL, Ojeda SR and Dees WL (1996) Insulin-like growth factor I of peripheral origin acts centrally to accelerate the initiation of female puberty. Endocrinology 137: 3717–3728Google Scholar
  37. Hsieh C-C, DeFord JH, Flurkey K, Harrison DE and Papaconstantinou J (2002a) Implications of the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Mech Ageing Dev 123: 1229–1243Google Scholar
  38. Hsieh C-C, DeFord JH, Flurkey K, Harrison DE and Papaconstantinou J (2002b) Effects of the Pit 1 mutation on the insulin signaling pathway: implications on the longevity of the longlived Snell dwarf mouse. Mech Ageing Dev 123: 1244–1255Google Scholar
  39. Kalu DN, Orhii PB, Chen C, Lee DY, Hubbard GB, Lee S and Olatunjibello Y (1998) Aged-rodent models of long-term growth hormone therapy - lack of deleterious effect on longevity. J Gerontol: Biol Sci Med Sci 53: B452–B463Google Scholar
  40. Khansari DN and Gustad T (1991) Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mech Ageing Dev 57: 87–100Google Scholar
  41. Kinney BA, Coschigano KT, Kopchick JJ and Bartke A (2001a) Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 72: 653–660Google Scholar
  42. Kinney BA, Meliska CJ, Steger RW and Bartke A (2001b) Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav 39: 277–284Google Scholar
  43. Krzisnik C, Kolacio Z, Battelino T, Brown M, Parks JS and Laron Z (1999) The ‘Little People' of the island of Krk - revisited. Etiology of hypopituitarism revealed. The Journal of Endocrine Genetics 1: 9–19Google Scholar
  44. LeRoith D, Bondy CA, Yakar S, Liu J-L and Butler A (2001) The somatomedin hypothesis. Endocr Rev 22: 53–74Google Scholar
  45. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE and Riddle DR (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107: 603–613Google Scholar
  46. Liu J-P, Baker J, Perkins AS, Robertson EJ and Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor 1 (Igf1) and type 1 IGF receptor (Igf2r). Cell 75: 59–72Google Scholar
  47. Lupu F, Terwillinger JD, Lee K, Segre GV and Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor I in mouse postnatal growth. Dev Biol 229: 141–162Google Scholar
  48. Maison P, Balkau B, Simon D, Chanson P, Rosselin G and Eschwège E (1998) Growth hormone as a risk for premature mortality in healthy subjects: data from the Paris prospective study. BMJ 316: 1132–1133Google Scholar
  49. Markowska AL, Mooney M and Sonntag WE (1998) Insulin-like growth factor-I (IGF-I) ameliorates age-related behavioral deficits. Neuroscience 87: 559–569Google Scholar
  50. Masoro EJ (2001) Dietary restriction: an experimental approach to the study of the biology of aging. In: Masoro EJ and Austad SN (eds) Handbook of The Biology of Aging, 5th ed. Academic Press, San Diego, CaliforniaGoogle Scholar
  51. Mattison JA, Wright JC, Bronson RT, Roth GS, Ingram DK and Bartke A (2000) Studies of aging in Ames dwarf mice: effects of caloric restriction. J Am Aging Assoc 23: 9–16Google Scholar
  52. McCarty MF (2003) A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process. Medical Hypotheses (in press)Google Scholar
  53. Ong K, Kratzsch J, Kiess W, Dunger D and ALSPAC Study Team (2002) Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate. J Clin Endocrinol Metab 87: 1042–1044Google Scholar
  54. Orme SM, McNally RJQ, Cartwright RA and Belchetz PE (1998) Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 83: 2730–2734Google Scholar
  55. Paolisso G, Gambardella A, Ammendola S, D'Amore A, Balbi V, Varricchio M and D'Onofrio F (1996) Glucose tolerance and insulin action in healthy centenarians. Am J Physiol 270: E890–E894Google Scholar
  56. Paolisso G, Barbieri M, Rizzo MR, Carella C, Rotondi M, Bonafe M, Franceschi C, Rose G and De Benedictis G (2001) Low insulin resistance and preverved beta-cell function contribute to human longevity but are not associated with TH-INS genes. Exp Gerontol 37: 149–156Google Scholar
  57. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M and Grunfeld C (1996) Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med 124: 708–716Google Scholar
  58. Parr T (1997) Insulin exposure and aging theory. Gerontology 43: 182–200Google Scholar
  59. Patronek GJ, Waters DJ and Glickman LT (1997) Comparative longevity of pet dogs and humans: implications for gerontology research. J Gerontol 52A: B171–B178Google Scholar
  60. Roberts RC (1961) The lifetime growth and reproduction of selected strains of mice. Heredity 16: 369–381Google Scholar
  61. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW and Mattson DE (1990) Effects of human growth hormone in men over 60 years old. New Engl J Med 323: 1–6Google Scholar
  62. Sacca L, Cittadini A and Fazio S (1994) Growth hormone and the heart. Endocr Rev 15: 555–573Google Scholar
  63. Samaras TT and Elrick H (2002) Less is better. J Natl Med Assoc 94: 88–99Google Scholar
  64. Sjogren K, Bohlooly YM, Olsson B, Coschigano K, Tornell J, Mohan S, Isaksson OGP, Baumann G, Kopchick J and Ohlsson C (2000) Disproportional skeletal growth and markedly decreased bond mineral content in growth hormone receptor -/- mice. Biochem Biophys Res Commun 267: 603–608Google Scholar
  65. Sonntag WE, Cefalu WT, Ingram RL, Bennett SA, Lynch CD, Cooney PT, Thornton PL and Khan AS (1999) Pleiotropic effects of growth hormone and insulin-like growth factor (IGF) on biological aging: inferences from moderate caloric restricted animals. J Gerontol 54A: B521–B538Google Scholar
  66. Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S and Ingram R (2000) The effects of growth hormone and IGF-I deficiency on cerebrovascular and brain ageing. J Anat 4: 575–585Google Scholar
  67. Sortino MA and Caboibucim OK (1996) Neuroprotective effect of insulin-like growth factor I in immortalized hypothalamic cells. Endocrinology 137: 1416–1422Google Scholar
  68. Tatar M, Kopelman A, Epstein D, Tu M-P, Yin C-M and Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292: 107–110Google Scholar
  69. Tretli S (1989) Height and weight in relation to breast cancer morbidity and mortality. A prospective study of 570,000 women in Norway. Int J Cancer 44: 23–30Google Scholar
  70. Vance ME and Mauras N (1999) Growth hormone therapy in adults and children. New Engl J Med 341: 1206–1216Google Scholar
  71. Wolf E, Kahnt E, Ehrlein J, Hermanns W, Brem G and Wanke R (1993) Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: lessons from transgenic animal models. Mech Ageing Dev 68: 71–87Google Scholar
  72. Zaczek DJ, Hammond JM, Suen L, Wandji S, Service D, Bartke A, Chandrashekar V, Coschigano K and Kopchick J (2002) Impact of growth hormone resistance on female reproductive function: new insight from growth hormone receptor knockout mice. Biol Reprod 67: 1115–1124Google Scholar
  73. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Wagner TE, Cataldo LA, Coschigano K, Baumann G and Kopchick JJ (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (The Laron mouse). Proc Natl Acad Sci USA 94: 13215–13220Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • A. Bartke
    • 1
    • 1
    Email author
  • F. Dominici
    • 2
  • D. Turyn
    • 2
  • B. Kinney
    • 1
  • R. Steger
    • 1
  • J.J. Kopchick
    • 3
  1. 1.Department of PhysiologySouthern Illinois University School of MedicineCarbondaleUSA
  2. 2.Facultad de Farmacia y BioquímicaInstituto de Química y Fisicoquímica Biológicas (UBA-CONICET)Buenos AiresArgentina
  3. 3.Edison Biotechnology Institute and Department of Clinical ResearchOhio University College of Osteopathic Medicine, Ohio UniversityAthensUSA

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