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The enigmatic role of growth hormone in age-related diseases, cognition, and longevity


Growth hormone (GH) is secreted by the anterior pituitary gland and regulates various metabolic processes throughout the body. GH and IGF-1 levels are markedly reduced in older humans, leading some to hypothesize GH supplementation could be a viable “anti-aging” therapy. However, there is still much debate over the benefits and risks of GH administration. While an early study of GH administration reported reduced adiposity and lipid levels and increased bone mineral density, subsequent studies failed to show significant benefits. Conversely, other studies found positive effects of GH deficiency including extended life span, improved cognitive function, resistance to diseases such as cancer and diabetes, and improved insulin sensitivity despite a higher fat percentage. Thus, the roles of GH in aging and cognition remain unclear, and there is currently not enough evidence to support use of GH as an anti-aging or cognitive impairment therapy. Additional robust and longer-duration studies of efficacy and safety of GH administration are needed to determine if modulating GH levels could be a successful strategy for treating aging and age-related diseases.

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  1. Aguiar-Oliveira MH, Bartke A (2019) Growth hormone deficiency: health and longevity. Endocr Rev 40(2):575–601

  2. Aleman A et al (1999) Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab 84(2):471–475

  3. Ashpole NM et al (2015) Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol 68:76–81

  4. Ashpole NM et al (2017) IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience 39(2):129–145

  5. Baker LD et al (2012) Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol 69(11):1420–1429

  6. Balasubramanian P, Hall D, Subramanian M (2019) Sympathetic nervous system as a target for aging and obesity-related cardiovascular diseases. Geroscience 41(1):13–24

  7. Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146(9):3718–3723

  8. Bartke A (2008) Growth hormone and aging: a challenging controversy. Clin Interv Aging 3(4):659–665

  9. Bartke A (2017) Somatic growth, aging, and longevity. NPJ Aging Mech Dis 3:14

  10. Bartke A (2019) Growth hormone and aging: updated review. World J Mens Health 37(1):19–30

  11. Bartke A, Kopchick JJ (2015) The forgotten lactogenic activity of growth hormone: important implications for rodent studies. Endocrinology 156(5):1620–1622

  12. Bartke A, Westbrook R (2012) Metabolic characteristics of long-lived mice. Front Genet 3:288

  13. Bartke A et al (2001) Extending the lifespan of long-lived mice. Nature 414(6862):412

  14. Basu A, McFarlane HG, Kopchick JJ (2017) Spatial learning and memory in male mice with altered growth hormone action. Horm Behav 93:18–30

  15. Baum HB et al (1998) Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 83(9):3184–3189

  16. Ben-Avraham D et al (2017) The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. Sci Adv 3(6):e1602025

  17. Bennis MT et al (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience 39(1):51–59

  18. Berryman DE, List EO (2017) Growth hormone’s effect on adipose tissue: quality versus quantity. Int J Mol Sci 18(8)

  19. Berryman DE et al (2004) Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Hormon IGF Res 14(4):309–318

  20. Berryman DE et al (2010) Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci 65(1):31–40

  21. Besson A et al (2003) Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab 88(8):3664–3667

  22. Blackman MR et al (2002) Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288(18):2282–2292

  23. Boguszewski CL, Boguszewski MC, Kopchick JJ (2016) Growth hormone, insulin-like growth factor system and carcinogenesis. Endokrynol Pol 67(4):414–426

  24. Bonkowski MS et al (2009) Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS One 4(2):e4567

  25. Brod M et al (2014) Impact of adult growth hormone deficiency on daily functioning and well-being. BMC Res Notes 7:813

  26. Cuneo RC et al (1992) The growth hormone deficiency syndrome in adults. Clin Endocrinol 37(5):387–397

  27. Darcy J, Bartke A (2017) Functionally enhanced brown adipose tissue in Ames dwarf mice. Adipocyte 6(1):62–67

  28. Darcy J et al (2016) Brown adipose tissue function is enhanced in long-lived, male Ames dwarf mice. Endocrinology 157(12):4744–4753

  29. Devesa J, Almenglo C, Devesa P (2016a) Multiple effects of growth hormone in the body: is it really the hormone for growth? Clin Med Insights Endocrinol Diabetes 9:47–71

  30. Devesa J et al (2016b) Learning and memory recoveries in a young girl treated with growth hormone and neurorehabilitation. J Clin Med 5(2)

  31. Dominici FP et al (2002) Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. J Endocrinol 173(1):81–94

  32. Donahue CP, Kosik KS, Shors TJ (2006) Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. Proc Natl Acad Sci U S A 103(15):6031–6036

  33. Evans HM, Long JA (1922) Characteristic effects upon growth, oestrus and ovulation induced by the intraperitoneal administration of fresh anterior hypophyseal substance. Proc Natl Acad Sci U S A 8(3):38–39

  34. Farias Quipildor GE et al (2019) Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. Geroscience 41(2):185–208

  35. Feldt-Rasmussen U, Klose M (2016) Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients. Endocrine 54(1):15–23

  36. Friedman SD et al (2013) Growth hormone-releasing hormone effects on brain gamma-aminobutyric acid levels in mild cognitive impairment and healthy aging. JAMA Neurol 70(7):883–890

  37. Gilchrist FJ, Murray RD, Shalet SM (2002) The effect of long-term untreated growth hormone deficiency (GHD) and 9 years of GH replacement on the quality of life (QoL) of GH-deficient adults. Clin Endocrinol 57(3):363–370

  38. Guevara-Aguirre J et al (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3(70):70ra13

  39. Guevara-Aguirre J et al (2015) GH receptor deficiency in Ecuadorian adults is associated with obesity and enhanced insulin sensitivity. J Clin Endocrinol Metab 100(7):2589–2596

  40. Hascup KN et al (2017) Enhanced cognition and hypoglutamatergic signaling in a growth hormone receptor knockout mouse model of successful aging. J Gerontol A Biol Sci Med Sci 72(3):329–337

  41. Hulthen L et al (2001) GH is needed for the maturation of muscle mass and strength in adolescents. J Clin Endocrinol Metab 86(10):4765–4770

  42. Ikeno Y et al (2003) Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 58(4):291–296

  43. Janssen YJ, Doornbos J, Roelfsema F (1999) Changes in muscle volume, strength, and bioenergetics during recombinant human growth hormone (GH) therapy in adults with GH deficiency. J Clin Endocrinol Metab 84(1):279–284

  44. Johannsson G et al (2002) GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis. J Clin Endocrinol Metab 87(4):1743–1749

  45. Jorgensen JO et al (1996) Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition. Clin Endocrinol 45(6):681–688

  46. Kalmijn S et al (2000) A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab 85(12):4551–4555

  47. Kinney BA et al (2001a) Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 72(5):653–660

  48. Kinney BA et al (2001b) Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav 39(4):277–284

  49. Labandeira-Garcia JL et al (2017) Insulin-like growth factor-1 and neuroinflammation. Front Aging Neurosci 9:365

  50. Laron Z (2005) Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? Mech Ageing Dev 126(2):305–307

  51. Le Greves M et al (2002) Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats. Proc Natl Acad Sci U S A 99(10):7119–7123

  52. Lichtenwalner RJ et al (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107(4):603–613

  53. List EO, et al (2014) Liver-specific GH receptor gene disrupted (LiGHRKO) mice have decreased endocrine IGF-1, increased local IGF-1 as well as altered body size, body composition and adipokine profiles. Endocrinology en20132086

  54. Littley MD et al (1989) Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 70(262):145–160

  55. Liu H et al (2007) Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 146(2):104–115

  56. Logan S et al (2018) Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-beta uptake in astrocytes. Mol Metab 9:141–155

  57. Lupu F et al (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229(1):141–162

  58. Markowska AL, Mooney M, Sonntag WE (1998) Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87(3):559–569

  59. Masternak MM, Bartke A (2012) Growth hormone, inflammation and aging. Pathobiol Aging Age Relat Dis. 2

  60. Masternak MM et al (2004) Divergent effects of caloric restriction on gene expression in normal and long-lived mice. J Gerontol A Biol Sci Med Sci 59(8):784–788

  61. Masternak MM et al (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11(1):73–81

  62. Masternak MM et al (2018) Dwarf mice and aging. Prog Mol Biol Transl Sci 155:69–83

  63. Menon V et al (2014) The contribution of visceral fat to improved insulin signaling in Ames dwarf mice. Aging Cell 13:497–506

  64. Merola B et al (1996) Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months’ growth hormone replacement therapy. Eur J Endocrinol 135(5):553–558

  65. Modesto Mde J et al (2014) Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height. J Pediatr Endocrinol Metab 27(9–10):813–820

  66. Moller J et al (1996) Decreased plasma and extracellular volume in growth hormone deficient adults and the acute and prolonged effects of GH administration: a controlled experimental study. Clin Endocrinol 44(5):533–539

  67. Murray PG, Clayton PE (2000) Disorders of growth hormone in childhood

  68. Nashiro K et al (2017) Brain structure and function associated with younger adults in growth hormone receptor-deficient humans. J Neurosci 37(7):1696–1707

  69. Nass R et al (2008) Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med 149(9):601–611

  70. Netchine I et al (2009) Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab 94(10):3913–3921

  71. Nielsen J, Jensen RB, Afdeling AJ (2015) Growth hormone deficiency in children. Ugeskr Laeger 177(26):1260–1263

  72. Nyberg F (2000) Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance. Front Neuroendocrinol 21(4):330–348

  73. Pan W et al (2005) Permeation of growth hormone across the blood-brain barrier. Endocrinology 146(11):4898–4904

  74. Paolisso G et al (1997) Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab 82(7):2204–2209

  75. Perls TT, Reisman NR, Olshansky SJ (2005) Provision or distribution of growth hormone for “antiaging”: clinical and legal issues. JAMA 294(16):2086–2090

  76. Podlutsky A et al (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience 39(2):147–160

  77. Quinlan P et al (2017) Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia. Psychoneuroendocrinology 86:169–175

  78. Ramsey MM et al (2004) Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience 129(1):119–127

  79. Ransome MI et al (2004) Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness. Eur J Neurosci 19(8):2069–2079

  80. Renna M et al (2013) IGF-1 receptor antagonism inhibits autophagy. Hum Mol Genet 22(22):4528–4544

  81. Rudman D et al (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med 323(1):1–6

  82. Salvatori R et al (2001) Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib. J Clin Endocrinol Metab 86(1):273–279

  83. Sanz A, Bartke A, Barja G (2002) Long-lived Ames dwarf mice: oxidative damage to mitochondrial DNA in heart and brain. J Am Aging Assoc 25(3):119–122

  84. Sathiavageeswaran M et al (2007) Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study. Eur J Endocrinol 156(4):439–447

  85. Sevigny JJ et al (2008) Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology 71(21):1702–1708

  86. Shevah O, Laron Z (2007) Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Hormon IGF Res 17(1):54–57

  87. Simpson JA et al (2001) Body water compartment measurements: a comparison of bioelectrical impedance analysis with tritium and sodium bromide dilution techniques. Clin Nutr 20(4):339–343

  88. Sonntag WE et al (1980) Decreased pulsatile release of growth hormone in old male rats. Endocrinology 107(6):1875–1879

  89. Sonntag WE et al (1981) Effects of CNS active drugs and somatostatin antiserum on growth hormone release in young and old male rats. Neuroendocrinology 33(2):73–78

  90. Sonntag WE et al (2000) The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat 197(Pt 4):575–585

  91. Sonntag WE, Ramsey M, Carter CS (2005) Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev 4(2):195–212

  92. Sonntag WE et al (2012) Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67(6):587–598

  93. Sonntag WE et al (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5:27

  94. Sun LY et al (2005a) Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging 26(6):929–937

  95. Sun LY et al (2005b) Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146(3):1138–1144

  96. Sun LY et al (2017) Longevity is impacted by growth hormone action during early postnatal period. Elife 6

  97. Swerdlow AJ et al (2017) Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study. J Clin Endocrinol Metab 102(5):1661–1672

  98. Tarantini S et al (2017) Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell 16(3):469–479

  99. Thorner MO (2009) Statement by the growth hormone research society on the GH/IGF-I axis in extending health span. J Gerontol A Biol Sci Med Sci 64(10):1039–1044

  100. Thornton PL, Ingram RL, Sonntag WE (2000) Chronic [D-Ala2]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory. J Gerontol A Biol Sci Med Sci 55(2):B106–B112

  101. Toth P et al (2015) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14(6):1034–1044

  102. van Dam PS et al (2005) Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate. Psychoneuroendocrinology 30(4):357–363

  103. van Heemst D et al (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4(2):79–85

  104. Vergara M et al (2004) Hormone-treated Snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci 59(12):1244–1250

  105. Vitiello MV et al (2006) Growth hormone releasing hormone improves the cognition of healthy older adults. Neurobiol Aging 27(2):318–323

  106. Walenkamp MJ et al (2005) Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 90(5):2855–2864

  107. Weaver JU et al (1995) The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab 80(1):153–159

  108. Westbrook R et al (2009) 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 64(4):443–451

  109. Widdowson WM, Gibney J (2008) The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a metaanalysis. J Clin Endocrinol Metab 93(11):4413–4417

  110. Zhang H et al (2014) The effect and mechanism of growth hormone replacement on cognitive function in rats with traumatic brain injury. PLoS One 9(9):e108518

  111. Zhou Y et al (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 U S A 94(24):13215–13220

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This work was supported by NIH grants AG059190 (M. M. M.), AG059846 (M. M. M.), AG13925 (J.L.K.), AG041122 (J.L.K.), AG31736 (Project 4: J.L.K.), and AG044396 (J.L.K.), Robert and Arlene Kogod, the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Ted Nash Long Life (J.L.K.) and Noaber Foundations (J.L.K.). N.M. is supported by a grants from the American Diabetes Association (7-13-GSK-01), the National Institutes of Health (AG030979, DK80157, DK089229, and DK080157), the San Antonio Nathan Shock Center (AG013319), and the San Antonio Claude D. Pepper Older Americans Independence Center (AG044271). Pathology Core in the San Antonio Nathan Shock Center: P30-AG013319 (Y. I.) also supported this work. D.M.H. is supported by AG037574, AG055026, AG057429; the American Federation for Aging Research (AFAR); and the Einstein Nathan Shock Center (P30 AG038072).

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Correspondence to Michal M. Masternak.

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Colon, G., Saccon, T., Schneider, A. et al. The enigmatic role of growth hormone in age-related diseases, cognition, and longevity. GeroScience 41, 759–774 (2019). https://doi.org/10.1007/s11357-019-00096-w

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  • Growth hormone
  • IGF-1
  • Aging
  • GH deficiency
  • Longevity
  • Cognition