Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.
Growth hormone (GH) is a potent metabolic hormone that has been touted as a 'fountain of youth'
Recombinant human (rh) GH and insulin-like growth factor 1 (IGF-1) are approved therapeutics for patients with GH deficiency or primary IGF-1 deficiency, respectively; however, these drugs have been misused
Currently available data do not suggest that rhGH treatment should be used to promote longevity
Lack of GH action in mouse models is associated with extended longevity, but the mechanism underlying the increased lifespan has yet to be established
Given the effects of reduced GH/IGF-1 signalling on lifespan in rodents, decreased GH action might be beneficial for humans, but clinical trials are needed to assess long-term outcome of GH/IGF-1 inhibition
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Møller, N & Jørgensen, J. O. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009).
Zadik, Z., Chalew, S. A., McCarter, R. J. Jr, Meistas, M. & Kowarski, A. A. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J. Clin. Endocrinol. Metab. 60, 513–516 (1985).
Bartke, A. Growth hormone and aging: a challenging controversy. Clin. Interv. Aging 3, 659–665 (2008).
Rudman, D. et al. Effects of human growth hormone in men over 60 years old. N. Engl. J. Med. 323, 1–6 (1990).
Liu, H. et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann. Intern. Med. 146, 104–115 (2007).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span—from yeast to humans. Science 328, 321–326 (2010).
Snell, G. D. Dwarf, a new Mendelian recessive character of the house mouse. Proc. Natl Acad. Sci. USA 15, 733–734 (1929).
Eicher, E. M. & Beamer, W. G. New mouse dw allele: genetic location and effects on lifespan and growth hormone levels. J. Hered. 71, 187–190 (1980).
Li, S. et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347, 528–533 (1990).
Flurkey, K., Papaconstantinou, J., Miller, R. A. & Harrison, D. E. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736–6741 (2001).
Brooks, N. L. et al. Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J. Biol. Chem. 282, 35069–35077 (2007).
Vergara, M., Smith-Wheelock, M., Harper, J. M., Sigler, R. & Miller, R. A. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J. Gerontol. A. Biol. Sci. Med. Sci. 59, 1244–1250 (2004).
Schaible, R. & Gowen, J. W. A new dwarf mouse. Genetics 46, 896 (1961).
Buckwalter, M. S., Katz, R. W. & Camper, S. A. Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross. Genomics 10, 515–526 (1991).
Andersen, B. et al. The Ames dwarf gene is required for Pit-1 gene activation. Dev. Biol. 172, 495–503 (1995).
Sornson, M. W. et al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384, 327–333 (1996).
Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996).
Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001).
Panici, J. A. et al. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J. 24, 5073–5079 (2010).
Krzisnik, C., Grgurić, S. Cvijović, K. & Laron, Z. Longevity of the hypopituitary patients from the island Krk: a follow-up study. Pediatr. Endocrinol. Rev. 7, 357–362 (2010).
Krzisnik, C. et al. The “little people” of the island of Krk—revisited. Etiology of hypopituitarism revealed. J. Endocr. Genet. 1, 9–19 (1999).
Eicher, E. M. & Beamer, W. G. Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J. Hered. 67, 87–91 (1976).
Godfrey, P. et al. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat. Genet. 4, 227–232 (1993).
Donahue, L. R. & Beamer, W. G. Growth hormone deficiency in 'little' mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4. J. Endocrinol. 136, 91–104 (1993).
Salvatori, R. et al. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J. Clin. Endocrinol. Metab. 84, 917–923 (1999).
Aguiar-Oliveira, M. H. et al. Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J. Clin. Endocrinol. Metab. 95, 714–721 (2010).
Baumann, G. & Maheshwari, H. The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Paediatr. Suppl. 423, 33–38 (1997).
Maheshwari, H. G., Silverman, B. L., Dupuis, J. & Baumann, G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J. Clin. Endocrinol. Metab. 83, 4065–4074 (1998).
Besson, A. et al. Reduced longevity in untreated patients with isolated growth hormone deficiency. J. Clin. Endocrinol. Metab. 88, 3664–3667 (2003).
Dobbs, A. K. et al. Cutting edge: a hypomorphic mutation in Igβ (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J. Immunol. 179, 2055–2059 (2007).
Zhou, Y. et al. 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, 13215–13220 (1997).
Laron, Z. & Kopchick, J. (Eds) Laron Syndrome—From Man to Mouse (Springer, 2011).
List, E. O. et al. Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR−/−) mouse. Endocr. Rev. 32, 356–386 (2011).
Coschigano, K. T., Clemmons, D., Bellush, L. L. & Kopchick, J. J. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608–2613 (2000).
Coschigano, K. T. et al. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin and IGF-1 levels and increased lifespan. Endocrinology 144, 3799–3810 (2003).
Berryman, D. E. et al. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm. IGF Res. 14, 309–318 (2004).
Berryman, D. E. et al. Two-year body composition analyses of long-lived GHR null mice. J. Gerontol. A. Biol. Sci. Med. Sci. 65, 31–40 (2010).
Methuselah Foundation. Latest Mprize Winners [online], (2013)
Bonkowski, M. S., Rocha, J. S., Masternak, M. M., Al Regaiey, K. A. & Bartke, A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc. Natl Acad. Sci. USA 103, 7901–7905 (2006).
Laron, Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003. J. Clin. Endocrinol. Metab. 89, 1031–1044 (2004).
Laron, Z., Avitzur, Y. & Klinger, B. Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment. Metabolism 44 (Suppl. 4), 113–118 (1995).
Laron, Z. The GH–IGF1 axis and longevity. The paradigm of IGF1 deficiency. Hormones (Athens) 7, 24–27 (2008).
Rosenbloom, A. L., Guevara Aguirre, J., Rosenfeld, R. G. & Fielder, P. J. The little women of Loja—growth hormone-receptor deficiency in an inbred population of southern Ecuador. N. Engl. J. Med. 323, 1367–1374 (1990).
Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl. Med. 3, 70ra13 (2011).
Steuerman, R., Shevah, O. & Laron, Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur. J. Endocrinol. 164, 485–489 (2011).
Chen, W. Y., Wight, D. C., Mehta, B. V., Wagner, T. E. & Kopchick, J. J. Glycine 119 of bovine growth hormone is critical for growth-promoting activity. Mol. Endocrinol. 5, 1845–1852 (1991).
Chen, W. Y., White, M. E., Wagner, T. E. & Kopchick, J. J. Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 129, 1402–1408 (1991).
Palmiter, R. D. et al. Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 300, 611–615 (1982).
Palmer, A. J. et al. Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology 150, 1353–1360 (2009).
Bartke, A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 78, 210–216 (2003).
Quaife, C. J. et al. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124, 40–48 (1989).
Chanson, P. & Salenave, S. Acromegaly. Orphanet J. Rare Dis. 3, 17, (2008).
Eugster, E. A. & Pescovitz, O. H. Gigantism. J. Clin. Endocrinol. Metab. 84, 4379–4384 (1999).
Katznelson, L. Alterations in body composition in acromegaly. Pituitary 12, 136–142 (2008).
Ayuk, J. & Sheppard, M. C. Does acromegaly enhance mortality? Rev. Endocr. Metab. Disord. 9, 33–39 (2008).
Melmed, S. Acromegaly pathogenesis and treatment. J. Clin. Invest. 119, 3189–3202 (2009).
Holdaway, I. M., Bolland, M. J. & Gamble, G. D. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur. J. Endocrinol. 159, 89–95 (2008).
Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993).
Sjögren, K. et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Natl Acad. Sci. USA 96, 7088–7092 (1999).
Yakar, S. et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl Acad. Sci. USA 96, 7324–7329, (1999).
Svensson, J. et al. Liver-derived IGF-I regulates mean life span in mice. PLoS ONE 6, e22640 (2011).
Novosyadlyy, R. & Leroith, D. Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 67, 640–651 (2012).
Li, Q., Ceylan-Isik, A. F., Li, J. & Ren, J. Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. Rejuvenation Res. 11, 725–733 (2008).
Conover, C. A. et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 131, 1187–1194 (2004).
Conover, C. A. & Bale, L. K. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6, 727–729 (2007).
Conover, C. A. Key questions and answers about pregnancy-associated plasma protein-A. Trends Endocrinol. Metab. 23, 242–249 (2012).
Conover, C. A. et al. Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. J. Gerontol. A Biol. Sci. Med. Sci. 65, 590–599 (2010).
Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).
Bokov, A. F. et al. Does reduced IGF-1R signaling in Igf1r+/− mice alter aging? PLoS ONE 6, e26891 (2011).
Ladiges, W. et al. Lifespan extension in genetically modified mice. Aging Cell 8, 346–352 (2009).
Tazearslan, C., Huang, J., Barzilai, N. & Suh, Y. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell 10, 551–554 (2011).
Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (2008).
Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).
Wolf, I. et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27, 7094–7105 (2008).
Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).
Withers, D. J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).
Previs, S. F., Withers, D. J., Ren, J. M., White, M. F. & Shulman, G. I. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J. Biol. Chem. 275, 38990–38994 (2000).
Tamemoto, H. et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186 (1994).
Selman, C. et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (2008).
Selman, C., Partridge, L. & Withers, D. J. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS ONE 6, e16144 (2011).
Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).
Selman, C., Lingard, S., Gems, D., Partridge, L. & Withers, D. J. Comment on “Brain IRS2 signaling coordinates life span and nutrient homeostasis”. Science 320, 1012 (2008).
Barbieri, M. et al. The IRS2 Gly1057Asp variant is associated with human longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 65, 282–286 (2010).
Ranieri, S. C. et al. Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance. Proc. Natl Acad. Sci. USA 107, 13420–13425 (2010).
Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).
Bartke, A. Healthy aging: is smaller better?—a mini-review. Gerontology 58, 337–343 (2012).
Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
Kregel, K. C. & Zhang, H. J. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R18–R36 (2007).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Haruna, Y. et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc. Natl Acad. Sci. USA 104, 2331–2336 (2007).
Harper, J. M., Durkee, S. J., Dysko, R. C., Austad, S. N. & Miller, R. A. Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice. J. Gerontol. A. Biol. Sci. Med. Sci. 61, 1019–1029 (2006).
Murakami, S. Stress resistance in long-lived mouse models. Exp. Gerontol. 41, 1014–1019 (2006).
Fulda S., Gorman A. M., Hori O. & Samali A. Cellular stress responses: cell survival and cell death. Int. J. Cell Biol. 2010, 214074 (2010).
Wullschleger S, Loewith R. & Hall M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).
Zoncu R., Efeyan A. & Sabatini D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35 (2011).
Pérez, V. I. et al. Is the oxidative stress theory of aging dead? Biochim. Biophys. Acta 1790, 1005–1014 (2009).
Amador-Noguez, D. et al. Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell 6, 453–470 (2007).
Chhabra, Y., Waters, M. J. & Brooks, A. J. Role of the growth hormone-IGF-1 axis in cancer. Expert Rev. Endocrinol. Metab. 6, 71–84 (2011).
Ikeno, Y., Bronson, R. T., Hubbard, G. B., Lee, S. & Bartke, A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 58, 291–296 (2003).
Majeed, N. et al. A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24, 4736–4740 (2005).
Ikeno, Y. et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 522–529 (2009).
Pollak, M., Blouin, M. J., Zhang, J. C. & Kopchick, J. J. Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br. J. Cancer 85, 428–430 (2001).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Wang, M. & Miller, R. A. Augmented autophagy pathways and MTOR modulation in fibroblasts from long-lived mutant mice. Autophagy 8, (2012).
Thorner, M. O. 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, 1039–1044 (2009).
Elbornsson M. et al. Fifteen years of growth hormone (GH) replacement improves body composition and cardiovascular risk factors. Eur. J. Endocrinol. http://dx.doi.org/10.1530/EJE-12-1083.
Blackman M. R. et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288, 2282–2292 (2002).
Vestergaard, P. et al. Local administration of growth hormone stimulates tendon collagen synthesis in elderly men. J. Appl. Physiol. 113, 1432–1438 (2012).
Trainer, P. J. ACROSTUDY: the first 5 years. Eur. J. Endocrinol. 161 (Suppl. 1), S19–S24 (2009).
van der Lely, A. J. et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J. Clin. Endocrinol. Metab. 97, 1589–1597 (2012).
Parkinson C. et al. A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. J. Clin. Endocrinol. Metab. 4, 1797–1804 (2002).
Liang, H. et al. Genetic mouse models of extended lifespan. Exp. Gerontol. 38, 1353–1364, (2003).
Yakar, S. et al. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes 50, 1110–1118 (2001).
McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of the life span and upon the ultimate body size. 1935. Nutrition 5, 155–171 (1989).
Katic M. & Kahn C. R. The role of insulin and IGF-1 signaling in longevity. Cell. Mol. Life Sci. 62, 320–343 (2005).
Omodei, D. & Fontana, L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 585, 1537–1542 (2011).
Larson-Meyer, D. E. et al. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity (Silver Spring) 16, 1355–1362 (2008).
Heilbronn, L. K. et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295, 1539–1548 (2006).
Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).
The authors thank J. Sattler at Ohio University Heritage College for Osteopathic Medicine, Athens, OH, USA for taking the mouse photograph. J. J. Kopchick is supported by the State of Ohio's Eminent Scholar Program, which includes a gift from Milton and Lawrence Goll, by AMVETS, and by NIH (P01AG031736).
J. J. Kopchick declares that he is an inventor of US patent 5350836 entitled 'Growth hormone antagonists'. The other authors declare no competing interests.
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Junnila, R., List, E., Berryman, D. et al. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 9, 366–376 (2013). https://doi.org/10.1038/nrendo.2013.67
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