The following post will be fairly speculative, so view it as a researched opinion piece. This post may have its inaccuracies and will evolve as I continue to research this topic. Herein I will be proposing some of my views on growth hormone and its downstream protein IGF-1 with particular respect to its role in aging and longevity.
Growth hormone is, as its name so unambiguously suggests, a hormone of growth. It is produced by the pituitary gland and increases the growth of tissues, including muscle and bone, both directly and by inducing the production of another growth hormone called IGF-1. Due to these effects a lack of or insensitivity to either growth hormone or IGF-1 produces symptoms such as low muscle mass, increased body fat, and, if occurring in childhood, short stature (including dwarfism).
However, despite the obvious downsides to a growth hormone deficiency some have suggested growth hormone is a significant hormonal cause of aging and disease. One of the observations leading to this speculation comes from experiments on rodents where a hypophysectomy (the surgical removal of the pituitary gland) prolongs the animal’s lifespan. However, because the pituitary gland produces numerous hormones (including prolactin, TSH, FSH, LH, ACTH, and more) which themselves induce the production of various other hormones (including estrogen, thyroid hormone, testosterone, and cortisol), it seems incredibly difficult to conclude that decreased growth hormone is responsible for the anti-aging effects of a hypophysectomy.
Additional support for the role of growth hormone as a negative factor in aging, though indirect, comes from observation of animal size. Among animals of the same species there is a tendency for smaller animals to live longer than larger animals. Smaller mice and rats live longer than larger mice and rats, smaller dogs live longer than bigger dogs, and shorter people often live longer than taller people (more on this later). Because growth hormone and IGF-1 have been found to be major factors determining animal size this is consistent with the idea that these growth hormones negatively associate with lifespan. Although one might think the positive correlation between the size of different species of animals and lifespan (e.g. an elephant lives longer than a horse, which lives longer than a cat, which lives longer than a mouse) is inconsistent with the theory of a life shortening effect of growth hormone, this doesn’t seem to be the case. A fair amount of research suggests size differences between species is influenced more strongly by genetic, non-hormonal chemical signaling, rather than the endocrine signaling of growth hormones. In fact, IGF-1 levels seem to somewhat inversely follow lifespan. For example, among humans, elephants, American black bears, golden mantled ground squirrels, and brown rats it is the species with the shorter lifespan, not the largest size, which has higher IGF-1.
Stronger evidence supporting the argument that growth hormone shortens the lifespan comes from observing various genetically manipulated mice. The Ames, Snell, Lit, GHRKO, and IGF1RKO are all breeds of mice which have genetically impaired growth hormone production or downstream signaling and which all tend to live longer than their normal counterparts. However, the Ames and Snell Mice also fail to produce other pituitary hormones such as prolactin and TSH, suggesting other factors could be increasing the longevity of these animals. Additionally, a few experiments have found administering moderate amounts of growth hormone to mice (including the Snell and Balb/c strains) actually increases their lifespan.
Given the conflicting evidence regarding the effects growth hormone on rodents it would seem valuable to look at some of the studies and observations involving growth hormone in human beings, the species I’m assuming most of the readers of this article are. A variety of factors can reduce growth hormone production or signaling. A damaged pituitary (due most commonly to tumors) results in deficient production of growth hormone (as well as other pituitary hormones) and several studies have reported shorter lifespan in people with such conditions. However, these folks usually take a variety of hormones to manage their condition, making extrapolations about their lifespan difficult. Perhaps the better evidence comes from untreated people with mutations of certain growth hormone pathway genes. People with PROP-1 mutations have a low production of most pituitary hormones, including growth hormone, and seem to have a normal, possibly even longer life than unaffected people but yet again the lack of other pituitary hormones make such an observation far less useful.
Three useful populations come from people mutations of their GH-1 gene (which makes growth hormone), GHRH (which signals the pituitary to make growth hormone), and the GHR gene (which produces the receptor for growth hormone). People with a GH-1 mutation have been shown to live shorter lives than their unaffected siblings. People with a GHRH mutation seem to have shorter lifespans, but largely due to a higher mortality rate in childhood and adolescence. Upon surviving to the age of 20 GHRH mutants had lifespans roughly 10 years shorter than their unaffected siblings, a non-statistically significant finding. Finally, people with a GHR mutation, which causes a condition called Laron syndrome, seem to have the same lifespan as the rest of the population.
Although these represent extreme cases, the nonetheless fail to support the alleged negative effects of growth hormone on longevity. So how do we reconcile all the information suggesting growth hormone shortens life? Well, I have a theory. I believe growth hormone has both positive and negative effects on health. These effects are numerous so for simplicity I will be focusing on growth hormone’s effect cardiovascular disease and cancer.
On the one hand, a lack of growth hormone may increase cardiovascular disease risk. Hypopituitary people die more often of strokes and heart attacks and they have higher levels of atherosclerosis, or plaque build up in the arteries characteristic of cardiovascular disease. Some small clinical studies have shown the administration of growth hormone reverses this atherosclerosis, sometimes to normals. Additionally, growth hormone often improves blood lipid levels (particularity raising HDL levels), reduces inflammation (indicated by lowering CRP), and increases thyroid hormone levels, although not always. These characteristics all have a large amount of support for their beneficial role in cardiovascular disease prevention.
Nicotinic acid, a form of vitamin B3 (aka niacin) taken in large quantities for its drug like effects, is an interesting piece of evidence here in my opinion. Nicotinic acid raises growth hormone levels. Interestingly, it also seems to produce many of growth hormone’s effects: it raises HDL, lowers CRP, and can reverse atherosclerosis. Nicotinic also seems to worsen blood sugar control, another feature it shares with growth hormone. Finally, several large, randomized, controlled trials have found nicotinic acid prevents death from cardiovascular disease. Thus, if nicotonic acid not only mimics many of the effects of growth hormone but also increases growth hormone itself the fact that can prevent heart attacks would seem good evidence that growth hormone can as well.
On the other hand, growth hormone seems to be implicated in cancer risk. This may be because growth hormone and IGF-1 encourage growth of cells and tissues, which can be problematic when those cells and tissues are cancerous. A number of growth hormone deficient populations, including people with Laron syndrome, show a resistance to cancer compared to the normal population. Additionally, experiments on mice using the growth hormone and growth hormone pathway blocking drugs JV-1-38, RC-160, and M2-5-156 have reducing cancer risk and progression in a variety of cancer types. A number of phase II trials on humans using the anti-IGF-1 drugs R1507, Gantimab, and IMCA12 have also suggested some benefits to cancer patients, although without a control group it’s very hard to say for sure.
Finally, the last observation supporting these two ideas comes from human height, which again is heavily influenced by growth hormone/IGF-1. A number of studies have shown shorter people (indicating less growth hormone) are more likely to die of a heart attack while taller people (indicating more growth hormone) are more likely to die of cancer.
So, what does all this mean for you? Truthfully, I can’t say. The only take away message I have from this is to view growth hormone as a double edged sword, although the overall effect may not even be so significant as to warrant calling it a sword, perhaps a double edged…fly swatter?
To be continued in part 2…
W D Denckla J Clin Invest. 1974 February; 53(2): 572–581. Role of the pituitary and thyroid glands in the decline of minimal O2 consumption with age.
Powers RW 3rd, Harrison DE, Flurkey K. Pituitary removal in adult mice increases life span. Mech Ageing Dev. 2006 Aug;127(8):658-9. Epub 2006 Apr 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 Aug;88(8):3664-7.
Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res. 2002 Apr;54(1):25-35. Review.
Laron Z. The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency. Hormones (Athens). 2008 Jan-Mar;7(1):24-7.
Everitt A, Meites J. Aging and anti-aging effects of hormones. J Gerontol. 1989 Nov 44(6):B139-47. Review.
Insulin-like growth factor-1 is associated with life-history variation across Mammalia Eli M. Swanson and Ben Dantzer Proc. R. Soc. B 2014 281, 20132458, published 11 March 2014
Aguiar-Oliveira MH, Oliveira FT, Pereira RM, Oliveira CR, Blackford A, Valenca EH, Santos EG, Gois-Junior MB, Meneguz-Moreno RA, Araujo VP, Oliveira-Neto LA, Almeida RP, Santos MA, Farias NT, Silveira DC, Cabral GW, Calazans FR, Seabra JD, Lopes TF, Rodrigues EO, Porto LA, Oliveira IP, Melo EV, Martari M, Salvatori R. Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J Clin Endocrinol Metab. 2010 Feb;95(2):714-21.
van Heemst D. Insulin, IGF-1 and longevity. Aging and Disease. 2010;1:147–157.
Crickmore MA, Mann RS. The control of size in animals: insights from selector genes. Bioessays. 2008 Sep;30(9):843-53. doi: 10.1002/bies.20806. Review.
The lifespan of Animals: Volume 5 (Colloquia on Aging) By CIBA Foundation Symposium
Bartke A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology. 2005 Sep;146(9):3718-23. Epub 2005 May 26. Review.
Laron Z. Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? Mech Ageing Dev. 2005 Feb;126(2):305-7. Review.
Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sönksen PH, Tanaka T, Thorne M. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab. 1998 Feb;83(2):382-95. Review.
Speakman JR, van Acker A, Harper EJ. Age-related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy. Aging Cell. 2003 Oct;2(5):265-75.
Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R. The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat. 2000 Nov;197 Pt 4:575-85.
Wolf E, Kahnt E, Ehrlein J, Hermanns W, Brem G, Wanke R. Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: lessons from transgenic animal models. Mech Ageing Dev. 1993 May;68(1-3):71-87.
Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50.
The Size–Life Span Trade-Off Decomposed: Why Large Dogs Die Young. Author(s): Cornelia Kraus, Samuel Pavard, and Daniel E. L. Promislow Source: The American Naturalist, Vol. 181, No. 4 (April 2013), pp. 492-505
Khansari DN, Gustad T. Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mech Ageing Dev. 1991 Jan;57(1):87-100.
Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A. Genetic mouse models of extended lifespan. Exp Gerontol. 2003 Nov-Dec;38(11-12):1353-64. Review.
Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans KA, Cunningham J. 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. 1995 Jan;80(1):153-9.
Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 1999 Feb;84(2):453-7.
Soares DV, Spina LD, de Lima Oliveira Brasil RR, da Silva EM, Lobo PM, Salles E, Coeli CM, Conceição FL, Vaisman M. Carotid artery intima-media thickness and lipid profile in adults with growth hormone deficiency after long-term growth hormone replacement. Metabolism. 2005 Mar;54(3):321-9.
Fowelin J, Attvall S, Lager I, Bengtsson BA. Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism. 1993 Nov;42(11):1443-7.
Wyatt DT, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation. J Clin Endocrinol Metab. 1998 Oct;83(10):3493-7.
Kalina-Faska B, Kalina M, Koehler B. Effects of recombinant growth hormone therapy on thyroid hormone concentrations. Int J Clin Pharmacol Ther. 2004 Jan;42(1):30-4.
Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson BA. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 1993 Sep;129(3):195-200.
Portes ES, Oliveira JH, MacCagnan P, Abucham J. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children. Clin Endocrinol (Oxf). 2000 Aug;53(2):183-9. PubMed PMID: 10931099.
Smyczynska J, Hilczer M, Stawerska R, Lewinski A. Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy – clinical implications. Thyroid Res. 2010 Mar 22;3(1):2.
McCallum RW, Sainsbury CA, Spiers A, Dominiczak AF, Petrie JR, Sattar N, Connell JM. Growth hormone replacement reduces C-reactive protein and large-artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency. Clin Endocrinol (Oxf). 2005 Apr;62(4):473-9.
Edén S, Wiklund O, Oscarsson J, Rosén T, Bengtsson BA. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb. 1993 Feb;13(2):296-301.
Nolte W, Rädisch C, Armstrong VW, Hüfner M, von zur Mühlen A. The effect of recombinant human GH replacement therapy on lipoprotein(a) and other lipid parameters in adults with acquired GH deficiency: results of a double-blind and placebo-controlled trial. Eur J Endocrinol. 1997 Nov;137(5):459-66.
Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med. 2002 Jul 22;162(14):1568-76
Garg A Grundy SM ”Nicotinic acid as therapy for dyslipedemia in non–insulin-dependent diabetes mellitus” JAMA. 1990; 264723-726
“Effect of Niacin on Lipid and Lipoprotein Levels and Glycemic Control in Patients With Diabetes and Peripheral Arterial Disease: The ADMIT Study: A Randomized Trial”
J Hum Hypertens. 2000 Sep;14(9):567-72. “Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects” Kelly JJ, Lawson JA, Campbell LV, Storlien LH, Jenkins AB, Whitworth JA, O’Sullivan AJ. Departments of Medicine and Renal Medicine, University of New South Wales and St George Hospital, Sydney, Australia.
“Effect of Fenofibrate and Niacin on Intrahepatic Triglyceride Content, Very Low-Density Lipoprotein Kinetics, and Insulin Action in Obese Subjects with Nonalcoholic Fatty Liver Disease”
Metabolism. 2003 Jun;52(6):699-704. Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content.
Poynten AM, Gan SK, Kriketos AD, O’Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, Campbell LV.
“Effect of Low-Dose Niacin on Glucose Control in Patients With Non-Insulin-Dependent Diabetes Mellitus and Hyperlipidemia”
“Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project)”
“Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A Double-Blind, Placebo-Controlled Study of Extended-Release Niacin on Atherosclerosis Progression in Secondary Prevention Patients Treated With Statins”
“Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study”
“Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin”
“Nutrition Intervention Trials in Linxian, China: Supplementation With Specific Vitamin/Mineral Combinations, Cancer Incidence, and Disease-Specific Mortality in the General Population”
Minoru Irie, Maki Sakuma, Toshio Tsushima, Kazuo Shizume, Kiku Nakao Effect of Nicotinic Acid Administration on Plasma Growth Hormone Concentrations. The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Hertelendy F, Kipnis DM. Studies on growth hormone secretion. V. Influence of plasma free fatty acid levels. Endocrinology. 1973 Feb;92(2):402-10.
Quabbe HJ, Luyckx AS, L’age M, Schwarz C. Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189). J Clin Endocrinol Metab. 1983 Aug;57(2):410-4.
Murray R, Bartoli WP, Eddy DE, Horn MK. Physiological and performance responses to nicotinic-acid ingestion during exercise. Med Sci Sports Exerc. 1995 Jul;27(7):1057-62.
Szepeshazi K, Schally AV, Armatis P, Groot K, Hebert F, Feil A, Varga JL, Halmos G. Antagonists of GHRH decrease production of GH and IGF-I in MXT mouse mammary cancers and inhibit tumor growth. Endocrinology. 2001 Oct;142(10):4371-8.
Chatzistamou I, Schally AV, Varga JL, Groot K, Armatis P, Busto R, Halmos G. Antagonists of growth hormone-releasing hormone and somatostatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice. J Clin Endocrinol Metab. 2001 May;86(5):2144-52..
Chatzistamou I, Schally AV, Varga JL, Groot K, Busto R, Armatis P, Halmos G. Inhibition of growth and metastases of MDA-MB-435 human estrogen-independent breast cancers by an antagonist of growth hormone-releasing hormone. Anticancer Drugs. 2001 Oct;12(9):761-8. PubMed PMID: 11593058.
Banks WA, Morley JE, Farr SA, Price TO, Ercal N, Vidaurre I, Schally AV. Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice. Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22272-7.
Pappo AS, Patel SR, Crowley J, et al. et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29:4541–4547. [PMC free article] [PubMed]
Tap WD, Demetri G, Barnette P, et al. et al. Phase II study of ganitumab, a fully human anti–type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30:1849–1856. [PubMed]
Malempati S, Weigel B, Ingle AM, et al. et al. Phase I/Il trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:256–262. [PMC free article] [PubMed]
Rothenberg ML, Tolcher A, Sarantopoulos J, et al. et al. AMG479 monotherapy to treat patients with advanced Gl carcinoid tumors: a subset analysis from the first-in-human study. 2009 Gastrointestinal Cancers Symposium. 2009:A386.
Rajan A, Riely GJ, Carter CA, et al. et al. Phase II study of cixutumumab (IMC-A12) in thymic malignancies. J Clin Oncol. 2012;30(suppl):abstr 7033.
Abou-Alfa GK, Gansukh B, Chou JF, et al. et al. Phase II study of cixutumumab (IMC-A12, NSC742460; c) in hepatocellular carcinoma (HCC) J Clin Oncol. 2011;29(suppl):abstr 4043.
Haluska P, Worden F, Olmos D, et al. et al. Safety, tolerability, and pharmacokinetics of the anti–IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol. 2010;65:765–773. [PMC free article] [PubMed]
Higano C, Alumkal J, Ryan C, et al. et al. A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (mAb), against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastatic, asymptomatic castration-resistant prostate cancer. J Clin Oncol. 2009;27(suppl):abstr 5142.
Higano CS, Alumkal JJ, Ryan CJ, et al. et al. A phase II study of cixutumumab (IMC-A12), a monoclonal antibody (mAb) against the insulin-like growth factor 1 receptor (IGF-IR), monotherapy in metastatic castration-resistant prostate cancer (mCRPC): Feasibility of every 3-week dosing and updated results. Genitourinary Cancers Symposium. 2010. p. Abstract 189. ( http://meetinglibrary.asco.org/content/30567-30573)