A report of extended longevity in mice homozygous for a mutation producing growth hormone (GH) deficiency () was quickly followed by the demonstration of extensive homology between one of the key longevity genes in a worm, Caenorhabditis elegans, and genes coding for insulin and insulin-like growth factor-1 (IGF-1) receptors in mammals (). Since GH is the key determinant of hepatic IGF-1 expression and circulating IGF-1 levels, and has major impact on insulin signaling (Figure 1), these findings led to an exciting conclusion that the insulin/insulin-like growth factor signaling (IIS) is an evolutionarily conserved mechanism which controls aging in organisms ranging from yeast and worms to insects and mammals. Subsequent work provided much evidence in support of this exciting realization (Tissenbaum and Ruvkun, 1998; ; Tatar et al., 2001; Tatar et al., 2003; ; ), and this has led to a focus on IIS, rather than GH signaling, in analyzing genetic control of mammalian aging. This is an important distinction. Although biosynthesis and blood plasma levels of GH and IGF-1 are closely linked, the actions of these hormones are not identical and, in some cases, opposite. For example, IGF-1 mimics some of the insulin actions and promotes insulin sensitivity, while GH is anti-insulinemic and promotes insulin resistance; IGF-1 promotes fat deposition, while GH is lipolytic (Figure 2) (; Veldhuis et al., 2005; ). Actions of GH not shared with IGF-1 include other effects relevant to aging such as impact on reactive radicals production and anti-oxidative defenses (; ), DNA damage and repair (; ), macrophage reprogramming (), ovarian primordial follicle reserve (), bone resorption and turnover (Thomas and Monson, 2009), kidney dysfunction (), and cognitive functioning ().
FIGURE 1
FIGURE 2
Evidence for the ability of GH to influence healthspan and lifespan of laboratory mice is very strong and includes significant extension of longevity in both sexes of mice with hypopituitarism (combined deficiency of GH, prolactin, and TSH) (; ), in mice with isolated GH deficiency due to mutation of Ghrhr gene or deletion of Ghrh (; ), and in mice with GH resistance due to Ghr gene disruption (Zhou et al., 1997; ). This evidence for association of genetically reduced GH signaling with extended longevity was obtained in different laboratories and included animals with different genetic background (; ; ). Importantly, extended longevity of hypopituitary Ames dwarf mice can be reduced by GH replacement therapy during the period of rapid peri-pubertal growth (; ). This provides evidence that the association of GH deficiency and increased lifespan in Ames dwarf mice is causal (mechanistic).
In contrast to the remarkable extension of longevity in female and male mice lacking GH or GH receptors, the impact of reduced IGF-1 signaling on longevity of IGF1R ± mice and mice treated with an antibody to IGF-1 receptor is modest and seen only in one sex (; ; ) (Table 1). This difference between the effects of reduced IGF-1 and GH signaling is likely related to IGF-1 exerting both beneficial and detrimental effects on aging and age-related disease (including opposite effects on the risk of type 2 diabetes vs cardiovascular disease and cognitive decline) and GH having primarily “pro-aging” effects. Both hormones impact growth, but the metabolic effects of GH are significantly greater. Growth hormone has different and more potent effects on glucose regulation when compared to IGF-1. Growth hormone is a regulator of IGF-1 by controlling much of its production and release from the liver and other tissues, and thus regulating plasma concentrations of IGF-1 (; Vijayakumar et al., 2011). Liver-derived IGF-1 represents >75% of the circulating hormone (; ). In contrast to the effects on somatic growth, the effects of GH and IGF-1 on glucose homeostasis are markedly different. Growth hormone promotes insulin resistance acting as a counterregulatory mechanism for hypoglycemia (protection during fasting, food deprivation). While GH counteracts insulin action, IGF-1 enhances insulin sensitivity and mimics some of its actions. Both GH and IGF-1 influence insulin production. When GH levels are reduced, insulin levels are also reduced, whereas IGF-1 inhibits insulin secretion (). Another complexity is suggested by the evidence that most of IGF-1’s actions on glucose homeostasis and insulin sensitivity are mediated indirectly (through GH suppression), while circulating IGF-1 is bound to high-affinity binding proteins and has low affinity for insulin receptors (Vijayakumar et al., 2011). Direct effects of IGF-1 on glucose management occur mostly in skeletal muscle by increasing glucose uptake (; Vijayakumar et al., 2011). Growth hormone influences insulin signaling in liver and adipocytes, whereas no IGF-1 receptors are present in these tissues (). Other actions of GH that impact lifespan are also not shared by IGF-1, and thus GH deficiency promotes health and lifespan extension more profoundly than suppression of the levels or action of IGF-1 (). Sex-specific responses to suppressing IGF-1 signaling in mice () add to the emerging evidence that, in this species, aging of males is related primarily to the insulin arm of IIS while in females effects of the IGF-1 arm predominate.
TABLE 1
| Yeast | Worms | Insects | Mammals | |||
|---|---|---|---|---|---|---|
| Mice | Humans | |||||
| IIS | healthspan | ? | ↑ | ↑ | ? | ? |
| lifespan | ↑ | ↑ | ↑ | ↑ (♀ ♀) | — | |
| GH | healthspan | NA | NA | NA | ↑ | ↑ |
| lifespan | NA | NA | NA | ↑ | — | |
Effects of reduced IIS and GH signaling on healthspan and lifespan in different taxonomic groups.
In contrast to the findings of extended longevity of IGF-1R heterozygous mice by Holzenberger et al. (), Bokov and his colleagues reported that such animals had very small lifespan extension, no indications of delayed aging, and no changes in end-of-life pathology (). Discrepancies between the results of a loss of one IGF-1R allele in these two studies were subsequently shown to be related to differences in constitutive IGF-1 signaling and in endocrine responses to reducing the number of IGF-1 receptors in the employed strains of mice (Xu et al., 2014). In further contrast between the effects of suppressing GH and IGF-1 signaling, complete (homologous) disruption of Igf1 or Igf1r genes can have severe detrimental effects on development, postnatal survival and fertility (; ; Yakar et al., 1999), while GH-deficient and GH-resistant mice are viable and fertile.
Reduced insulin levels and improved insulin sensitivity are associated with extension of longevity in response to calorie restriction or disruption of GH signaling. However, the effects of genetic alterations of insulin levels, global or organ-specific insulin sensitivity, or early steps of intracellular insulin signaling on longevity of laboratory mice are not consistent. Interpretation of the available data is complicated by the negative regulation of expression of the insulin receptors by insulin and by indications that insulin resistance can have both detrimental and protective effects (). Templeman and her colleagues reported an 11 percent increase in median longevity of female Ins2+/− Ins1−/− mice in which insulin levels are reduced by approximately 30 percent (Templeman et al., 2017). This association of improved insulin sensitivity and longevity was also seen in other mutants (; Zhang et al., 2012), but was absent or reversed in others (; ; Takeda et al., 2017). Deletion of Insulin receptor substrate 1 (Irs1) extended longevity, but the effects of Irs2 deletion were not consistent in different studies, likely due to difference in the composition of the diet used in the two laboratories (; ).
Reports of GH signaling and lifespan in rats are very limited. Spontaneous dwarf rats exhibit reduced GH and IIS signaling and longer lifespans compared to controls (; ). GH-deficient rats generated by antisense GH gene suppression (±) also live 7% longer, but −/− animals do not (). Lewis dwarf rats do not live longer, but are not profoundly GH/IGF-1 deficient (∼55% reduced), exhibit additional endocrine abnormalities (i.e. hyporesponsive HPA axis), and a general tendency towards pro-inflammation resulting in nephropathy and intracerebral hemorrhage, among other issues (; ; ; Ungvari et al., 2010; ; Ungvari et al., 2011; ).
Collectively, the available evidence suggests that in addition to the evolutionarily conserved role of IIS in the control of aging, GH (which has no known homologs in invertebrates) emerges as a major regulator of aging and longevity in mammals. Alterations in IIS in long-lived GH signaling-related mutants represent some of the multiple mechanisms believed to link GH deficiency or resistance with increases in the healthspan and lifespan ().
In humans, the impact of GH and growth/anabolic processes on longevity is more subtle than in laboratory mice, likely reflecting major differences in the pace-of-life including the reproductive strategies (; ). Genetic syndromes of GH deficiency or resistance do not extend human longevity, even though some individuals with these mutations can reach very advanced age (). However, pathological excess of GH reduces life expectancy in both humans and mice (; ; Wolf et al., 1993) and familial longevity was shown to be associated with reduced GH secretion (van der Spoel et al., 2016). Intriguingly, there is considerable overlap of phenotypic and metabolic consequences of genetic disruption of GH signaling in mice and humans (), and humans with these syndromes show a remarkable degree of protection from several age-associated chronic diseases along with indications of extended healthspan, that is “healthy aging” (; ).
Statements
Author contributions
Article concept and design, AB. Writing of manuscript, AB, HB-B. Approval of final manuscript, AB.
Funding
William E. McElroy Charitable Foundation, NIH R21AG062985, and American Diabetes Association 1-19-IBS-126 to AB and NIH R56AG067724 to HB-B.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1
Aguiar-OliveiraM. H.BartkeA. (2019). Growth Hormone Deficiency: Health and Longevity. Endocr. Rev.40 (2), 575–601. 10.1210/er.2018-00216
2
AguirreG. A.De ItaJ. R.de la GarzaR. G.Castilla-CortazarI. (2016). Insulin-like Growth Factor-1 Deficiency and Metabolic Syndrome. J. Transl Med.14 (1), 3. 10.1186/s12967-015-0762-z
3
AshpoleN. M.LoganS.YabluchanskiyA.MitschelenM. C.YanH.FarleyJ. A.et al (2017). IGF-1 Has Sexually Dimorphic, Pleiotropic, and Time-dependent Effects on Healthspan, Pathology, and Lifespan. Geroscience39 (2), 129–145. 10.1007/s11357-017-9971-0
4
BartkeA. (2020). Growth Hormone and Aging. Rev. Endocr. Metab. Disord.22 (1), 71–80. 10.1007/s11154-020-09593-2
5
BartkeA.TurynD. (2001). Mechanisms of Prolonged Longevity: Mutants, Knock-Outs, and Caloric Restriction. J. Anti-Aging Med.4 (3), 197–203. 10.1089/109454501753249966
6
BarzilaiN.HuffmanD. M.MuzumdarR. H.BartkeA. (2012). The Critical Role of Metabolic Pathways in Aging. Diabetes61 (6), 1315–1322. 10.2337/db11-1300
7
BengtssonB. A.EdénS.ErnestI.OdénA.SjögrenB. (1988). Epidemiology and Long-Term Survival in Acromegaly. A Study of 166 Cases Diagnosed between 1955 and 1984. Acta Med. Scand.223 (4), 327–335. 10.1111/j.0954-6820.1988.tb15881.x
8
BokovA. F.GargN.IkenoY.ThakurS.MusiN.DeFronzoR. A.et al (2011). Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging. PLoS One6 (11), e26891. 10.1371/journal.pone.0026891
9
BokovA. F.LindseyM. L.KhodrC.SabiaM. R.RichardsonA. (2009). Long-lived ames dwarf Mice Are Resistant to Chemical Stressors. J. Gerontol. A. Biol. Sci. Med. Sci.64A (8), 819–827. 10.1093/gerona/glp052
10
Brown-BorgH. M.BorgK. E.MeliskaC. J.BartkeA. (1996). Dwarf Mice and the Ageing Process. Nature384, 33. 10.1038/384033a0
11
Brown-BorgH. M.RakoczyS. G.RomanickM. A.KennedyM. A. (2002). Effects of Growth Hormone and Insulin-like Growth Factor-1 on Hepatocyte Antioxidative Enzymes. Exp. Biol. Med. (Maywood)227 (2), 94–104. 10.1177/153537020222700203
12
ChesnokovaV.MelmedS. (2019). Growth Hormone in the Tumor Microenvironment. Arch. Endocrinol. Metab.63 (6), 568–575. 10.20945/2359-3997000000186
13
ChesnokovaV.ZonisS.BarrettR. J.GleesonJ. P.MelmedS. (2019). Growth Hormone Induces Colon DNA Damage Independent of IGF-1. Endocrinology160 (6), 1439–1447. 10.1210/en.2019-00132
14
CoschiganoK. T.HollandA. N.RidersM. E.ListE. O.FlyvbjergA.KopchickJ. J. (2003). 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. Endocrinology144 (9), 3799–3810. 10.1210/en.2003-0374
15
FabrizioP.PozzaF.PletcherS. D.GendronC. M.LongoV. D. (2001). Regulation of Longevity and Stress Resistance by Sch9 in Yeast. Science292 (5515), 288–290. 10.1126/science.1059497
16
FinchC. E.RuvkunG. (2001). The Genetics of Aging. Annu. Rev. Genom. Hum. Genet.2, 435–462. 10.1146/annurev.genom.2.1.435
17
FlurkeyK.PapaconstantinouJ.MillerR. A.HarrisonD. E. (2001). Lifespan Extension and Delayed Immune and Collagen Aging in Mutant Mice with Defects in Growth Hormone Production. Proc. Natl. Acad. Sci.98 (12), 6736–6741. 10.1073/pnas.111158898
18
GarrattM.NakagawaS.SimonsM. J. P. (2017). Life-span Extension with Reduced Somatotrophic Signaling: Moderation of Aging Effect by Signal Type, Sex, and Experimental Cohort. J. Gerontol. A. Biol. Sci. Med. Sci.72 (12), 1620–1626. 10.1093/gerona/glx010
19
GroenewegF. L.KarstH.de KloetE. R.JoëlsM. (2011). Rapid Non-genomic Effects of Corticosteroids and Their Role in the central Stress Response. J. Endocrinol.209 (2), 153–167. 10.1530/joe-10-0472
20
Guevara-AguirreJ.BalasubramanianP.Guevara-AguirreM.WeiM.MadiaF.ChengC. W.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. 70ra13. 10.1126/scitranslmed.3001845
21
HaluzikM.YakarS.GavrilovaO.SetserJ.BoisclairY.LeRoithD. (2003). Insulin Resistance in the Liver-specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex: Relative Roles of Growth Hormone and IGF-1 in Insulin Resistance. Diabetes52 (10), 2483–2489. 10.2337/diabetes.52.10.2483
22
HolzenbergerM.DupontJ.DucosB.LeneuveP.GéloënA.EvenP. C.et al (2003). IGF-1 Receptor Regulates Lifespan and Resistance to Oxidative Stress in Mice. Nature421 (6919), 182–187. 10.1038/nature01298
23
HuD.PawlikowskaL.KanayaA.HsuehW.-C.ColbertL.NewmanA. B.et al (2009). Serum Insulin-like Growth Factor-1 Binding Proteins 1 and 2 and Mortality in Older Adults: the Health, Aging, and Body Composition Study. J. Am. Geriatr. Soc.57 (7), 1213–1218. 10.1111/j.1532-5415.2009.02318.x
24
KimuraK. D.TissenbaumH. A.LiuY.RuvkunG. (1997). daf-2 , an Insulin Receptor-like Gene that Regulates Longevity and Diapause in Caenorhabditis elegans. Science277 (5328), 942–946. 10.1126/science.277.5328.942
25
KuramotoK.TaharaS.SasakiT.MatsumotoS.KanekoT.KondoH.et al (2010). Spontaneous dwarf Rat: a Novel Model for Aging Research. Geriatr. Gerontol. Int.10 (1), 94–101. 10.1111/j.1447-0594.2009.00559.x
26
LiuJ.-P.BakerJ.PerkinsA. S.RobertsonE. J.EfstratiadisA. (1993). Mice Carrying Null Mutations of the Genes Encoding Insulin-like Growth Factor I (Igf-1) and Type 1 IGF Receptor (Igf1r). Cell75 (1), 59–72. 10.1016/s0092-8674(05)80084-4
27
MaoK.QuipildorG. F.TabrizianT.NovajA.GuanF.WaltersR. O.et al (2018). Late-life Targeting of the IGF-1 Receptor Improves Healthspan and Lifespan in Female Mice. Nat. Commun.9 (1), 2394. 10.1038/s41467-018-04805-5
28
MasternakM. M.PaniciJ. A.BonkowskiM. S.HughesL. F.BartkeA. (2009). Insulin Sensitivity as a Key Mediator of Growth Hormone Actions on Longevity. Journals Gerontol. Ser. A: Biol. Sci. Med. Sci.64A (5), 516–521. 10.1093/gerona/glp024
29
NelsonJ. F.StrongR.BokovA.DiazV.WardW. (2012). Probing the Relationship between Insulin Sensitivity and Longevity Using Genetically Modified Mice. J. Gerontol. A. Biol. Sci. Med. Sci.67 (12), 1332–1338. 10.1093/gerona/gls199
30
NybergF.HallbergM. (2013). Growth Hormone and Cognitive Function. Nat. Rev. Endocrinol.9 (6), 357–365. 10.1038/nrendo.2013.78
31
OitzlM. S.van HaarstA. D.SutantoW.Ron de KloetE. (1995). Corticosterone, Brain Mineralocorticoid Receptors (MRs) and the Activity of the Hypothalamic-Pituitary-Adrenal (HPA) axis: the Lewis Rat as an Example of Increased central MR Capacity and a Hyporesponsive HPA axis. Psychoneuroendocrinology20 (6), 655–675. 10.1016/0306-4530(95)00003-7
32
PaniciJ. A.HarperJ. M.MillerR. A.BartkeA.SpongA.MasternakM. M. (2010). Early Life Growth Hormone Treatment Shortens Longevity and Decreases Cellular Stress Resistance in Long-Lived Mutant Mice. FASEB J.24 (12), 5073–5079. 10.1096/fj.10-163253
33
PerrettiM.DuncanG. S.FlowerR. J.PeersS. H. (1993). Serum Corticosterone, Interleukin-1 and Tumour Necrosis Factor in Rat Experimental Endotoxaemia: Comparison between Lewis and Wistar Strains. Br. J. Pharmacol.110 (2), 868–874. 10.1111/j.1476-5381.1993.tb13893.x
34
PiperM. D. W.SelmanC.McElweeJ. J.PartridgeL. (2008). Separating Cause from Effect: How Does Insulin/IGF Signalling Control Lifespan in Worms, Flies and Mice. J. Intern. Med.263 (2), 179–191. 10.1111/j.1365-2796.2007.01906.x
35
PodlutskyA.Valcarcel-AresM. N.YanceyK.PodlutskayaV.NagykaldiE.GautamT.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. Geroscience39 (2), 147–160. 10.1007/s11357-017-9966-x
36
Powell-BraxtonL.HollingsheadP.WarburtonC.DowdM.Pitts-MeekS.DaltonD.et al (1993). IGF-I Is Required for normal Embryonic Growth in Mice. Genes Dev.7 (12B), 2609–2617. 10.1101/gad.7.12b.2609
37
SacconT. D.MoreiraF.CruzL. A.MondadoriR. G.FangY.BarrosC. C.et al (2017). Ovarian Aging and the Activation of the Primordial Follicle reserve in the Long-Lived Ames dwarf and the Short-Lived bGH Transgenic Mice. Mol. Cell Endocrinol.455, 23–32. 10.1016/j.mce.2016.10.015
38
SasakiT.TaharaS.ShinkaiT.KuramotoK.MatsumotoS.YanabeM.et al (2013). Lifespan Extension in the Spontaneous dwarf Rat and Enhanced Resistance to Hyperoxia-Induced Mortality. Exp. Gerontol.48 (5), 457–463. 10.1016/j.exger.2013.02.015
39
ScavoL. M.KarasM.MurrayM.LeroithD. (2004). Insulin-like Growth Factor-I Stimulates Both Cell Growth and Lipogenesis during Differentiation of Human Mesenchymal Stem Cells into Adipocytes. J. Clin. Endocrinol. Metab.89 (7), 3543–3553. 10.1210/jc.2003-031682
40
SchneiderA.WoodH. N.GedenS.GreeneC. J.YatesR. M.MasternakM. M.et al (2019). Growth Hormone-Mediated Reprogramming of Macrophage Transcriptome and Effector Functions. Sci. Rep.9 (1), 19348. 10.1038/s41598-019-56017-6
41
SelmanC.LingardS.ChoudhuryA. I.BatterhamR. L.ClaretM.ClementsM.et al (2008). Evidence for Lifespan Extension and Delayed Age-Related Biomarkers in Insulin Receptor Substrate 1 Null Mice. FASEB j.22 (3), 807–818. 10.1096/fj.07-9261com
42
ShimizuT.BabaT.OgawaraM.ShirasawaT. (2011). Lifespan and Glucose Metabolism in Insulin Receptor Mutant Mice. J. Aging Res.2011, 315640. 10.4061/2011/315640
43
ShimokawaI.HigamiY.UtsuyamaM.TuchiyaT.KomatsuT.ChibaT.et al (2002). Life Span Extension by Reduction in Growth Hormone-insulin-like Growth Factor-1 axis in a Transgenic Rat Model. Am. J. Pathol.160 (6), 2259–2265. 10.1016/s0002-9440(10)61173-x
44
SolimanA. R.SolimanM. A.SadekK. M. (2019). Association of Insulin Growth Factor-1 and Growth Hormone Levels in Elderly Renal Transplant Recipients with Cardiac Dysfunction. Saudi J. Kidney Dis. Transpl.30 (1), 62–67.
45
SonntagW. E.CarterC. S.IkenoY.EkenstedtK.CarlsonC. S.LoeserR. F.et al (2005). Adult-onset Growth Hormone and Insulin-like Growth Factor I Deficiency Reduces Neoplastic Disease, Modifies Age-Related Pathology, and Increases Life Span. Endocrinology146 (7), 2920–2932. 10.1210/en.2005-0058
46
StegerR. W.BartkeA.CecimM. (1993). Premature Ageing in Transgenic Mice Expressing Different Growth Hormone Genes. J. Reprod. Fertil. Suppl.46, 61–75.
47
SunL. Y.FangY.PatkiA.KoopmanJ. J.AllisonD. B.HillC. M.et al (2017). Longevity Is Impacted by Growth Hormone Action during Early Postnatal Period. Elife6. 10.7554/eLife.24059
48
SunL. Y.SpongA.SwindellW. R.FangY.HillC.HuberJ. A.et al (2013). Growth Hormone-Releasing Hormone Disruption Extends Lifespan and Regulates Response to Caloric Restriction in Mice. Elife2, e01098. 10.7554/eLife.01098
49
TaguchiA.WartschowL. M.WhiteM. F. (2007). Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis. Science317 (5836), 369–372. 10.1126/science.1142179
50
TakedaE.SuzukiY.YamadaT.KatagiriH.SatoY. (2017). Knockout of Vasohibin-1 Gene in Mice Results in Healthy Longevity with Reduced Expression of Insulin Receptor, Insulin Receptor Substrate 1, and Insulin Receptor Substrate 2 in Their White Adipose Tissue. J. Aging Res.2017, 9851380. 10.1155/2017/9851380
51
TatarM.BartkeA.AntebiA. (2003). The Endocrine Regulation of Aging by Insulin-like Signals. Science299 (5611), 1346–1351. 10.1126/science.1081447
52
TatarM.KopelmanA.EpsteinD.TuM.-P.YinC.-M.GarofaloR. S. (2001). A Mutant Drosophila Insulin Receptor Homolog that Extends Life-Span and Impairs Neuroendocrine Function. Science292 (5514), 107–110. 10.1126/science.1057987
53
TemplemanN. M.FlibotteS.ChikJ. H. L.SinhaS.LimG. E.FosterL. J.et al (2017). Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan. Cel Rep.20 (2), 451–463. 10.1016/j.celrep.2017.06.048
54
ThomasJ. D.MonsonJ. P. (2009). Adult GH Deficiency throughout Lifetime. Eur. J. Endocrinol.161 Suppl 1 (Suppl. 1), S97–S106. 10.1530/EJE-09-0258
55
TissenbaumH. A.RuvkunG. (1998). An Insulin-like Signaling Pathway Affects Both Longevity and Reproduction in Caenorhabditis elegans. Genetics148 (2), 703–717. 10.1093/genetics/148.2.703
56
UngvariZ.GautamT.KonczP.HenthornJ. C.PintoJ. T.BallabhP.et al (2010). Vasoprotective Effects of Life Span-Extending Peripubertal GH Replacement in Lewis dwarf Rats. Journals Gerontol. Ser. A: Biol. Sci. Med. Sci.65A (11), 1145–1156. 10.1093/gerona/glq147
57
UngvariZ.SosnowskaD.PodlutskyA.KonczP.SonntagW. E.CsiszarA. (2011). Free Radical Production, Antioxidant Capacity, and Oxidative Stress Response Signatures in Fibroblasts from Lewis dwarf Rats: Effects of Life Span-Extending Peripubertal GH Treatment. Journals Gerontol. Ser. A: Biol. Sci. Med. Sci.66A (5), 501–510. 10.1093/gerona/glr004
58
van der SpoelE.JansenS. W.AkintolaA. A.BallieuxB. E.CobbaertC. M.SlagboomP. E.et al (2016). Growth Hormone Secretion Is Diminished and Tightly Controlled in Humans Enriched for Familial Longevity. Aging Cell15 (6), 1126–1131. 10.1111/acel.12519
59
VeldhuisJ. D.IranmaneshA.BowersC. Y. (2005). Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men. J. Clin. Endocrinol. Metab.90 (7), 4177–4183. 10.1210/jc.2005-0336
60
VijayakumarA.YakarS.LeroithD. (2011). The Intricate Role of Growth Hormone in Metabolism. Front. Endocrin.2, 32. 10.3389/fendo.2011.00032
61
WolfE.KahntE.EhrleinJ.HermannsW.BremG.WankeR. (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 (1-3), 71–87. 10.1016/0047-6374(93)90141-d
62
XuJ.GontierG.ChakerZ.LacubeP.DupontJ.HolzenbergerM. (2014). Longevity Effect of IGF-1R+/−mutation Depends on Genetic Background-specific Receptor Activation. Aging Cell13 (1), 19–28. 10.1111/acel.12145
63
YakarS.LiuJ.-L.StannardB.ButlerA.AcciliD.SauerB.et al (1999). Normal Growth and Development in the Absence of Hepatic Insulin-like Growth Factor I. Proc. Natl. Acad. Sci.96 (13), 7324–7329. 10.1073/pnas.96.13.7324
64
ZhangY.XieY.BerglundE. D.CoateK. C.HeT. T.KatafuchiT.et al (2012). The Starvation Hormone, Fibroblast Growth Factor-21, Extends Lifespan in Mice. Elife1, e00065. 10.7554/eLife.00065
65
ZhouY.XuB. C.MaheshwariH. G.HeL.ReedM.LozykowskiM.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.94 (24), 13215–13220. 10.1073/pnas.94.24.13215
Summary
Keywords
insulin/insulin-like growth factor signaling, mammalian aging, growth hormone, lifespan, healthspan
Citation
Bartke A and Brown-Borg H (2021) Mutations Affecting Mammalian Aging: GH and GHR vs IGF-1 and Insulin. Front. Genet. 12:667355. doi: 10.3389/fgene.2021.667355
Received
12 February 2021
Accepted
08 November 2021
Published
24 November 2021
Volume
12 - 2021
Edited by
Michael Rera, Centre de Recherches Interdisciplinaires (CRI), France
Reviewed by
Adam Salmon, The University of Texas Health Science Center at San Antonio, United States
Jenny C. Regan, University of Edinburgh, United Kingdom
Updates
Copyright
© 2021 Bartke and Brown-Borg.
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*Correspondence: Andrzej Bartke, abartke@siumed.edu
This article was submitted to Genetics of Aging, a section of the journal Frontiers in Genetics
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