title: Longevity effect of IGF-1R(+/-) mutation depends on genetic background-specific receptor activation.
abstract: Growth hormone (GH) and insulin-like growth factor (IGF) signaling regulates lifespan in mice. The modulating effects of genetic background gained much attention because it was shown that life-prolonging effects in Snell dwarf and GH receptor knockout vary between mouse strains. We previously reported that heterozygous IGF-1R inactivation (IGF-1R(+/-) ) extends lifespan in female mice on 129/SvPas background, but it remained unclear whether this mutation produces a similar effect in other genetic backgrounds and which molecules possibly modify this effect. Here, we measured the life-prolonging effect of IGF-1R(+/-) mutation in C57BL/6J background and investigated the role of insulin/IGF signaling molecules in strain-dependent differences. We found significant lifespan extension in female IGF-1R(+/-) mutants on C57BL/6J background, but the effect was smaller than in 129/SvPas, suggesting strain-specific penetrance of longevity phenotypes. Comparing GH/IGF pathways between wild-type 129/SvPas and C57BL/6J mice, we found that circulating IGF-I and activation of IGF-1R, IRS-1, and IRS-2 were markedly elevated in 129/SvPas, while activation of IGF pathways was constitutively low in spontaneously long-lived C57BL/6J mice. Importantly, we demonstrated that loss of one IGF-1R allele diminished the level of activated IGF-1R and IRS more profoundly and triggered stronger endocrine feedback in 129/SvPas background than in C57BL/6J. We also revealed that acute oxidative stress entails robust IGF-1R pathway activation, which could account for the fact that IGF-1R(+/-) stress resistance phenotypes are fully penetrant in both backgrounds. Together, these results provide a possible explanation why IGF-1R(+/-) was less efficient in extending lifespan in C57BL/6J compared with 129/SvPas.
authors.affiliation: INSERM, Hôpital Saint-Antoine, Paris, 75012, France; Université Pierre et Marie Curie, UPMC, Paris, 75005, France.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Géraldine
authors.initials: G
authors.lastname: Gontier
authors.forename: Zayna
authors.initials: Z
authors.lastname: Chaker
authors.forename: Philippe
authors.initials: P
authors.lastname: Lacube
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dupont
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
mesh_terms: D000818:Animals; D049628:Body Size / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity; D019000:Phosphotyrosine / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D013002:Somatomedins; D019000:Phosphotyrosine; D017526:Receptor, IGF Type 1; D005947:Glucose; D010269:Paraquat
keywords: Genetic background; IGF-I; IRS; gene knockout; lifespan; stress resistance
references.citation: Diabetes. 2003 Jun;52(6):1528-34
references.pmid: 12765966
references.citation: Aging Cell. 2010 Feb;9(1):92-5
references.pmid: 19878144
references.citation: Exp Gerontol. 2003 Nov-Dec;38(11-12):1353-64
references.pmid: 14698816
references.citation: Science. 2003 Jan 24;299(5606):572-4
references.pmid: 12543978
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92
references.pmid: 18765803
references.citation: Endocrinology. 2000 Jul;141(7):2608-13
references.pmid: 10875265
references.citation: Respir Res. 2005 Apr 08;6:31
references.pmid: 15819984
references.citation: Endocrinology. 2003 Sep;144(9):3799-810
references.pmid: 12933651
references.citation: Mol Endocrinol. 2004 Mar;18(3):747-60
references.pmid: 14684848
references.citation: Biochem Biophys Res Commun. 2011 Sep 30;413(3):476-80
references.pmid: 21910970
references.citation: Nature. 2010 Mar 25;464(7288):504-12
references.pmid: 20336132
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7324-9
references.pmid: 10377413
references.citation: Endocrinology. 2000 Jul;141(7):2557-66
references.pmid: 10875258
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42
references.pmid: 18316725
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):302-10
references.pmid: 17315038
references.citation: PLoS One. 2011;6(11):e26891
references.pmid: 22132081
references.citation: Aging Cell. 2009 Jun;8(3):277-87
references.pmid: 19627267
references.citation: Science. 2008 May 23;320(5879):1012; author reply 1012
references.pmid: 18497277
references.citation: Aging Cell. 2009 Aug;8(4):346-52
references.pmid: 19485964
references.citation: Mol Biol Cell. 2008 May;19(5):2014-25
references.pmid: 18287535
references.citation: J Endocrinol. 2011 Feb;208(2):119-29
references.pmid: 21045135
references.citation: PLoS One. 2012;7(9):e44777
references.pmid: 23024761
references.citation: FASEB J. 2008 Mar;22(3):807-18
references.pmid: 17928362
references.citation: Science. 2007 Jul 20;317(5836):369-72
references.pmid: 17641201
references.citation: Endocrinology. 2004 Jul;145(7):3307-23
references.pmid: 15044376
references.citation: Genome Res. 2004 Sep;14(9):1806-11
references.pmid: 15342563
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6736-41
references.pmid: 11371619
references.citation: Mech Ageing Dev. 2002 Jan;123(2-3):121-30
references.pmid: 11718806
references.citation: Cell. 2005 Feb 25;120(4):449-60
references.pmid: 15734678
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2700-5
references.pmid: 19196970
references.citation: Nature. 2003 Jan 9;421(6919):182-7
references.pmid: 12483226
references.citation: Hum Mol Genet. 2002 Oct 1;11(20):2463-8
references.pmid: 12351582
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7901-5
references.pmid: 16682650
references.citation: J Clin Invest. 2004 Jan;113(1):96-105
references.pmid: 14702113
references.citation: J Biol Chem. 2002 Sep 27;277(39):36740-7
references.pmid: 12101187
references.citation: Cell. 1993 Oct 8;75(1):59-72
references.pmid: 8402901
references.citation: Aging Cell. 2010 Oct;9(5):823-36
references.pmid: 20735370
references.citation: Nat Genet. 1999 Sep;23(1):32-40
references.pmid: 10471495
references.citation: Growth Horm IGF Res. 2008 Dec;18(6):455-71
references.pmid: 18710818
references.citation: PLoS One. 2011;6(7):e22640
references.pmid: 21799924
references.citation: Aging Cell. 2009 Aug;8(4):460-72
references.pmid: 19489743
references.citation: Mamm Genome. 1997 Jun;8(6):390-3
references.pmid: 9166580
references.citation: Science. 2009 Oct 2;326(5949):140-4
references.pmid: 19797661
references.citation: PLoS One. 2011 Jan 25;6(1):e16144
references.pmid: 21283571
references.citation: Aging Cell. 2010 Dec;9(6):1010-7
references.pmid: 20849522
references.citation: Hum Mol Genet. 2009 Dec 15;18(24):4897-904
references.pmid: 19793722
references.citation: Nat Genet. 1997 May;16(1):19-27
references.pmid: 9140391
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7088-92
references.pmid: 10359843
references.citation: J Biol Chem. 2000 Nov 17;275(46):35893-901
references.pmid: 10967123
references.citation: Mol Pharmacol. 2009 Aug;76(2):215-28
references.pmid: 19483103
references.citation: PLoS Biol. 2008 Oct 28;6(10):e254
references.pmid: 18959478
references.citation: Endocrinology. 2009 Jan;150(1):314-23
references.pmid: 18801897
references.citation: Ageing Res Rev. 2012 Apr;11(2):254-70
references.pmid: 22210149
references.citation: Proc Natl Acad Sci U S A. 2012 May 22;109(21):8224-9
references.pmid: 22566614
references.citation: Growth Horm IGF Res. 2001 Oct;11(5):303-13
references.pmid: 11735249