Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function.
Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson-Gilford progeria syndrome. In this work, we report that progeroid Zmpste24(-/-) mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24(-/-) mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.
Mariño
Guillermo
G
Departamento de Bioquímica y Biología Molecular and Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Ugalde
Alejandro P
AP
Fernández
Alvaro F
AF
Osorio
Fernando G
FG
Fueyo
Antonio
A
Freije
José M P
JM
López-Otín
Carlos
C
D019588:Aging, Premature / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000187:drug effects*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D008666:Metalloendopeptidases / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D052683:Somatotrophs / Q000187:drug effects*
D008565:Membrane Proteins; D035683:MicroRNAs; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse
J Biol Chem. 1993 Mar 15;268(8):5376-81
8449901
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6868-73
10823924
Nat Med. 2005 Jul;11(7):780-5
15980864
Hormones (Athens). 2008 Jan-Mar;7(1):24-7
18359741
Endocrinology. 1999 Aug;140(8):3693-704
10433229
Nature. 2003 Jan 9;421(6919):182-7
12483226
Cell. 2005 Feb 25;120(4):437-47
15734677
Mol Endocrinol. 2010 Jan;24(1):204-17
19884384
PLoS Genet. 2006 Dec 15;2(12):e192
17173483
PLoS Biol. 2007 Jan;5(1):e2
17326724
Hum Mol Genet. 2008 Jul 15;17(14):2196-211
18443001
Endocrinology. 1997 Jul;138(7):2937-47
9202238
Nat Rev Mol Cell Biol. 2005 Jan;6(1):21-31
15688064
Nature. 2008 Aug 28;454(7208):1065-71
18756247
Autophagy. 2008 Aug;4(6):807-9
18612261
Nat Genet. 2002 May;31(1):94-9
11923874
Nat Cell Biol. 2009 May;11(5):604-15
19363488
Am J Med Genet A. 2006 Dec 1;140(23):2603-24
16838330
Growth Horm IGF Res. 2000 Oct;10(5):236-41
11042019
Nat Rev Drug Discov. 2007 Oct;6(10):821-33
17906644
Endocrinology. 2005 Sep;146(9):3718-23
15919742
Nature. 2006 Dec 21;444(7122):1038-43
17183314
J Endocrinol Invest. 2005;28(5 Suppl):43-6
16114275
Nature. 2005 Sep 22;437(7058):564-8
16079796
Nature. 1993 Dec 2;366(6454):461-4
8247153
Mech Ageing Dev. 2008 Jul-Aug;129(7-8):449-59
18513784
Science. 2001 Apr 6;292(5514):107-10
11292875
Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R490-7
18495839
J Clin Invest. 2004 Jan;113(1):96-105
14702113
N Engl J Med. 2009 Oct 8;361(15):1475-85
19812404
J Clin Endocrinol Metab. 2004 Mar;89(3):1031-44
15001582
Nat Rev Mol Cell Biol. 2007 May;8(5):394-404
17450177
Circulation. 2009 Dec 8;120(23):2377-85
19933931
Biochem Biophys Res Commun. 2009 Apr 17;381(4):597-601
19245789
Nat Cell Biol. 2008 Nov;10(11):1241-7
18978832
Mol Endocrinol. 2006 Feb;20(2):241-53
16037128
J Cell Biol. 1999 Nov 29;147(5):913-20
10579712
Methods. 2001 Dec;25(4):402-8
11846609
Transgenic Res. 2009 Feb;18(1):7-15
19015945
J Cell Biol. 2008 Apr 7;181(1):27-35
18378773
Annu Rev Cell Dev Biol. 2007;23:175-205
17506695
Endocrinology. 2003 Sep;144(9):3799-810
12933651
Nat Rev Mol Cell Biol. 2007 Sep;8(9):681-91
17684529
Mech Ageing Dev. 1993 May;68(1-3):71-87
8350664
Mol Cell Biol. 2005 Jan;25(1):66-77
15601831
Cell Mol Life Sci. 2007 Jan;64(2):155-70
17131053
Endocrinology. 2002 Feb;143(2):492-503
11796503
Nat Med. 2008 Jul;14(7):767-72
18587406
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13049-54
12235369
Cell. 1984 Apr;36(4):805-12
6323022
Metabolism. 1997 Aug;46(8):851-6
9258264