title: Metformin improves healthspan and lifespan in mice.
abstract: Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martin-Montalvo
authors.forename: Evi M
authors.initials: EM
authors.lastname: Mercken
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.forename: Hector H
authors.initials: HH
authors.lastname: Palacios
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Mote
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ward
authors.forename: Robin K
authors.initials: RK
authors.lastname: Minor
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Blouin
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yinbing
authors.initials: Y
authors.lastname: Yu
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.forename: Norman S
authors.initials: NS
authors.lastname: Wolf
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spindler
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D031204:Caloric Restriction; D004579:Electron Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006262:Health; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D008136:Longevity / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D008687:Metformin; D055372:AMP-Activated Protein Kinases
references.citation: Diabetologia. 2010 Nov;53(11):2406-16
references.pmid: 20652679
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2497-506
references.pmid: 18375721
references.citation: Cell Metab. 2008 Aug;8(2):157-68
references.pmid: 18599363
references.citation: J Nutr. 2012 Feb;142(2):213-20
references.pmid: 22223580
references.citation: Toxicol Pathol. 1995 Jul-Aug;23(4):458-76
references.pmid: 7501958
references.citation: Biochim Biophys Acta. 2012 Oct;1817(10):1768-75
references.pmid: 22386881
references.citation: Aging (Albany NY). 2011 Oct;3(10):1028-38
references.pmid: 22067284
references.citation: Am J Epidemiol. 2010 Sep 1;172(5):558-65
references.pmid: 20682520
references.citation: J Hepatol. 2012 Sep;57(3):642-54
references.pmid: 22634126
references.citation: Sci Transl Med. 2012 Mar 7;4(124):124ra27
references.pmid: 22323820
references.citation: Physiol Genomics. 2005 Nov 17;23(3):343-50
references.pmid: 16189280
references.citation: Diabet Med. 1992 Jan-Feb;9(1):61-5
references.pmid: 1551312
references.citation: BMC Bioinformatics. 2005 Jun 08;6:144
references.pmid: 15941488
references.citation: Oncogene. 2013 Mar 21;32(12):1475-87
references.pmid: 22665053
references.citation: Mini Rev Med Chem. 2008 Nov;8(13):1343-54
references.pmid: 18991752
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8977-82
references.pmid: 22611195
references.citation: Curr Drug Targets Immune Endocr Metabol Disord. 2003 Jun;3(2):151-69
references.pmid: 12769787
references.citation: Free Radic Biol Med. 2010 Sep 15;49(6):1082-7
references.pmid: 20600832
references.citation: J Mol Diagn. 2003 May;5(2):73-81
references.pmid: 12707371
references.citation: J Clin Invest. 2001 Oct;108(8):1167-74
references.pmid: 11602624
references.citation: Nature. 2009 Jul 16;460(7253):392-5
references.pmid: 19587680
references.citation: FEBS Lett. 2008 Jan 9;582(1):97-105
references.pmid: 18053812
references.citation: Biochem Biophys Res Commun. 2010 May 28;396(2):199-205
references.pmid: 20398632
references.citation: Aging (Albany NY). 2011 Feb;3(2):148-57
references.pmid: 21386129
references.citation: Toxicol Lett. 2009 Mar 10;185(2):132-41
references.pmid: 19136048
references.citation: Aging (Albany NY). 2010 Dec;2(12):945-58
references.pmid: 21164223
references.citation: Diabetes. 2008 Feb;57(2):306-14
references.pmid: 17909097
references.citation: Cancer Res. 2011 Jul 1;71(13):4366-72
references.pmid: 21540236
references.citation: Aging Cell. 2006 Feb;5(1):39-50
references.pmid: 16441842
references.citation: Nature. 2006 Nov 16;444(7117):337-42
references.pmid: 17086191
references.citation: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
references.pmid: 22436748
references.citation: Diabetes Care. 2010 Jul;33(7):1674-85
references.pmid: 20587728
references.citation: Diabetes Care. 2009 Sep;32(9):1620-5
references.pmid: 19564453
references.citation: Cancer Discov. 2012 Sep;2(9):778-90
references.pmid: 22926251
references.citation: PLoS One. 2012;7(10):e47699
references.pmid: 23077661
references.citation: J Biol Chem. 2004 Jun 18;279(25):25995-6004
references.pmid: 15078893
references.citation: Cardiovasc Res. 2010 May 1;86(2):211-8
references.pmid: 20202975
references.citation: Antioxid Redox Signal. 2013 Jul 20;19(3):310-20
references.pmid: 22901095
references.citation: Cell. 2009 May 15;137(4):635-46
references.pmid: 19450513
references.citation: J Biol Chem. 2011 Jun 3;286(22):19270-9
references.pmid: 21467030
references.citation: J Gerontol A Biol Sci Med Sci. 2010 May;65(5):468-74
references.pmid: 20304770
references.citation: Ugeskr Laeger. 2012 Jun 4;174(23):1598-602
references.pmid: 22673379
references.citation: Diabetes. 2004 Apr;53(4):1052-9
references.pmid: 15047621
references.citation: Rev Esp Anestesiol Reanim. 2012 May;59(5):276-9
references.pmid: 22609263
references.citation: PLoS One. 2010 Jan 18;5(1):e8758
references.pmid: 20090912
references.citation: Oncogene. 2011 Feb 3;30(5):505-20
references.pmid: 21057541
references.citation: Brain Res Mol Brain Res. 2005 Mar 24;134(1):109-18
references.pmid: 15790535
references.citation: Cancer Prev Res (Phila). 2012 Apr;5(4):536-43
references.pmid: 22262811
references.citation: Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E182-9
references.pmid: 16478780
references.citation: Diabetologia. 2012 Feb;55(2):443-9
references.pmid: 22009334
references.citation: J Biol Chem. 2000 Jan 7;275(1):223-8
references.pmid: 10617608