title: FOXO3: A Major Gene for Human Longevity--A Mini-Review.
abstract: BACKGROUND
  The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations.
  
  
  OBJECTIVE
  Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity.
  
  
  METHODS
  The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword.
  
  
  RESULTS
  We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis.
  
  
  CONCLUSIONS
  The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.
authors.affiliation: Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
authors.forename: Donald Craig
authors.initials: DC
authors.lastname: Willcox
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Donlon
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Willcox
mesh_terms: D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D008136:Longevity / Q000235:genetics*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors
references.citation: J Biol Chem. 2008 Mar 28;283(13):8211-7
references.pmid: 18195003
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19697-702
references.pmid: 23150562
references.citation: Cell Metab. 2012 Mar 7;15(3):372-81
references.pmid: 22405072
references.citation: J Biol Chem. 2005 Aug 19;280(33):29864-73
references.pmid: 15961397
references.citation: J Hypertens. 2005 Jul;23(7):1285-309
references.pmid: 15942449
references.citation: Aging Cell. 2013 Dec;12 (6):1041-9
references.pmid: 23834676
references.citation: Cell Metab. 2013 Apr 2;17(4):491-506
references.pmid: 23562075
references.citation: Eur J Hum Genet. 2007 Mar;15(3):294-301
references.pmid: 17245409
references.citation: Biochim Biophys Acta. 2011 Nov;1813(11):1978-86
references.pmid: 21440011
references.citation: Asian J Androl. 2014 May-Jun;16(3):446-52
references.pmid: 24589462
references.citation: Dev Growth Differ. 2010 Jan;52(1):15-25
references.pmid: 19891641
references.citation: J Gerontol A Biol Sci Med Sci. 2015 Jan;70(1):110-8
references.pmid: 25199915
references.citation: Nature. 2010 Jan 21;463(7279):369-73
references.pmid: 20090753
references.citation: J Biol Chem. 2003 Dec 12;278(50):49795-805
references.pmid: 14527951
references.citation: Ann N Y Acad Sci. 2007 Oct;1114:407-18
references.pmid: 17804521
references.citation: Nat Immunol. 2009 May;10 (5):504-13
references.pmid: 19363483
references.citation: PLoS One. 2012;7(4):e34218
references.pmid: 22514624
references.citation: Mol Syst Biol. 2013;9:638
references.pmid: 23340844
references.citation: J Clin Endocrinol Metab. 2011 Jan;96(1):E119-24
references.pmid: 20881262
references.citation: J Gerontol A Biol Sci Med Sci. 2015 Apr;70(4):426-33
references.pmid: 24895270
references.citation: PLoS One. 2014 May 07;9(5):e94385
references.pmid: 24804734
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):101-12
references.pmid: 18371339
references.citation: PLoS One. 2013 Dec 20;8(12 ):e83620
references.pmid: 24376725
references.citation: J Biol Chem. 2005 May 27;280(21):20814-23
references.pmid: 15781459
references.citation: Immunity. 2004 Aug;21(2):203-13
references.pmid: 15308101
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92
references.pmid: 18765803
references.citation: BMC Cancer. 2014 Sep 11;14 :661
references.pmid: 25208626
references.citation: Cell Metab. 2014 Mar 4;19(3):418-30
references.pmid: 24606899
references.citation: J Biol Chem. 2013 Oct 11;288(41):29252-9
references.pmid: 23974119
references.citation: Trends Pharmacol Sci. 2014 Mar;35(3):146-54
references.pmid: 24439680
references.citation: Bioessays. 2013 Nov;35(11):994-1003
references.pmid: 24037777
references.citation: EMBO J. 2013 Oct 2;32(19):2589-602
references.pmid: 24013118
references.citation: Science. 2003 Jan 24;299(5606):572-4
references.pmid: 12543978
references.citation: Genome Res. 2014 May;24(5):733-42
references.pmid: 24760347
references.citation: Cell. 2007 Jan 26;128(2):325-39
references.pmid: 17254970
references.citation: Cell. 2011 Sep 2;146(5):697-708
references.pmid: 21884932
references.citation: Cell Rep. 2013 Aug 15;4(3):477-91
references.pmid: 23891001
references.citation: Cell. 2007 Jan 26;128(2):309-23
references.pmid: 17254969
references.citation: Nat Rev Mol Cell Biol. 2013 Feb;14(2):83-97
references.pmid: 23325358
references.citation: Lancet. 2012 Mar 10;379(9819):895-904
references.pmid: 22336189
references.citation: Bioessays. 2013 Dec;35(12):1101-10
references.pmid: 24142536
references.citation: J Gerontol A Biol Sci Med Sci. 2012 Nov;67(11):1132-9
references.pmid: 22459618
references.citation: Nat Cell Biol. 2011 Jul 31;13(9):1092-9
references.pmid: 21804543
references.citation: Nature. 2010 Mar 25;464(7288):504-12
references.pmid: 20336132
references.citation: J Biol Chem. 2011 Sep 2;286(35):30888-97
references.pmid: 21730069
references.citation: Ann N Y Acad Sci. 2010 Aug;1204:156-62
references.pmid: 20738286
references.citation: J Cell Biochem. 2012 Mar;113(3):833-40
references.pmid: 22021079
references.citation: Stem Cell Reports. 2014 Jun 06;3(1):44-59
references.pmid: 25068121
references.citation: Hum Genet. 2013 Dec;132(12):1323-38
references.pmid: 23925498
references.citation: Science. 2001 Apr 6;292(5514):107-10
references.pmid: 11292875
references.citation: Science. 2004 Jul 16;305(5682):361
references.pmid: 15192154
references.citation: J Clin Invest. 2007 Aug;117(8):2133-44
references.pmid: 17671650
references.citation: J Biol Chem. 2011 Mar 4;286(9):7468-78
references.pmid: 21159781
references.citation: Mol Cell Biol. 2008 Oct;28(19):5886-98
references.pmid: 18644865
references.citation: Mech Ageing Dev. 2007 Jan;128(1):92-105
references.pmid: 17116321
references.citation: Nature. 1993 Dec 2;366(6454):461-4
references.pmid: 8247153
references.citation: Oncogene. 2005 Mar 31;24(14 ):2317-29
references.pmid: 15688014
references.citation: Circ Res. 2007 Feb 16;100(3):372-80
references.pmid: 17234971
references.citation: Stem Cell Reports. 2014 Mar 20;2(4):414-26
references.pmid: 24749067
references.citation: Mol Cell Biol. 2007 Jul;27(13):4917-30
references.pmid: 17452451
references.citation: Cell. 2013 Sep 26;155(1):57-69
references.pmid: 24035192
references.citation: Stem Cell Reports. 2013 Oct 24;1(5):397-410
references.pmid: 24286028
references.citation: Free Radic Biol Med. 2013 Mar;56:133-71
references.pmid: 23104101
references.citation: Dev Cell. 2010 Apr 20;18(4):592-604
references.pmid: 20412774
references.citation: Autoimmunity. 2007 Sep;40(6):462-9
references.pmid: 17729040
references.citation: J Gerontol A Biol Sci Med Sci. 2012 May;67(5):470-9
references.pmid: 22499766
references.citation: Trends Biochem Sci. 2014 Apr;39(4):159-69
references.pmid: 24630600
references.citation: Microsc Res Tech. 2002 Nov 15;59(4):331-4
references.pmid: 12424797
references.citation: J Exp Med. 2006 Jul 10;203(7):1657-63
references.pmid: 16801400