title: Stem cell aging: mechanisms, regulators and therapeutic opportunities.
abstract: Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Oh
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA. [3] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Yang David
authors.initials: YD
authors.lastname: Lee
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Joslin Diabetes Center, Boston, Massachusetts, USA. [3] Howard Hughes Medical Institute, Cambridge, Massachusetts, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D017382:Reactive Oxygen Species; D055153:Stem Cell Niche / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species
references.citation: Nature. 2003 Jul 17;424(6946):277-83
references.pmid: 12845331
references.citation: Blood. 2010 May 20;115(20):4030-8
references.pmid: 20354168
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Feb;64(2):167-70
references.pmid: 19228787
references.citation: Nat Cell Biol. 2010 Feb;12(2):153-63
references.pmid: 20081841
references.citation: Cell. 2010 Nov 24;143(5):813-25
references.pmid: 21111239
references.citation: Cell Res. 2013 Jan;23(1):70-80
references.pmid: 23229514
references.citation: Stem Cells Transl Med. 2013 May;2(5):328-36
references.pmid: 23572052
references.citation: Genome. 2013 Jan;56(1):9-15
references.pmid: 23379334
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: FASEB J. 2004 Feb;18(2):355-7
references.pmid: 14688209
references.citation: Annu Rev Pathol. 2010;5:99-118
references.pmid: 20078217
references.citation: Annu Rev Biochem. 2009;78:959-91
references.pmid: 19298183
references.citation: FASEB J. 2001 Jul;15(9):1589-91
references.pmid: 11427495
references.citation: Nat Genet. 2006 Feb;38(2):251-7
references.pmid: 16380712
references.citation: Nat Rev Mol Cell Biol. 2010 Aug;11(8):567-78
references.pmid: 20651707
references.citation: Nat Cell Biol. 2012 Mar 18;14(4):355-65
references.pmid: 22426077
references.citation: Nat Commun. 2011 Sep 13;2:472
references.pmid: 21915114
references.citation: Cell. 2008 Feb 22;132(4):598-611
references.pmid: 18295578
references.citation: Cell. 2011 Sep 2;146(5):682-95
references.pmid: 21884931
references.citation: Cell. 2010 Dec 23;143(7):1059-71
references.pmid: 21145579
references.citation: Cell Metab. 2007 Apr;5(4):265-77
references.pmid: 17403371
references.citation: Sci Signal. 2009 Nov 24;2(98):ra75
references.pmid: 19934433
references.citation: Nature. 2012 Oct 18;490(7420):355-60
references.pmid: 23023126
references.citation: In Vivo. 2000 Jan-Feb;14(1):183-8
references.pmid: 10757076
references.citation: Cell. 2008 Feb 22;132(4):681-96
references.pmid: 18295583
references.citation: J Exp Med. 2011 Mar 14;208(3):455-67
references.pmid: 21339326
references.citation: Nat Neurosci. 2013 May;16(5):529-31
references.pmid: 23563579
references.citation: Cell Stem Cell. 2009 Nov 6;5(5):527-39
references.pmid: 19896443
references.citation: N Engl J Med. 2006 Apr 27;354(17):1813-26
references.pmid: 16641398
references.citation: Nature. 2011 Nov 02;479(7372):232-6
references.pmid: 22048312
references.citation: Genes Dev. 2008 Mar 1;22(5):654-67
references.pmid: 18283121
references.citation: Nature. 2010 Mar 25;464(7288):520-8
references.pmid: 20336134
references.citation: Blood. 2007 Oct 15;110(8):3056-63
references.pmid: 17595331
references.citation: Cell Metab. 2008 Aug;8(2):99-104
references.pmid: 18680711
references.citation: Cell. 2008 Dec 12;135(6):1118-29
references.pmid: 19062086
references.citation: Nat Rev Mol Cell Biol. 2011 Mar;12(3):198-202
references.pmid: 21304553
references.citation: Nat Biotechnol. 2009 Jan;27(1):84-90
references.pmid: 19060879
references.citation: Nature. 1997 Nov 6;390(6655):30
references.pmid: 9363888
references.citation: Cell Stem Cell. 2013 Apr 4;12(4):413-25
references.pmid: 23415915
references.citation: Cell Stem Cell. 2012 May 4;10(5):515-9
references.pmid: 22560075
references.citation: Nat Med. 2014 Mar;20(3):265-71
references.pmid: 24531379
references.citation: Science. 2000 Apr 28;288(5466):665-9
references.pmid: 10784448
references.citation: Genes Dev. 2005 Mar 15;19(6):756-67
references.pmid: 15769947
references.citation: Science. 2014 May 9;344(6184):649-52
references.pmid: 24797481
references.citation: EMBO J. 1996 Jan 15;15(2):216-25
references.pmid: 8617197
references.citation: Cell. 2007 Jan 26;128(2):325-39
references.pmid: 17254970
references.citation: Cell. 2005 Feb 25;120(4):513-22
references.pmid: 15734683
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):470-8
references.pmid: 18371382
references.citation: J Exp Med. 2008 Sep 29;205(10):2397-408
references.pmid: 18809716
references.citation: Cell Rep. 2013 Feb 21;3(2):319-27
references.pmid: 23375372
references.citation: Cell. 2013 May 9;153(4):828-39
references.pmid: 23663781
references.citation: Trends Genet. 2013 Sep;29(9):513-20
references.pmid: 23876621
references.citation: Cell Stem Cell. 2011 Jan 7;8(1):31-45
references.pmid: 21185252
references.citation: Nature. 2010 Jul 15;466(7304):383-7
references.pmid: 20555324
references.citation: Aging Cell. 2009 Dec;8(6):676-89
references.pmid: 19732043
references.citation: Nature. 2011 Jan 6;469(7328):102-6
references.pmid: 21113150
references.citation: Nature. 2013 Feb 21;494(7437):323-7
references.pmid: 23389440
references.citation: Aging Cell. 2004 Apr;3(2):53-4
references.pmid: 15038818
references.citation: Nat Cell Biol. 2010 Jun;12(6):572-82
references.pmid: 20473297
references.citation: Stem Cell Reports. 2014 Mar 27;2(4):534-46
references.pmid: 24749076
references.citation: Stem Cells. 2014 Feb;32(2):462-72
references.pmid: 24123326
references.citation: Nature. 2014 Feb 20;506(7488):316-21
references.pmid: 24522534
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):846-51
references.pmid: 9927656
references.citation: Nature. 2011 Oct 19;479(7373):365-71
references.pmid: 22012258
references.citation: Mech Ageing Dev. 1994 Oct 20;76(2-3):215-24
references.pmid: 7885066
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):458-69
references.pmid: 18371381
references.citation: Mech Ageing Dev. 2008 Mar;129(3):163-73
references.pmid: 18241911
references.citation: Nat Cell Biol. 2014 Mar;16(3):201-7
references.pmid: 24576896
references.citation: Nature. 2007 Jun 7;447(7145):725-9
references.pmid: 17554309
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20376-81
references.pmid: 22021441
references.citation: Nature. 2003 Feb 6;421(6923):643-8
references.pmid: 12540856
references.citation: Aging (Albany NY). 2009 Dec 30;1(12):979-87
references.pmid: 20157581
references.citation: Nat Med. 2008 Sep;14(9):959-65
references.pmid: 18690243
references.citation: Cancer Cell. 2010 Jan 19;17(1):41-52
references.pmid: 20129246
references.citation: Nature. 2006 May 25;441(7092):518-22
references.pmid: 16633340
references.citation: Nature. 2003 Jan 9;421(6919):182-7
references.pmid: 12483226
references.citation: J Clin Invest. 2014 Jan;124(1):353-66
references.pmid: 24316971
references.citation: J Pharmacol Sci. 2008 Apr;106(4):571-7
references.pmid: 18385540
references.citation: Cell. 2008 Jul 11;134(1):37-47
references.pmid: 18614009
references.citation: Cell Stem Cell. 2012 Jan 6;10(1):96-103
references.pmid: 22226359
references.citation: Cell Stem Cell. 2009 Nov 6;5(5):540-53
references.pmid: 19896444
references.citation: Hepatology. 2009 May;49(5):1655-63
references.pmid: 19309719
references.citation: Gastroenterology. 2008 Feb;134(2):500-10
references.pmid: 18242216
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4230-5
references.pmid: 20160104
references.citation: PLoS One. 2009 Jun 11;4(6):e5888
references.pmid: 19517018
references.citation: Cell. 2008 Nov 14;135(4):609-22
references.pmid: 19013273
references.citation: Gastroenterology. 2012 Nov;143(5):1266-1276
references.pmid: 22841781
references.citation: Science. 2008 Feb 15;319(5865):916-9
references.pmid: 18276881
references.citation: Trends Cell Biol. 2012 Jan;22(1):42-9
references.pmid: 22177962
references.citation: Genes Dev. 2014 Jan 15;28(2):99-114
references.pmid: 24449267
references.citation: Exp Gerontol. 1980;15(6):575-91
references.pmid: 7009178
references.citation: Nature. 2004 Oct 21;431(7011):997-1002
references.pmid: 15496926
references.citation: Nature. 2012 Jun 28;486(7404):490-5
references.pmid: 22722868
references.citation: Mol Biol Cell. 2004 Feb;15(2):657-64
references.pmid: 14668486
references.citation: Trends Biochem Sci. 2010 Sep;35(9):505-13
references.pmid: 20430626
references.citation: Aging (Albany NY). 2012 Oct;4(10):686-94
references.pmid: 23104863
references.citation: Mutat Res. 2013 Mar-Apr;743-744:160-168
references.pmid: 23562804
references.citation: Ageing Res Rev. 2014 Jan;13:55-64
references.pmid: 24333965
references.citation: J Clin Invest. 2013 Mar;123(3):951-7
references.pmid: 23454757
references.citation: J Embryol Exp Morphol. 1962 Dec;10:622-40
references.pmid: 13951335
references.citation: Stem Cells. 2006 Jun;24(6):1505-11
references.pmid: 16456131
references.citation: Mutat Res. 2006 Jul 25;599(1-2):11-20
references.pmid: 16490220
references.citation: Nat Commun. 2012 Feb 28;3:708
references.pmid: 22426229
references.citation: Mol Cell Biol. 2004 May;24(10):4275-93
references.pmid: 15121848
references.citation: J Neurosci. 1996 Mar 15;16(6):2027-33
references.pmid: 8604047
references.citation: Cell Signal. 2011 Jul;23(7):1076-81
references.pmid: 21144894
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12325-30
references.pmid: 21746928
references.citation: Mol Ther. 2010 Oct;18(10):1865-73
references.pmid: 20664528
references.citation: Cell Stem Cell. 2011 May 6;8(5):499-510
references.pmid: 21549326
references.citation: Cell Metab. 2007 Oct;6(4):280-93
references.pmid: 17908557
references.citation: Development. 2011 Sep;138(17):3625-37
references.pmid: 21828091
references.citation: Blood. 2013 May 23;121(21):4257-64
references.pmid: 23476050
references.citation: Cell Stem Cell. 2014 May 1;14(5):673-88
references.pmid: 24792119
references.citation: Cell Stem Cell. 2012 May 4;10(5):610-9
references.pmid: 22560081
references.citation: Am J Clin Nutr. 1972 Aug;25(8):839-43
references.pmid: 5046729
references.citation: EMBO J. 2001 Jun 1;20(11):2619-30
references.pmid: 11387197
references.citation: Oncogene. 2008 Apr 7;27(16):2320-36
references.pmid: 18391974
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):101-12
references.pmid: 18371339
references.citation: Nature. 2006 Sep 28;443(7110):421-6
references.pmid: 16957735
references.citation: J Biol Chem. 2008 Sep 12;283(37):25692-25705
references.pmid: 18424439
references.citation: Science. 2010 May 7;328(5979):753-6
references.pmid: 20448184
references.citation: Dev Biol. 2013 Oct 1;382(1):124-35
references.pmid: 23895933
references.citation: Nat Med. 2006 Apr;12(4):446-51
references.pmid: 16565722
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 May 1;302(9):G914-24
references.pmid: 22345551
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8191-6
references.pmid: 12034875
references.citation: Cell. 2005 Feb 25;120(4):437-47
references.pmid: 15734677
references.citation: PLoS One. 2012;7(12):e52787
references.pmid: 23300777
references.citation: Nat Commun. 2014 Jun 10;5:4082
references.pmid: 24915299
references.citation: Nature. 1999 Dec 2;402(6761):551-5
references.pmid: 10591218
references.citation: Aging Cell. 2003 Apr;2(2):131-9
references.pmid: 12882326
references.citation: Bioinformatics. 2009 Apr 1;25(7):875-81
references.pmid: 19189975
references.citation: Nature. 2012 Sep 13;489(7415):304-8
references.pmid: 22972301
references.citation: J Clin Invest. 2003 Nov;112(9):1351-60
references.pmid: 14597761
references.citation: Pulm Pharmacol Ther. 2007;20(1):9-22
references.pmid: 16458553
references.citation: Cell Metab. 2012 Jan 4;15(1):100-9
references.pmid: 22225879
references.citation: Nature. 2011 Jan 20;469(7330):415-8
references.pmid: 21113151
references.citation: Nat Med. 2014 Mar;20(3):255-64
references.pmid: 24531378
references.citation: Trends Genet. 2007 Aug;23(8):413-8
references.pmid: 17559965
references.citation: Cell Stem Cell. 2013 Jan 3;12(1):49-61
references.pmid: 23290136
references.citation: Nature. 2007 Jun 7;447(7145):686-90
references.pmid: 17554302
references.citation: J Neurosci. 2004 Feb 18;24(7):1726-33
references.pmid: 14973255
references.citation: Cell Stem Cell. 2013 Feb 7;12(2):238-51
references.pmid: 23246482
references.citation: Nature. 2002 Apr 4;416(6880):507-11
references.pmid: 11932737
references.citation: Cell Stem Cell. 2013 Jan 3;12(1):62-74
references.pmid: 23290137
references.citation: J Immunol. 2008 Apr 15;180(8):5707-19
references.pmid: 18390756
references.citation: Mol Cell. 2010 Oct 22;40(2):179-204
references.pmid: 20965415
references.citation: Science. 2005 Jul 15;309(5733):481-4
references.pmid: 16020738
references.citation: Cell Mol Life Sci. 2013 Jun;70(11):2015-29
references.pmid: 23283301
references.citation: Cell Stem Cell. 2012 May 4;10(5):520-30
references.pmid: 22560076
references.citation: Nature. 2010 Dec 2;468(7324):653-8
references.pmid: 21124450
references.citation: Ageing Res Rev. 2013 Mar;12(2):661-84
references.pmid: 22353384
references.citation: Oncogene. 2009 Jun 4;28(22):2238-43
references.pmid: 19398954
references.citation: Science. 2003 Nov 28;302(5650):1575-7
references.pmid: 14645852
references.citation: PLoS One. 2011 Mar 07;6(3):e17487
references.pmid: 21408175
references.citation: Stem Cell Reports. 2013 Nov 27;1(6):620-31
references.pmid: 24371814
references.citation: J Cell Mol Med. 2012 Jul;16(7):1353-64
references.pmid: 22129481
references.citation: Semin Cell Dev Biol. 2011 Jul;22(5):482-7
references.pmid: 21571086
references.citation: Antioxid Redox Signal. 2009 Nov;11(11):2777-89
references.pmid: 19650689
references.citation: Nature. 2009 Sep 24;461(7263):537-41
references.pmid: 19727075
references.citation: Cell Metab. 2012 May 2;15(5):675-90
references.pmid: 22560220
references.citation: Nature. 2011 Aug 31;477(7362):90-4
references.pmid: 21886162
references.citation: Mol Biol Cell. 2008 Mar;19(3):1210-9
references.pmid: 18184747
references.citation: Nature. 2005 Feb 17;433(7027):760-4
references.pmid: 15716955
references.citation: Development. 2013 Jun;140(12):2457-61
references.pmid: 23715538
references.citation: Cell Stem Cell. 2013 Apr 4;12(4):393-4
references.pmid: 23561441
references.citation: Antioxid Redox Signal. 2014 Apr 20;20(12):1902-16
references.pmid: 24383555
references.citation: Ann N Y Acad Sci. 2000 Jun;908:244-54
references.pmid: 10911963
references.citation: Annu Rev Pathol. 2013 Jan 24;8:441-75
references.pmid: 23121053
references.citation: Cell. 2013 Dec 19;155(7):1624-38
references.pmid: 24360282
references.citation: Blood. 2013 Mar 28;121(13):2483-93
references.pmid: 23341543
references.citation: J Mol Med (Berl). 2012 Apr;90(4):389-400
references.pmid: 22038097
references.citation: Nat Rev Immunol. 2013 May;13(5):376-89
references.pmid: 23584423
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:365-73
references.pmid: 15033754
references.citation: Hum Mol Genet. 2001 Jul 1;10(14):1511-8
references.pmid: 11448943
references.citation: Am J Pathol. 2012 Mar;180(3):963-972
references.pmid: 22210478
references.citation: Rejuvenation Res. 2008 Apr;11(2):489-92
references.pmid: 18442329
references.citation: Cell Stem Cell. 2010 Aug 6;7(2):174-85
references.pmid: 20619762
references.citation: Aging (Albany NY). 2013 Sep;5(9):662-81
references.pmid: 24038661
references.citation: Nat Rev Mol Cell Biol. 2013 Jun;14(6):329-40
references.pmid: 23698583
references.citation: J Neurosci Res. 2009 Aug 1;87(10):2183-200
references.pmid: 19301431
references.citation: Nature. 2004 May 27;429(6990):417-23
references.pmid: 15164064
references.citation: Philos Trans R Soc Lond B Biol Sci. 2011 Jan 12;366(1561):85-93
references.pmid: 21115534
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723
references.citation: Cell Metab. 2011 Nov 2;14(5):623-34
references.pmid: 22055505
references.citation: Cell Stem Cell. 2014 Jul 3;15(1):37-50
references.pmid: 24813857
references.citation: Cold Spring Harb Perspect Biol. 2011 May 01;3(5):
references.pmid: 21441594
references.citation: Science. 2014 May 9;344(6184):630-4
references.pmid: 24797482
references.citation: Brain. 2012 Nov;135(Pt 11):3298-310
references.pmid: 23169920
references.citation: Nature. 2006 Sep 28;443(7110):448-52
references.pmid: 16957738
references.citation: J Neurochem. 2002 Sep;82(6):1367-75
references.pmid: 12354284
references.citation: Biochim Biophys Acta. 1995 Dec 27;1264(3):397-402
references.pmid: 8547329
references.citation: Science. 2000 Mar 10;287(5459):1804-8
references.pmid: 10710306