One of the key characteristics of aging is a progressive loss of physiological integrity, which weakens bodily functions and increases the risk of death. A robust biomarker is important for the assessment of biological age, the rate of aging, and a person's health status. DNA methylation clocks, novel biomarkers of aging, are composed of a group of cytosine-phosphate-guanine dinucleotides, the DNA methylation status of which can be used to accurately measure subjective age. These clocks are considered accurate biomarkers of chronological age for humans and other vertebrates. Numerous studies have demonstrated these clocks to quantify the rate of biological aging and the effects of longevity and anti-aging interventions. In this review, we describe the purpose and use of DNA methylation clocks in aging research.
Soto-Perez-de-CelisELiDYuanYLauYMHurriaA.Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol2018;
19:e305–16
2.
StubbsTMBonderMJStarkAKKruegerFvon MeyennFStegleOReikW.Multi-tissue DNA methylation age predictor in mouse. Genome Biol2017;
18:68
3.
HannumGGuinneyJZhaoLZhangLHughesGSaddaSKlotzleBBibikovaMFanJBGaoYDecondeRChenMRajapakseIFriendSIdekerTZhangK.Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell2013;
49:359–67
4.
HorvathS.DNA methylation age of human tissues and cell types. Genome Biol2013;
14:R115
5.
HorvathSOshimaJMartinGMLuATQuachACohenHFeltonSMatsuyamaMLoweDKabacikSWilsonJGReinerAPMaierhoferAFlunkertJAvivAHouLBaccarelliAALiYStewartJDWhitselEAFerrucciLMatsuyamaSRajK.Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY)2018;
10:1758–75
FahyGMBrookeRTWatsonJPGoodZVasanawalaSSMaeckerHLeipoldMDLinDTSKoborMSHorvathS.Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell2019;
18:e13028
8.
JylhäväJPedersenNLHäggS.Biological age predictors. EBioMedicine2017;
21:29–36
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor MGL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigó R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X. The sequence of the human genome. Science 2001;291:1304-51
11.
JonesPA.Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet2012;
13:484–92
12.
ChiappinelliKBStrisselPLDesrichardALiHHenkeCAkmanBHeinARoteNSCopeLMSnyderAMakarovVBudhuSSlamonDJWolchokJDPardollDMBeckmannMWZahnowCAMerghoubTChanTABaylinSBStrickR.Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell2015;
162:974–86
13.
OhtaniHLiuMZhouWLiangGJonesPA.Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. Genome Res2018;
28:1147–57
14.
LiSYParkJGuanYChungKShresthaRPalmerMBSusztakK.DNMT1 in Six2 progenitor cells is essential for transposable element silencing and kidney development. J Am Soc Nephrol2019;
30:594–609
15.
MohandasTSparkesRSShapiroLJ.Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. Science1981;
211:393–6
16.
LessingDDialTOWeiCPayerBCarretteLLKesnerBSzantoAJadhavAMaloneyDJSimeonovATheriaultJHasakaTBedalovABartolomeiMSLeeJT.A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation. Proc Natl Acad Sci USA2016;
113:14366–71
17.
WatersSALivernoisAMPatelHO'MeallyDCraigJMMarshallGJASuterCMWatersPD.Landscape of DNA methylation on the marsupial X. Mol Biol Evol2018;
35:431–9
18.
GoldenLCItohYItohNIyengarSCoitPSalamaYArnoldAPSawalhaAHVoskuhlRR.Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes. Proc Natl Acad Sci USA2019;
116:26779–87
19.
Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, Das PK, Kivioja T, Dave K, Zhong F, Nitta KR, Taipale M, Popov A, Ginno PA, Domcke S, Yan J, Schübeler D, Vinson C, Taipale J. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 2017;
356:eaaj2239
20.
Wiehle L, Thorn GJ, Raddatz G, Clarkson CT, Rippe K, Lyko F, Breiling A, Teif VB.
DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries. Genome Res2019;
29:750–61
21.
Wiehle L, Thorn GJ, Raddatz G, Clarkson CT, Rippe K, Lyko F, Breiling A, Teif VB. DNA (de)methylation in embryonic stem cells controls CTCF-dependent chromatin boundaries. Genome Res 2019;29:750-61
22.
GreenbergMVCBourc'HisD.The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol2019;
20:590–607
23.
LiTWangLDuYXieSYangXLianFZhouZQianC.Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA methylation. Nucleic Acids Res2018;
46:3218–31
24.
ZhangHGaoQTanSYouJLyuCZhangYHanMChenZLiJWangHLiaoLQinJLiJWongJ.SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1. Nucleic Acids Res2019;
47:9053–68
25.
ArandJSpielerDKariusTBrancoMRMeilingerDMeissnerAJenuweinTXuGLeonhardtHWolfVWalterJ.In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet2012;
8:e1002750
26.
LiYZhangZChenJLiuWLaiWLiuBLiXLiuLXuSDongQWangMDuanXTanJZhengYZhangPFanGWongJXuGLWangZWangHGaoSZhuB.Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature2018;
564:136–40
27.
YarychkivskaOShahabuddinZComfortNBoulardMBestorTH.BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo. J Biol Chem2018;
293:19466–75
FangSLiJXiaoYLeeMGuoLHanWLiTHillMCHongTMoWXuRZhangPWangFChangJZhouYSunDMartinJFHuangY.TET inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development. Nat Commun2019;
10:4297
30.
BeckDBPetracoviciAHeCMooreHWLouieRJAnsarMDouzgouSSithambaramSCottrellTSantos-CortezRLPPrijolesEJBendRKerenBMignotCNouguesMCÕunapKReimandTPajusaluSZahidMSaqibMANBurattiJSeabyEGMcWalterKTelegrafiABaldridgeDShinawiMLealSMSchaeferGBStevensonREBankaSBonasioRFahrnerJA.Delineation of a human Mendelian disorder of the DNA demethylation machinery: TET3 deficiency. Am J Hum Genet2020;
106:234–45
31.
StevensonTJPrendergastBJ.Reversible DNA methylation regulates seasonal photoperiodic time measurement. Proc Natl Acad Sci USA2013;
110:16651–6
32.
CoulsonRLYasuiDHDunawayKWLauferBIVogelCAZhuYMordauntCETotahTSLaSalleJM.Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nat Commun2018;
9:1616
33.
WangLOzarkPASmithERZhaoZMarshallSARendlemanEJPiuntiARyanCWhelanALHelminKAMorganMAZouLSingerBDShilatifardA.TET2 coactivates gene expression through demethylation of enhancers. Sci Adv2018;
4:eaau6986
34.
MaegawaSHinkalGKimHSShenLZhangLZhangJZhangNLiangSDonehowerLAIssaJP.Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res2010;
20:332–40
35.
SliekerRCvan ItersonMLuijkR, Beekman M, Zhernakova DV, Moed MH, Mei H, van Galen M, Deelen P, Bonder MJ, Zhernakova A, Uitterlinden AG, Tigchelaar EF, Stehouwer CD, Schalkwijk CG, van der Kallen CJ, Hofman A, van Heemst D, de Geus EJ, van Dongen J, Deelen J, van den Berg LH, van Meurs J, Jansen R, T HPA, Franke L, Wijmenga C, Veldink JH, Swertz MA, van Greevenbroek MM, van Duijn CM, Boomsma DI, Slagboom PE, HeijmansBT.Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biol2016;
17:191
36.
Hernando-HerraezIEvanoBStubbsTCommerePHJanBMClarkSAndrewsSTajbakhshSReikW.Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat Commun2019;
10:4361
37.
HeynHLiNFerreiraHJMoranSPisanoDGGomezADiezJSanchez-MutJVSetienFCarmonaFJPucaAASayolsSPujanaMASerra-MusachJIglesias-PlatasIFormigaFFernandezAFFragaMFHeathSCValenciaAGutIGWangJEstellerM.Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci USA2012;
109:10522–7
38.
RakyanVKDownTAMaslauSAndrewTYangTPBeyanHWhittakerPMcCannOTFinerSValdesAMLeslieRDDeloukasPSpectorTD.Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res2010;
20:434–9
39.
BeermanIBockCGarrisonBSSmithZDGuHMeissnerARossiDJ.Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell2013;
12:413–25
40.
ZhouWDinhHQRamjanZWeisenbergerDJNicoletCMShenHLairdPWBermanBP.DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat Genet2018;
50:591–602
41.
ThompsonRFAtzmonGGheorgheCLiangHQLowesCGreallyJMBarzilaiN.Tissue-specific dysregulation of DNA methylation in aging. Aging Cell2010;
9:506–18
42.
BellCGLoweRAdamsPDBaccarelliAABeckSBellJTChristensenBCGladyshevVNHeijmansBTHorvathSIdekerTIssaJJKelseyKTMarioniREReikWReltonCLSchalkwykLCTeschendorffAEWagnerWZhangKRakyanVK.DNA methylation aging clocks: challenges and recommendations. Genome Biol2019;
20:249
43.
BocklandtSLinWSehlMESánchezFJSinsheimerJSHorvathSVilainE.Epigenetic predictor of age. PLoS One2011;
6:e14821
44.
LiCGaoWGaoYYuCLvJLvRDuanJSunYGuoXCaoWLiL.Age prediction of children and adolescents aged 6-17 years: an epigenome-wide analysis of DNA methylation. Aging (Albany NY)2018;
10:1015–26
45.
McEwenLMO'DonnellKJMcGillMG , Edgar RD, Jones MJ, MacIsaac JL, Lin DTS, Ramadori K, Morin A, Gladish N, Garg E, Unternaehrer E, Pokhvisneva I, Karnani N, Kee MZL, Klengel T, Adler NE, Barr RG, Letourneau N, Giesbrecht GF, Reynolds JN, Czamara D, Armstrong JM, Essex MJ, de Weerth C, Beijers R, Tollenaar MS, Bradley B, Jovanovic T, Ressler KJ, Steiner M, Entringer S, Wadhwa PD, Buss C, Bush NR, Binder EB, Boyce WT, Meaney MJ, Horvath S, KoborMS.The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells. Proc Natl Acad Sci USA2020;
117:23329–35
46.
WuXChenWLinFHuangQZhongJGaoHSongYLiangH.DNA methylation profile is a quantitative measure of biological aging in children. Aging (Albany NY)2019;
11:10031–51
47.
WeidnerCILinQKochCMEiseleLBeierFZieglerPBauerschlagDOJöckelKHErbelRMühleisenTWZenkeMBrümmendorfTHWagnerW.Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol2014;
15:R24
48.
BekaertBKamalanduaAZapicoSCVan de VoordeWDecorteR.Improved age determination of blood and teeth samples using a selected set of DNA methylation markers. Epigenetics2015;
10:922–30
49.
EipelMMayerFArentTFerreiraMRBirkhoferCGerstenmaierUCostaIGRitz-TimmeSWagnerW.Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures. Aging (Albany NY)2016;
8:1034–48
50.
HamanoYManabeSMorimotoCFujimotoSOzekiMTamakiK.Forensic age prediction for dead or living samples by use of methylation-sensitive high resolution melting. Leg Med (Tokyo)2016;
21:5–10
51.
BacaliniMGDeelenJPirazziniCDe CeccoMGiulianiCLanzariniCRavaioliFMarascoEvan HeemstDSuchimanHEDSliekerRGiampieriERecchioniRMarcheselliFSalvioliSVitaleGOlivieriFSpijkermanAMWDolléMETSedivyJMCastellaniGFranceschiCSlagboomPEGaragnaniP.Systemic age-associated DNA hypermethylation of ELOVL2 gene: in vivo and in vitro evidences of a cell replication process. J Gerontol A Biol Sci Med Sci2017;
72:1015–23
52.
DayKWaiteLLThalacker-MercerAWestABammanMMBrooksJDMyersRMAbsherD.Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol2013;
14:R102
53.
McEwenLMJonesMJLinDTSEdgarRDHusquinLTMacIsaacJLRamadoriKEMorinAMRiderCFCarlstenCQuintana-MurciLHorvathSKoborMS.Systematic evaluation of DNA methylation age estimation with common preprocessing methods and the Infinium MethylationEPIC BeadChip array. Clin Epigenetics2018;
10:123
54.
LevineMELuATQuachAChenBHAssimesTLBandinelliSHouLBaccarelliAAStewartJDLiYWhitselEAWilsonJGReinerAPAvivALohmanKLiuYFerrucciLHorvathS.An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY)2018;
10:573–91
PetkovichDAPodolskiyDILobanovAVLeeSGMillerRAGladyshevVN.Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab2017;
25:954–60.e6
59.
WangTTsuiBKreisbergJFRobertsonNAGrossAMYuMKCarterHBrown-BorgHMAdamsPDIdekerT.Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol2017;
18:57
60.
MeerMVPodolskiyDITyshkovskiyAGladyshevVN.A whole lifespan mouse multi-tissue DNA methylation clock. Elife2018;
7:e40675
61.
ThompsonMJVonHoldtBHorvathSPellegriniM.An epigenetic aging clock for dogs and wolves. Aging (Albany NY)2017;
9:1055–68
62.
ColeJJRobertsonNARatherMIThomsonJPMcBryanTSproulDWangTBrockCClarkWIdekerTMeehanRRMillerRABrown-BorgHMAdamsPD.Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol2017;
18:58
63.
HahnOGrönkeSStubbsTMFiczGHendrichOKruegerFAndrewsSZhangQWakelamMJBeyerAReikWPartridgeL.Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol2017;
18:56
64.
RusliFBoekschotenMVBorelliVSunCLuteCMenkeALvan den HeuvelJSalvioliSFranceschiCMüllerMSteegengaWT.Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age. Aging Cell2018;
17:e12696
65.
ThompsonMJChwiałkowskaKRubbiLLusisAJDavisRCSrivastavaAKorstanjeRChurchillGAHorvathSPellegriniM.A multi-tissue full lifespan epigenetic clock for mice. Aging (Albany NY)2018;
10:2832–54
66.
ZhangQVallergaCLWalkerRM, Lin T, Henders AK, Montgomery GW, He J, Fan D, Fowdar J, Kennedy M, Pitcher T, Pearson J, Halliday G, Kwok JB, Hickie I, Lewis S, Anderson T, Silburn PA, Mellick GD, Harris SE, Redmond P, Murray AD, Porteous DJ, Haley CS, Evans KL, McIntosh AM, Yang J, Gratten J, Marioni RE, Wray NR, Deary IJ, McRae AF, VisscherPM.Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing. Genome Med2019;
11:54
67.
AmbatipudiSHorvathSPerrierF, Cuenin C, Hernandez-Vargas H, Le Calvez-Kelm F, Durand G, Byrnes G, Ferrari P, Bouaoun L, Sklias A, Chajes V, Overvad K, Severi G, Baglietto L, Clavel-Chapelon F, Kaaks R, Barrdahl M, Boeing H, Trichopoulou A, Lagiou P, Naska A, Masala G, Agnoli C, Polidoro S, Tumino R, Panico S, Dollé M, Peeters PHM, Onland-Moret NC, Sandanger TM, Nøst TH, Weiderpass E, Quirós JR, Agudo A, Rodriguez-Barranco M, Huerta Castaño JM, Barricarte A, Fernández AM, Travis RC, Vineis P, Muller DC, Riboli E, Gunter M, Romieu I, HercegZ.DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility. Eur J Cancer)2017;
75:299–307
68.
KresovichJKXuZO'BrienKMWeinbergCRSandlerDPTaylorJA.Methylation-based biological age and breast cancer risk. J Natl Cancer Inst2019;
111:1051–8
69.
MarioniREShahSMcRaeAF, Chen BH, Colicino E, Harris SE, Gibson J, Henders AK, Redmond P, Cox SR, Pattie A, Corley J, Murphy L, Martin NG, Montgomery GW, Feinberg AP, Fallin MD, Multhaup ML, Jaffe AE, Joehanes R, Schwartz J, Just AC, Lunetta KL, Murabito JM, Starr JM, Horvath S, Baccarelli AA, Levy D, Visscher PM, Wray NR, DearyIJ.DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol2015;
16:25
70.
ChenBHMarioniREColicinoE, Peters MJ, Ward-Caviness CK, Tsai PC, Roetker NS, Just AC, Demerath EW, Guan W, Bressler J, Fornage M, Studenski S, Vandiver AR, Moore AZ, Tanaka T, Kiel DP, Liang L, Vokonas P, Schwartz J, Lunetta KL, Murabito JM, Bandinelli S, Hernandez DG, Melzer D, Nalls M, Pilling LC, Price TR, Singleton AB, Gieger C, Holle R, Kretschmer A, Kronenberg F, Kunze S, Linseisen J, Meisinger C, Rathmann W, Waldenberger M, Visscher PM, Shah S, Wray NR, McRae AF, Franco OH, Hofman A, Uitterlinden AG, Absher D, Assimes T, Levine ME, Lu AT, Tsao PS, Hou L, Manson JE, Carty CL, LaCroix AZ, Reiner AP, Spector TD, Feinberg AP, Levy D, Baccarelli A, van Meurs J, Bell JT, Peters A, Deary IJ, Pankow JS, Ferrucci L, HorvathS.DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY)2016;
8:1844–65
71.
DuguéPABassettJKJooJEJungCHMingWEMoreno-BetancurMSchmidtDMakalicELiSSeveriGHodgeAMBuchananDDEnglishDRHopperJLSoutheyMCGilesGGMilneRL.DNA methylation-based biological aging and cancer risk and survival: pooled analysis of seven prospective studies. Int J Cancer2018;
142:1611–9
72.
DuguéPABassettJKJooJEBagliettoLJungCHWongEMFioritoGSchmidtDMakalicELiSMoreno-BetancurMBuchananDDVineisPEnglishDRHopperJLSeveriGSoutheyMCGilesGGMilneRL.Association of DNA methylation-based biological age with health risk factors and overall and cause-specific mortality. Am J Epidemiol2018;
187:529–38
73.
MarioniREHarrisSEShahSMcRaeAFvon ZglinickiTMartin-RuizCWrayNRVisscherPMDearyIJ.The epigenetic clock and telomere length are independently associated with chronological age and mortality. Int J Epidemiol2018;
45:424–32
74.
FransquetPDWrigglesworthJWoodsRLErnstMERyanJ.The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis. Clin Epigenetics2019;
11:62
75.
PernaLZhangYMonsUHolleczekBSaumKUBrennerH.Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics2016;
8:64
76.
ChristiansenLLenartATanQVaupelJWAvivAMcGueMChristensenK.DNA methylation age is associated with mortality in a longitudinal Danish twin study. Aging Cell2016;
15:149–54
77.
KresovichJKXuZO'BrienKMWeinbergCRSandlerDPTaylorJA.Epigenetic mortality predictors and incidence of breast cancer. Aging (Albany NY)2019;
11:11975–87
78.
LevineMEHosgoodHDChenBAbsherDAssimesTHorvathS.DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative. Aging (Albany NY)2015;
7:690–700
79.
ZhengCLiLXuR.Association of epigenetic clock with consensus molecular subtypes and overall survival of colorectal cancer.Cancer Epidemiol Biomarkers Prev2019;
28:1720–4
80.
LindLIngelssonESundströmJSiegbahnALampaE.Methylation-based estimated biological age and cardiovascular disease. Eur J Clin Invest2018;
48
81.
RoetkerNSPankowJSBresslerJMorrisonACBoerwinkleE.Prospective study of epigenetic age acceleration and incidence of cardiovascular disease outcomes in the ARIC study (Atherosclerosis Risk in Communities). Circ Genom Precis Med2018;
11:e001937
82.
HorvathSGurvenMLevineMETrumbleBCKaplanHAllayeeHRitzBRChenBLuATRickabaughTMJamiesonBDSunDLiSChenWQuintana-MurciLFagnyMKoborMSTsaoPSReinerAPEdlefsenKLAbsherDAssimesTL.An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol2016;
17:171
83.
Soriano-TárragaCGiralt-SteinhauerEMola-CaminalMVivanco-HidalgoRMOisARodríguez-CampelloACuadrado-GodiaESayols-BaixerasSElosuaRRoquerJJiménez-CondeJ.Ischemic stroke patients are biologically older than their chronological age. Aging (Albany NY)2016;
8:2655–66
84.
Soriano-TárragaCMola-CaminalMGiralt-SteinhauerEOisARodríguez-CampelloACuadrado-GodiaEGómez-GonzálezAVivanco-HidalgoRMFernández-CadenasICullellNRoquerJJiménez-CondeJ.Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke. Neurology2017;
89:830–6
85.
Soriano-TárragaCGiralt-SteinhauerEMola-CaminalMOisARodríguez-CampelloACuadrado-GodiaEFernández-CadenasICullellNRoquerJJiménez-CondeJ.Biological age is a predictor of mortality in ischemic stroke. Sci Rep2018;
8:4148
86.
MarioniREShahSMcRaeAFRitchieSJMuniz-TerreraGHarrisSEGibsonJRedmondPCoxSR, PACorleyJTaylorAMurphyLStarrJMHorvathSVisscherPMWrayNRDearyIJ.The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int J Epidemiol2015;
44:1388–96
87.
GaleCRMarioniREHarrisSEStarrJMDearyIJ.DNA methylation and the epigenetic clock in relation to physical frailty in older people: the Lothian Birth Cohort 1936. Clin Epigenetics2018;
10:101
88.
Hillary RF, Stevenson AJ, Cox SR, McCartney DL, Harris SE, Seeboth A, Higham J, Sproul D, Taylor AM, Redmond P, Corley J, Pattie A, Hernández M, Muñoz-Maniega S, Bastin ME, Wardlaw JM, Horvath S, Ritchie CW, Spires-Jones TL, McIntosh AM, Evans KL, Deary IJ, Marioni RE. An epigenetic predictor of death captures multi-modal measures of brain health. Molecular psychiatry 2019;
89.
LevineMELuATBennettDAHorvathS.Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning. Aging (Albany NY)2015;
7:1198–211
90.
HorvathSLangfelderPKwakSAaronsonJRosinskiJVogtTFEszesMFaullRLCurtisMAWaldvogelHJChoiOWTungSVintersHVCoppolaGYangXW.Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. Aging (Albany NY)2016;
8:1485–512
91.
Nwanaji-EnweremJCColicinoETrevisiLKloogIJustACShenJBrennanKDereixAHouLVokonasPSchwartzJBaccarelliAA.Long-term ambient particle exposures and blood DNA methylation age: findings from the VA normative aging study. Environ Epigenet2016;
2:dvw006
92.
Nwanaji-EnweremJCDaiLColicinoEOulhoteYDiQKloogIJustACHouLVokonasPBaccarelliAAWeisskopfMGSchwartzJD.Associations between long-term exposure to PM(2.5) component species and blood DNA methylation age in the elderly: the VA normative aging study. Environ Int2017;
102:57–65
93.
Ward-CavinessCKNwanaji-EnweremJCWolfKWahlSColicinoETrevisiLKloogIJustACVokonasPCyrysJGiegerCSchwartzJBaccarelliAASchneiderAPetersA.Long-term exposure to air pollution is associated with biological aging. Oncotarget2016;
7:74510–25
94.
WhiteAJKresovichJKKellerJPXuZKaufmanJDWeinbergCRTaylorJASandlerDP.Air pollution, particulate matter composition and methylation-based biologic age. Environ Int2019;
132:105071
95.
QuachALevineMETanakaTLuATChenBHFerrucciLRitzBBandinelliSNeuhouserMLBeasleyJMSnetselaarLWallaceRBTsaoPSAbsherDAssimesTLStewartJDLiYHouLBaccarelliAAWhitselEAHorvathS.Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY)2017;
9:419–46
96.
McCartneyDLStevensonAJWalkerRMGibsonJMorrisSWCampbellAMurrayADWhalleyHCPorteousDJMcIntoshAMEvansKLDearyIJMarioniRE.Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring2018;
10:429–37
97.
SimonsRLLeiMKBeachSRPhilibertRACutronaCEGibbonsFXBarrA.Economic hardship and biological weathering: the epigenetics of aging in a U.S. sample of black women. Soc Sci Med2016;
150:192–200
98.
BinderAMCorvalanCMericqVPereiraASantosJLHorvathSShepherdJMichelsKB.Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Epigenetics2018;
13:85–94
99.
AustinMKChenERossKMMcEwenLMMaclsaacJLKoborMSMillerGE.Early-life socioeconomic disadvantage, not current, predicts accelerated epigenetic aging of monocytes. Psychoneuroendocrinology2018;
97:131–4
100.
SimpkinAJHoweLDTillingKGauntTRLyttletonOMcArdleWLRingSMHorvathSSmithGDReltonCL.The epigenetic clock and physical development during childhood and adolescence: longitudinal analysis from a UK birth cohort. Int J Epidemiol2017;
46:549–58
101.
GaoXZhangYBreitlingLPBrennerH.Relationship of tobacco smoking and smoking-related DNA methylation with epigenetic age acceleration. Oncotarget2016;
7:46878–89
102.
IrvinMRAslibekyanSDoAZhiDHidalgoBClaasSASrinivasasainagendraVHorvathSTiwariHKAbsherDMArnettDK.Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. Clin Epigenetics2018;
10:56
103.
BeachSRDoganMVLeiMKCutronaCEGerrardMGibbonsFXSimonsRLBrodyGHPhilibertRA.Methylomic aging as a window onto the influence of lifestyle: tobacco and alcohol use alter the rate of biological aging. J Am Geriatr Soc2015;
63:2519–25
104.
de Toro-MartínJGuénardFTchernofAHouldFSLebelSJulienFMarceauSVohlMC.Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity. Clin Epigenetics2019;
11:172
105.
NevalainenTKananenLMarttilaSJylhäväJMononenNKähönenMRaitakariOTHervonenAJylhäMLehtimäkiTHurmeM.Obesity accelerates epigenetic aging in middle-aged but not in elderly individuals. Clin Epigenetics2017;
9:20
106.
HorvathSErhartWBroschMAmmerpohlOvon SchönfelsWAhrensMHeitsNBellJTTsaiPCSpectorTDDeloukasPSiebertRSiposBBeckerTRöckenCSchafmayerCHampeJ.Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci USA2014;
111:15538–43
107.
ChenMWongEMNguyenTLDiteGSStoneJDuguéPAGilesGGSoutheyMCMilneRLHopperJLLiS.DNA methylation-based biological age, genome-wide average DNA methylation, and conventional breast cancer risk factors. Sci Rep2019;
9:15055
108.
ZannasASArlothJCarrillo-RoaTIuratoSRöhSResslerKJNemeroffCBSmithAKBradleyBHeimCMenkeALangeJFBrücklTIsingMWrayNRErhardtABinderEBMehtaD.Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol2015;
16:266
109.
LawnRBAndersonELSudermanMSimpkinAJGauntTRTeschendorffAEWidschwendterMHardyRKuhDReltonCLHoweLD.Psychosocial adversity and socioeconomic position during childhood and epigenetic age: analysis of two prospective cohort studies. Hum Mol Genet2018;
27:1301–8
110.
WolfEJManiatesHNugentN, Maihofer AX, Armstrong D, Ratanatharathorn A, Ashley-Koch AE, Garrett M, Kimbrel NA, Lori A, Va Mid-Atlantic Mirecc W, Aiello AE, Baker DG, Beckham JC, Boks MP, Galea S, Geuze E, Hauser MA, Kessler RC, Koenen KC, Miller MW, Ressler KJ, Risbrough V, Rutten BPF, Stein MB, Ursano RJ, Vermetten E, Vinkers CH, Uddin M, Smith AK, Nievergelt CM, LogueMW.Traumatic stress and accelerated DNA methylation age: a meta-analysis. Psychoneuroendocrinology2018;
92:123–34
111.
BoksMPvan MierloHCRuttenBPRadstakeTRDe WitteLGeuzeEHorvathSSchalkwykLCVinkersCHBroenJCVermettenE.Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder. Psychoneuroendocrinology2015;
51:506–12
112.
MehtaDBruenigDLawfordBHarveyWCarrillo-RoaTMorrisCPJovanovicTYoungRMBinderEBVoiseyJ.Accelerated DNA methylation aging and increased resilience in veterans: the biological cost for soldiering on. Neurobiol Stress2018;
8:112–9
113.
WolfEJLogueMWStoopTBSchichmanSAStoneASadehNHayesJPMillerMW.Accelerated DNA methylation age: associations with posttraumatic stress disorder and mortality. Psychosom Med2018;
80:42–8
114.
WolfEJLogueMWHayesJPSadehNSchichmanSAStoneASalatDHMilbergWMcGlincheyRMillerMW.Accelerated DNA methylation age: associations with PTSD and neural integrity. Psychoneuroendocrinology2016;
63:155–62
115.
McKinneyBCLinHDingYLewisDASweetRA.DNA methylation age is not accelerated in brain or blood of subjects with schizophrenia. Schizophr Res2018;
196:39–44
116.
FriesGRBauerIEScainiGValvassoriSSWalss-BassCSoaresJCQuevedoJ.Accelerated hippocampal biological aging in bipolar disorder. Bipolar Disord2019.doi: 10.1111/bdi.12876.
117.
FriesGRBauerIEScainiGWuMJKazimiIFValvassoriSSZunta-SoaresGWalss-BassCSoaresJCQuevedoJ.Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder. Transl Psychiatry2017;
7:1283
118.
MatsuyamaMWuWongDJHorvathSMatsuyamaS.Epigenetic clock analysis of human fibroblasts in vitro: effects of hypoxia, donor age, and expression of hTERT and SV40 largeT. Aging (Albany NY)2019;
11:3012–22
119.
CarreauAEl Hafny-RahbiBMatejukAGrillonCKiedaC.Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med2011;
15:1239–53
120.
SturmGCardenasABindMAHorvathSWangSWangYHäggSHiranoMPicardM.Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts. Epigenetics2019;
14:961–76
121.
JylhäväJHjelmborgJSoerensenMMunozETanQKuja-HalkolaRMengel-FromJChristensenKChristiansenLHäggSPedersenNLReynoldsCA.Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age: evidence from two twin cohorts. EBioMedicine2019;
40:710–6
122.
KananenLMarttilaSNevalainenTKummolaLJunttilaIMononenNKähönenMRaitakariOTHervonenAJylhäMLehtimäkiTHurmeMJylhäväJ.The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies. Age (Dordr)2016;
38:65
123.
SøraasAMatsuyamaMde LimaMWaldDBuechnerJGedde-DahlTSøraasCLChenBFerrucciLDahlJAHorvathSMatsuyamaS.Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells. Aging Cell2019;
18:e12897
124.
LuATHannonELevineMEHaoKCrimminsEMLunnonKKozlenkovAMillJDrachevaSHorvathS.Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum. Nat Commun2016;
7:10561
125.
LuATHannonELevineMECrimminsEMLunnonKMillJGeschwindDHHorvathS.Genetic architecture of epigenetic and neuronal ageing rates in human brain regions. Nat Commun2017;
8:15353
126.
LuATXueLSalfatiELChenBH, Ferrucci L, Levy D, Joehanes R, Murabito JM, Kiel DP, Tsai PC, Yet I, Bell JT, Mangino M, Tanaka T, McRae AF, Marioni RE, Visscher PM, Wray NR, Deary IJ, Levine ME, Quach A, Assimes T, Tsao PS, Absher D, Stewart JD, Li Y, Reiner AP, Hou L, Baccarelli AA, Whitsel EA, Aviv A, Cardona A, Day FR, Wareham NJ, Perry JRB, Ong KK, Raj K, Lunetta KL, HorvathS.GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nat Commun2018;
9:387
127.
Martin-HerranzDEAref-EshghiEBonderMJStubbsTMChoufaniSWeksbergRStegleOSadikovicBReikWThorntonJM.Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1. Genome Biol2019;
20:146
128.
LiXWangJWangLFengGLiGYuMLiYLiuCYuanXZangGLiZZhaoLOuyangHQuanQWangGZhangCLiOXiangJZhuJKLiWZhouQZhangK.Impaired lipid metabolism by age-dependent DNA methylation alterations accelerates aging. Proc Natl Acad Sci USA2020;
117:4328–36
129.
SoukasAAHaoHWuL.Metformin as anti-aging therapy: is it for everyone?Trends Endocrinol Metab2019;
30:745–55
130.
HorvathSLuATCohenHRajK.Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation. Aging (Albany NY)2019;
11:3238–49
