2022
Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease
Thrush KL, Bennett DA, Gaiteri C, Horvath S, Dyck CHV, Higgins-Chen AT, Levine ME. Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer’s disease. Aging 2022, 14: 5641-5668. PMID: 35907208, PMCID: PMC9365556, DOI: 10.18632/aging.204196.Peer-Reviewed Original ResearchMeSH KeywordsAgingAlzheimer DiseaseBrainDNA MethylationEpigenesis, GeneticHumansReproducibility of ResultsConceptsDisease risk increasesBrain agingAD brain tissueΕ4 carrier statusClinical AD dementiaMultiple brain regionsEpigenetic alterationsReligious Orders StudyAD dementiaTest-retest reliabilityCortical samplesAD riskEpigenetic age accelerationSubcortical regionsPathologic ADAlzheimer's diseaseBrain regionsBrain tissueEpigenetic clocksCarrier statusStrong associationRush MemoryAge accelerationRisk increaseAging ProjectA computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking
Higgins-Chen AT, Thrush KL, Wang Y, Minteer CJ, Kuo PL, Wang M, Niimi P, Sturm G, Lin J, Moore AZ, Bandinelli S, Vinkers CH, Vermetten E, Rutten BPF, Geuze E, Okhuijsen-Pfeifer C, van der Horst MZ, Schreiter S, Gutwinski S, Luykx JJ, Picard M, Ferrucci L, Crimmins EM, Boks MP, Hägg S, Hu-Seliger TT, Levine ME. A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking. Nature Aging 2022, 2: 644-661. PMID: 36277076, PMCID: PMC9586209, DOI: 10.1038/s43587-022-00248-2.Peer-Reviewed Original ResearchEvidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes
Rozenblit M, Hofstatter E, Liu Z, O’Meara T, Storniolo AM, Dalela D, Singh V, Pusztai L, Levine M. Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes. Clinical Epigenetics 2022, 14: 30. PMID: 35209953, PMCID: PMC8876160, DOI: 10.1186/s13148-022-01249-z.Peer-Reviewed Original ResearchConceptsNormal breast tissueBreast cancerEpigenetic age accelerationBreast tissuePeripheral bloodAge accelerationStrong risk factorBreast cancer riskTissue/blood samplesGood surrogate markerBreast cancer diagnosisHealthy controlsRisk factorsSurrogate markerCancer riskBlood samplesTumor tissueCancerCancer diagnosisNew scoreTissueUnaffected individualsBloodEpigenetic aging signaturesEpigenetic agingTick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock
Minteer C, Morselli M, Meer M, Cao J, Higgins‐Chen A, Lang SM, Pellegrini M, Yan Q, Levine ME. Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock. Aging Cell 2022, 21: e13553. PMID: 35104377, PMCID: PMC8844113, DOI: 10.1111/acel.13553.Peer-Reviewed Original ResearchConceptsMouse embryonic fibroblastsDNA methylationEpigenetic agingImportant chromatin regulatorsPolycomb group (PcG) factorsAnti-aging interventionsChromatin regulatorsEmbryonic fibroblastsCellular senescenceTissue agingCellular agingEpigenetic clocksMultiple tissuesMouse tissuesCaloric restrictionMechanistic insightsAging changesKidney fibroblastsReduced representationTime pointsPhysiological agingMouse culturesSuch alterationsTick-TockTissueEpigenetic aging of the demographically non-aging naked mole-rat
Kerepesi C, Meer MV, Ablaeva J, Amoroso VG, Lee SG, Zhang B, Gerashchenko MV, Trapp A, Yim SH, Lu AT, Levine ME, Seluanov A, Horvath S, Park TJ, Gorbunova V, Gladyshev VN. Epigenetic aging of the demographically non-aging naked mole-rat. Nature Communications 2022, 13: 355. PMID: 35039495, PMCID: PMC8763950, DOI: 10.1038/s41467-022-27959-9.Peer-Reviewed Original Research
2021
The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study
Schmitz LL, Zhao W, Ratliff SM, Goodwin J, Miao J, Lu Q, Guo X, Taylor KD, Ding J, Liu Y, Levine M, Smith JA. The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study. Epigenetics 2021, 17: 589-611. PMID: 34227900, PMCID: PMC9235889, DOI: 10.1080/15592294.2021.1939479.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAgingAtherosclerosisChildDNA MethylationEpigenesis, GeneticHumansRetirementSocial ClassConceptsMulti-Ethnic StudySocioeconomic statusSocioeconomic gradientFaster biological agingEpigenetic agingBiological agingRetirement StudyAlcohol consumptionHealth behaviorsSignificant associationDisease riskSES gradientOlder adultsGenetic riskPolygenic riskEpigenetic clocksAtherosclerosisSES measuresAssociationInconsistent resultsRobust associationRiskMultiple tissuesA systematic review of biological, social and environmental factors associated with epigenetic clock acceleration
Oblak L, van der Zaag J, Higgins-Chen AT, Levine ME, Boks MP. A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Research Reviews 2021, 69: 101348. PMID: 33930583, DOI: 10.1016/j.arr.2021.101348.Peer-Reviewed Original ResearchAssociations of Age, Sex, Race/Ethnicity, and Education With 13 Epigenetic Clocks in a Nationally Representative U.S. Sample: The Health and Retirement Study
Crimmins EM, Thyagarajan B, Levine ME, Weir DR, Faul J. Associations of Age, Sex, Race/Ethnicity, and Education With 13 Epigenetic Clocks in a Nationally Representative U.S. Sample: The Health and Retirement Study. The Journals Of Gerontology Series A 2021, 76: 1117-1123. PMID: 33453106, PMCID: PMC8140049, DOI: 10.1093/gerona/glab016.Peer-Reviewed Original Research
2020
Reprogramming to recover youthful epigenetic information and restore vision
Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, Sinclair DA. Reprogramming to recover youthful epigenetic information and restore vision. Nature 2020, 588: 124-129. PMID: 33268865, PMCID: PMC7752134, DOI: 10.1038/s41586-020-2975-4.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsAxonsCell Line, TumorCell SurvivalCellular ReprogrammingDependovirusDioxygenasesDisease Models, AnimalDNA MethylationDNA-Binding ProteinsEpigenesis, GeneticEyeFemaleGenetic VectorsGlaucomaHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMiceMice, Inbred C57BLNerve RegenerationOctamer Transcription Factor-3Optic Nerve InjuriesProto-Oncogene ProteinsRetinal Ganglion CellsSOXB1 Transcription FactorsTranscriptomeVision, OcularConceptsDNA methylation patternsMethylation patternsTissue functionCentral nervous systemGene expression patternsCause of agingEpigenetic noiseEpigenetic informationDNA methylationEctopic expressionExpression patternsKLF4 geneMouse retinal ganglion cellsMammalian tissuesRetinal ganglion cellsAged miceGanglion cellsVision lossTissue dysfunctionMouse modelCNS tissueAxon regenerationNervous systemDegenerative processOlder individualsA rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin
Levine M, McDevitt RA, Meer M, Perdue K, Di Francesco A, Meade T, Farrell C, Thrush K, Wang M, Dunn C, Pellegrini M, de Cabo R, Ferrucci L. A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin. ELife 2020, 9: e59201. PMID: 33179594, PMCID: PMC7661040, DOI: 10.7554/elife.59201.Peer-Reviewed Original ResearchConceptsTranscriptional factor bindingNovel epigenetic clockEpigenetic signalsIntergenic regionEpigenetic age measuresDNA methylationFactor bindingSequencing dataEpigenetic clocksBiochemical advantagesNetwork analysisH3K9me3H3K27me3HeterochromatinCaloric restrictionRobust biomarkersSubstantial overlapMethylationPhenotypicCpGDNAmAgeBindingMiceClockSchizophrenia and Epigenetic Aging Biomarkers: Increased Mortality, Reduced Cancer Risk, and Unique Clozapine Effects
Higgins-Chen AT, Boks MP, Vinkers CH, Kahn RS, Levine ME. Schizophrenia and Epigenetic Aging Biomarkers: Increased Mortality, Reduced Cancer Risk, and Unique Clozapine Effects. Biological Psychiatry 2020, 88: 224-235. PMID: 32199607, PMCID: PMC7368835, DOI: 10.1016/j.biopsych.2020.01.025.Peer-Reviewed Original ResearchMeSH KeywordsAgingBiomarkersClozapineDNA MethylationEpigenesis, GeneticHumansMaleNeoplasmsSchizophreniaConceptsAge-associated proteinsEpigenetic clocksDNA methylation data setsMethylation data setsEpigenetic ageing biomarkersReduced cancer riskCD8 T cellsBody mass indexLong-term outcomesHorvath's epigenetic clockLower cancer ratesDNA methylationDNA methylation predictorsBiological age differencesMitotic clockMitotic divisionAge clocksCause mortalityNatural killerMass indexEarly mortalityMedication dataSZ casesClozapine's effectIncreased MortalityAssessment of Epigenetic Clocks as Biomarkers of Aging in Basic and Population Research
Levine ME. Assessment of Epigenetic Clocks as Biomarkers of Aging in Basic and Population Research. The Journals Of Gerontology Series A 2020, 75: 463-465. PMID: 31995162, PMCID: PMC7328198, DOI: 10.1093/gerona/glaa021.Peer-Reviewed Original Research
2017
Genetic architecture of epigenetic and neuronal ageing rates in human brain regions
Lu AT, Hannon E, Levine ME, Crimmins EM, Lunnon K, Mill J, Geschwind DH, Horvath S. Genetic architecture of epigenetic and neuronal ageing rates in human brain regions. Nature Communications 2017, 8: 15353. PMID: 28516910, PMCID: PMC5454371, DOI: 10.1038/ncomms15353.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAgingBrainBrain MappingCalcium-Binding ProteinsChildChild, PreschoolCognitive DysfunctionDNA MethylationEpigenesis, GeneticFemaleGenome, HumanGenome-Wide Association StudyHumansInfantMaleMiddle AgedNerve Tissue ProteinsNeurodegenerative DiseasesNeuronsQuantitative Trait LociConceptsGenome-wide association studiesCis-expression quantitative trait lociGenome-wide significant lociProportion of neuronsQuantitative trait lociEpigenetic aging ratesDNA methylation-based biomarkersEpigenetic agingMethylation-based biomarkersGenetic architectureTrait lociSignificant lociAssociation studiesBrain regionsAge-related macular degenerationType 2 diabetesAging rateGenesLociHuman brain regionsUlcerative colitisWaist circumferenceMacular degenerationParkinson's diseaseBrain samples
2016
DNA methylation-based measures of biological age: meta-analysis predicting time to death
Chen BH, Marioni RE, Colicino E, 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, Horvath S. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 2016, 8: 1844-1859. PMID: 27690265, PMCID: PMC5076441, DOI: 10.18632/aging.101020.Peer-Reviewed Original ResearchConceptsCause mortalityBlood cell compositionRisk factorsTraditional risk factorsBlood cell countAdditional risk factorsChronological ageEpigenetic ageCell compositionBiological ageEpigenetic age accelerationStudy ACell countEthnic groupsSignificant associationHuman cohortsRobust biomarkersMortalityTotal sample sizeMethylation-based measuresDNA methylation-based measuresEpigenetic age estimatesAgeAge accelerationDifferent cohortsAn epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease
Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, Ritz BR, Chen B, Lu AT, Rickabaugh TM, Jamieson BD, Sun D, Li S, Chen W, Quintana-Murci L, Fagny M, Kobor MS, Tsao PS, Reiner AP, Edlefsen KL, Absher D, Assimes TL. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biology 2016, 17: 171. PMID: 27511193, PMCID: PMC4980791, DOI: 10.1186/s13059-016-1030-0.Peer-Reviewed Original ResearchConceptsMortality rateRace/ethnicityRisk factorsTraditional cardio-metabolic risk factorsCardio-metabolic risk factorsCHD risk factorsCoronary heart diseaseCardio-metabolic diseasesEpigenetic clock analysisIntrinsic epigenetic age accelerationAfrican AmericansEpigenetic aging ratesLonger life expectancyCHD outcomesOlder African AmericansHeart diseaseHigh burdenEpigenetic age accelerationLower mortalityDifferent mortality ratesBrain samplesEthnic groupsBrain tissueBloodSocioeconomic differencesEpigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women’s Health Initiative Study
Carroll JE, Irwin MR, Levine M, Seeman TE, Absher D, Assimes T, Horvath S. Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women’s Health Initiative Study. Biological Psychiatry 2016, 81: 136-144. PMID: 27702440, PMCID: PMC5536960, DOI: 10.1016/j.biopsych.2016.07.008.Peer-Reviewed Original ResearchConceptsNaive T cellsWomen's Health Initiative studyDifferentiated T cellsT cellsInsomnia symptomsAge-related morbidityShort sleepSleep durationInitiative studyLarge population-based studyEpigenetic agePopulation-based studyLong sleep durationSymptoms of insomniaImmune senescenceImmune cellsLong sleepAdvanced epigenetic ageCell countSymptomsInfluence riskSleepCross-sectional dataAgeAge acceleration
2015
DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative
Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S. DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative. Aging 2015, 7: 690-700. PMID: 26411804, PMCID: PMC4600626, DOI: 10.18632/aging.100809.Peer-Reviewed Original ResearchConceptsIntrinsic epigenetic age accelerationWomen's Health InitiativeLung cancer incidenceLung cancer susceptibilityLung cancerHealth initiativesCancer incidenceCox proportional hazards modelCancer susceptibilityLung cancer casesProportional hazards modelCurrent smokersAge-related declineAge-associated diseasesAge-related diseasesFuture onsetCancer casesCigarette smokeHazards modelUseful biomarkerEpigenetic age accelerationCandidate biomarkersOlder individualsDNA methylation ageGenotoxic carcinogens