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 tissuesEpigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study
Xiao C, Beitler JJ, Peng G, Levine ME, Conneely KN, Zhao H, Felger JC, Wommack EC, Chico CE, Jeon S, Higgins KA, Shin DM, Saba NF, Burtness BA, Bruner DW, Miller AH. Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study. Cancer 2021, 127: 3361-3371. PMID: 34027995, DOI: 10.1002/cncr.33641.Peer-Reviewed Original ResearchMeSH KeywordsAccelerationEpigenesis, GeneticFatigueHead and Neck NeoplasmsHumansInflammationLongitudinal StudiesMaleConceptsC-reactive proteinIL-6 levelsEpigenetic age accelerationNeck cancerInterleukin-6Inflammatory markersHigher epigenetic age accelerationLower C-reactive proteinAge accelerationHigher C-reactive proteinMultidimensional Fatigue Inventory-20Poor functional outcomeBlood DNA methylationMonths postradiotherapyAdvanced diseaseConcurrent chemoradiationMost patientsDistant metastasisFunctional outcomeSevere fatigueTreatment completionRadiation therapyPatientsGreater fatigueInflammationA 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 ResearchAssociation of Epigenetic Age Acceleration With Risk Factors, Survival, and Quality of Life in Patients With Head and Neck Cancer
Xiao C, Miller AH, Peng G, Levine ME, Conneely KN, Zhao H, Eldridge RC, Wommack EC, Jeon S, Higgins KA, Shin DM, Saba NF, Smith AK, Burtness B, Park HS, Irwin ML, Ferrucci LM, Ulrich B, Qian DC, Beitler JJ, Bruner DW. Association of Epigenetic Age Acceleration With Risk Factors, Survival, and Quality of Life in Patients With Head and Neck Cancer. International Journal Of Radiation Oncology • Biology • Physics 2021, 111: 157-167. PMID: 33882281, PMCID: PMC8802868, DOI: 10.1016/j.ijrobp.2021.04.002.Peer-Reviewed Original ResearchMeSH KeywordsAgedBody Mass IndexEpigenesis, GeneticFemaleHead and Neck NeoplasmsHumansMaleMiddle AgedQuality of LifeRisk FactorsConceptsProgression-free survivalBody mass indexQuality of lifeHigher epigenetic age accelerationTreatment-related symptomsOverall survivalEpigenetic age accelerationRadiation therapyRisk factorsClinical characteristicsNeck cancerAge accelerationWorse overall survivalHuman papilloma virusFaster biological agingAdverse eventsDistant metastasisLifestyle factorsMass indexCancer outcomesBlood biomarkersPapilloma virusFunctional assessmentHigher HRPatientsAssociations 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 overlapMethylationPhenotypicCpGDNAmAgeBindingMiceClockVasomotor Symptoms and Accelerated Epigenetic Aging in the Women’s Health Initiative (WHI)
Thurston RC, Carroll JE, Levine M, Chang Y, Crandall C, Manson JE, Pal L, Hou L, Shadyab AH, Horvath S. Vasomotor Symptoms and Accelerated Epigenetic Aging in the Women’s Health Initiative (WHI). The Journal Of Clinical Endocrinology & Metabolism 2020, 105: dgaa081. PMID: 32080740, PMCID: PMC7069347, DOI: 10.1210/clinem/dgaa081.Peer-Reviewed Original ResearchConceptsVasomotor symptomsWomen's Health InitiativePostmenopausal womenHealth initiativesMenopausal vasomotor symptomsSevere hot flashesBody mass indexAdverse health indicatorsPoor health outcomesYears of ageBiological agingRace/ethnicityAccelerated Epigenetic AgingHormone therapyHot flashesMass indexMenopausal symptomsSleep disturbancesEpigenetic agingEarly deathDNAm PhenoAgeHealth outcomesTiming groupsDNAm GrimAgeSymptomsSchizophrenia 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
2019
The role of epigenetic aging in education and racial/ethnic mortality disparities among older U.S. Women
Liu Z, Chen BH, Assimes TL, Ferrucci L, Horvath S, Levine ME. The role of epigenetic aging in education and racial/ethnic mortality disparities among older U.S. Women. Psychoneuroendocrinology 2019, 104: 18-24. PMID: 30784901, PMCID: PMC6555423, DOI: 10.1016/j.psyneuen.2019.01.028.Peer-Reviewed Original Research
2018
An epigenetic biomarker of aging for lifespan and healthspan
Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S. An epigenetic biomarker of aging for lifespan and healthspan. Aging 2018, 10: 573-591. PMID: 29676998, PMCID: PMC5940111, DOI: 10.18632/aging.101414.Peer-Reviewed Original ResearchConceptsEpigenetic biomarkersDNA damage responseTranslational machineryMitochondrial signatureTranscriptional analysisDamage responseNew epigenetic biomarkersMultiple tissuesNovel CpGsInterferon pathwayHealthspanSorted cellsImportant pathwayPathwayCellsLifespanActivationBiological ageDiverse outcomesDNAm PhenoAgeMachineryMajor goalTissueCpGGeroscience
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 samplesEpigenetic clock analysis of diet, exercise, education, and lifestyle factors
Quach A, Levine ME, Tanaka T, Lu AT, Chen BH, Ferrucci L, Ritz B, Bandinelli S, Neuhouser ML, Beasley JM, Snetselaar L, Wallace RB, Tsao PS, Absher D, Assimes TL, Stewart JD, Li Y, Hou L, Baccarelli AA, Whitsel EA, Horvath S. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 2017, 9: 419-437. PMID: 28198702, PMCID: PMC5361673, DOI: 10.18632/aging.101168.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAgingCohort StudiesCross-Sectional StudiesDietEducational StatusEpigenesis, GeneticExerciseFemaleHumansLife StyleMiddle AgedConceptsIntrinsic epigenetic age accelerationExtrinsic epigenetic age accelerationModerate alcohol consumptionMetabolic syndromeLifestyle factorsAlcohol consumptionEpigenetic age accelerationHealth initiativesItalian cohort studyPostmenopausal female participantsFirst-line medicationWomen's Health InitiativeBlood carotenoid levelsType 2 diabetesAge accelerationAge-related functional declineHealth-related outcomesEpigenetic clock analysisFemale participantsIndicator of fruitCause mortalityCohort studyPoultry intakeChronic conditionsFish intake
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 ResearchMeSH KeywordsAgingDNA MethylationEpigenesis, GeneticFemaleHumansLogistic ModelsMaleMortalityRacial GroupsRisk FactorsSurvival AnalysisT-Lymphocyte SubsetsConceptsCause 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 cohorts