2024
Reliable detection of stochastic epigenetic mutations and associations with cardiovascular aging
Markov Y, Levine M, Higgins-Chen A. Reliable detection of stochastic epigenetic mutations and associations with cardiovascular aging. GeroScience 2024, 46: 5745-5765. PMID: 38736015, PMCID: PMC11493905, DOI: 10.1007/s11357-024-01191-3.Peer-Reviewed Original ResearchStochastic epigenetic mutationsAge-related DNA methylation changesEpigenetic mutationsBlood cell type compositionDNA methylation changesCell type compositionUnmethylated probesPresence of SNPsGenomic locationsMethylation patternsMethylation changesDinucleotide sitesMethylation probesTechnical noiseBlood cell compositionTechnical replicate dataR packageAging phenotypesFramingham Heart StudyMutationsCell compositionAging biomarkersSNPsType compositionProbeFasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk
Brandhorst S, Levine M, Wei M, Shelehchi M, Morgan T, Nayak K, Dorff T, Hong K, Crimmins E, Cohen P, Longo V. Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk. Nature Communications 2024, 15: 1309. PMID: 38378685, PMCID: PMC10879164, DOI: 10.1038/s41467-024-45260-9.Peer-Reviewed Original ResearchConceptsMultiple cardiometabolic risk factorsAssociated with reduced insulin resistanceCardiometabolic risk factorsFasting-mimicking dietImmune system agingRandomized clinical trialsAnalysis of blood samplesAutoimmune cellsBiological ageClinical trialsReduce inflammationMarker changesRisk factorsHepatic fatInsulin resistanceAdult study participantsBlood samplesNormal cellsWeight lossReducing biological ageBiomarker of biological agingDamaged cellsStudy participantsDisease riskAge
2023
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
Sturm G, Karan K, Monzel A, Santhanam B, Taivassalo T, Bris C, Ware S, Cross M, Towheed A, Higgins-Chen A, McManus M, Cardenas A, Lin J, Epel E, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller R, Lenaers G, Wallace D, St-Onge M, Tavazoie S, Procaccio V, Kaufman B, Seifert E, Hirano M, Picard M. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Communications Biology 2023, 6: 22. PMID: 36635485, PMCID: PMC9837150, DOI: 10.1038/s42003-022-04303-x.Peer-Reviewed Original ResearchConceptsIntegrated stress responseOXPHOS defectsMitochondrial diseaseCellular energy expenditureMitochondrial DNA instabilityPatient-derived fibroblastsMitochondrial oxidative phosphorylationCell divisionExtracellular secretionOxidative phosphorylationStress responseDNA instabilityMechanistic basisEnergetic costEpigenetic agingGeneral mechanismOXPHOSBiological agingExcess energy expenditurePotential mechanismsEnergy expenditureCellsMulti-system disorderMetabokinesRNAseq
2022
The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis.
Fiorito G, Pedron S, Ochoa-Rosales C, McCrory C, Polidoro S, Zhang Y, Dugué PA, Ratliff S, Zhao WN, McKay GJ, Costa G, Solinas MG, Harris KM, Tumino R, Grioni S, Ricceri F, Panico S, Brenner H, Schwettmann L, Waldenberger M, Matias-Garcia PR, Peters A, Hodge A, Giles GG, Schmitz LL, Levine M, Smith JA, Liu Y, Kee F, Young IS, McGuinness B, McKnight AJ, van Meurs J, Voortman T, Kenny RA, Vineis P, Carmeli C. The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis. The Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences 2022, 77: 1750-1759. PMID: 35172329, DOI: 10.1093/gerona/glac041.Peer-Reviewed Original ResearchAging 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 ResearchConceptsDisease 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 ResearchContribution of life course circumstances to the acceleration of phenotypic and functional aging: A retrospective study
Cao X, Ma C, Zheng Z, He L, Hao M, Chen X, Crimmins EM, Gill TM, Levine ME, Liu Z. Contribution of life course circumstances to the acceleration of phenotypic and functional aging: A retrospective study. EClinicalMedicine 2022, 51: 101548. PMID: 35844770, PMCID: PMC9284373, DOI: 10.1016/j.eclinm.2022.101548.Peer-Reviewed Original ResearchDisease Research CenterDisadvantaged subpopulationsAdulthood circumstancesAlzheimer's Disease Research CenterRetirement Longitudinal StudyFunctional agingLife course circumstancesAdvancing Translational SciencesRetrospective studyChronic diseasesGeneral linear regression modelHealth gapChina HealthBiomarker collectionOlder adultsLater lifeNational InstituteLongitudinal studySubpopulationsLinear regression modelsTranslational scienceRegression modelsChildhoodAdvantaged counterpartsHealthLife course traumas and cardiovascular disease—the mediating role of accelerated aging
Cao X, Zhang J, Ma C, Li X, Kuo C, Levine ME, Hu G, Allore H, Chen X, Wu X, Liu Z. Life course traumas and cardiovascular disease—the mediating role of accelerated aging. Annals Of The New York Academy Of Sciences 2022, 1515: 208-218. PMID: 35725988, PMCID: PMC10145586, DOI: 10.1111/nyas.14843.Peer-Reviewed Original ResearchLongitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination
Pang APS, Higgins-Chen AT, Comite F, Raica I, Arboleda C, Went H, Mendez T, Schotsaert M, Dwaraka V, Smith R, Levine ME, Ndhlovu LC, Corley MJ. Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination. Frontiers In Genetics 2022, 13: 819749. PMID: 35719387, PMCID: PMC9203887, DOI: 10.3389/fgene.2022.819749.Peer-Reviewed Original ResearchSevere COVID-19T cellsCOVID-19 diagnosisMRNA vaccinationCOVID-19B cellsCOVID-19 vaccine responsesNon-hospitalized COVID-19MRNA COVID-19 vaccineSARS-CoV-2 infectionHost epigenetic landscapeMedian time frameExhausted T cellsNaïve T cellsCOVID-19 vaccinationCOVID-19 exposureCOVID-19 vaccineEpigenetic clock analysisModerna mRNAVaccine responsesImmune cellsEpigenetic clocksHealthy individualsVaccinationLongitudinal assessmentResilience integrates concepts in aging research
Promislow D, Anderson RM, Scheffer M, Crespi B, DeGregori J, Harris K, Horowitz BN, Levine ME, Riolo MA, Schneider DS, Spencer SL, Valenzano DR, Hochberg ME. Resilience integrates concepts in aging research. IScience 2022, 25: 104199. PMID: 35494229, PMCID: PMC9044173, DOI: 10.1016/j.isci.2022.104199.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
Epigenetic Trajectories of Aging and Reprogramming
Niimi P, Meer M, Levine M. Epigenetic Trajectories of Aging and Reprogramming. Innovation In Aging 2021, 5: 668-668. PMCID: PMC8681446, DOI: 10.1093/geroni/igab046.2502.Peer-Reviewed Original ResearchExtending human healthspan and longevity: a symposium report
DeVito LM, Barzilai N, Cuervo AM, Niedernhofer LJ, Milman S, Levine M, Promislow D, Ferrucci L, Kuchel GA, Mannick J, Justice J, Gonzales MM, Kirkland JL, Cohen P, Campisi J. Extending human healthspan and longevity: a symposium report. Annals Of The New York Academy Of Sciences 2021, 1507: 70-83. PMID: 34498278, PMCID: PMC10231756, DOI: 10.1111/nyas.14681.Peer-Reviewed Original ResearchConceptsAge-related diseasesEarly-stage clinical trialsField of geroscienceReduction of morbidityBiological agingEnd of lifeClinical trialsNovel agentsClinical developmentGeroscience hypothesisFDA approvalDrug evaluationMultiple disordersTherapyDiseaseSymposium reportConcept studyHuman healthspanHealthspanAging processSignificant barriersMorbidityDysfunctionAgingTrialsThe 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 ResearchConceptsMulti-Ethnic StudySocioeconomic statusSocioeconomic gradientFaster biological agingEpigenetic agingBiological agingRetirement StudyAlcohol consumptionHealth behaviorsSignificant associationDisease riskSES gradientOlder adultsGenetic riskPolygenic riskEpigenetic clocksAtherosclerosisSES measuresAssociationInconsistent resultsRobust associationRiskMultiple tissuesGenetic associations for two biological age measures point to distinct aging phenotypes
Kuo C, Pilling LC, Liu Z, Atkins JL, Levine ME. Genetic associations for two biological age measures point to distinct aging phenotypes. Aging Cell 2021, 20: e13376. PMID: 34038024, PMCID: PMC8208797, DOI: 10.1111/acel.13376.Peer-Reviewed Original ResearchConceptsGenome-wide association scansAssociation scanEuropean descent participantsHomeostasis pathwaysPathway enrichmentAging phenotypesGenesGenetic associationCell functionStrong signalBiological age measuresPathwayUK BiobankGenetic predispositionClinical biochemistry markersImmune systemEnrichmentSNPsPhenotypeAPOE geneLipidsPredispositionDomainMarkersEpigenetic 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 ResearchConceptsC-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 ResearchConceptsProgression-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 HRPatients