2024
Challenges and recommendations for the translation of biomarkers of aging
Herzog C, Goeminne L, Poganik J, Barzilai N, Belsky D, Betts-LaCroix J, Chen B, Chen M, Cohen A, Cummings S, Fedichev P, Ferrucci L, Fleming A, Fortney K, Furman D, Gorbunova V, Higgins-Chen A, Hood L, Horvath S, Justice J, Kiel D, Kuchel G, Lasky-Su J, LeBrasseur N, Maier A, Schilling B, Sebastiano V, Slagboom P, Snyder M, Verdin E, Widschwendter M, Zhavoronkov A, Moqri M, Gladyshev V. Challenges and recommendations for the translation of biomarkers of aging. Nature Aging 2024, 4: 1372-1383. PMID: 39285015, DOI: 10.1038/s43587-024-00683-3.Peer-Reviewed Original ResearchReliable 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 compositionProbeValidation of biomarkers of aging
Moqri M, Herzog C, Poganik J, Ying K, Justice J, Belsky D, Higgins-Chen A, Chen B, Cohen A, Fuellen G, Hägg S, Marioni R, Widschwendter M, Fortney K, Fedichev P, Zhavoronkov A, Barzilai N, Lasky-Su J, Kiel D, Kennedy B, Cummings S, Slagboom P, Verdin E, Maier A, Sebastiano V, Snyder M, Gladyshev V, Horvath S, Ferrucci L. Validation of biomarkers of aging. Nature Medicine 2024, 30: 360-372. PMID: 38355974, PMCID: PMC11090477, DOI: 10.1038/s41591-023-02784-9.Peer-Reviewed Original Research
2023
EVALUATING STOCHASTIC EPIGENETIC MUTATIONS: RELIABILITY, SUBTYPES, AND AN ALTERNATIVE DETECTION APPROACH
Markov Y, Higgins-Chen A. EVALUATING STOCHASTIC EPIGENETIC MUTATIONS: RELIABILITY, SUBTYPES, AND AN ALTERNATIVE DETECTION APPROACH. Innovation In Aging 2023, 7: 1029-1030. PMCID: PMC10737955, DOI: 10.1093/geroni/igad104.3309.Peer-Reviewed Original ResearchGeroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research
Diniz B, Seitz-Holland J, Sehgal R, Kasamoto J, Higgins-Chen A, Lenze E. Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research. American Journal Of Geriatric Psychiatry 2023, 32: 1-16. PMID: 37845116, PMCID: PMC10841054, DOI: 10.1016/j.jagp.2023.09.014.Peer-Reviewed Original ResearchBiomarkers of aging for the identification and evaluation of longevity interventions
Moqri, Herzog C, Poganik J, Consortium B, Justice J, Belsky D, Higgins-Chen A, Moskalev A, Fuellen G, Cohen A, Bautmans I, Widschwendter M, Ding J, Fleming A, Mannick J, Han J, Zhavoronkov A, Barzilai N, Kaeberlein M, Cummings S, Kennedy B, Ferrucci L, Horvath S, Verdin E, Maier A, Snyder M, Sebastiano V, Gladyshev V. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell 2023, 186: 3758-3775. PMID: 37657418, PMCID: PMC11088934, DOI: 10.1016/j.cell.2023.08.003.Peer-Reviewed Original ResearchMore than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome
Minteer C, Thrush K, Gonzalez J, Niimi P, Rozenblit M, Rozowsky J, Liu J, Frank M, McCabe T, Sehgal R, Higgins-Chen A, Hofstatter E, Pusztai L, Beckman K, Gerstein M, Levine M. More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome. Science Advances 2023, 9: eadf4163. PMID: 37467337, PMCID: PMC10355820, DOI: 10.1126/sciadv.adf4163.Peer-Reviewed Original ResearchConceptsStem cell divisionImmortalized human cellsTissue-specific cancer riskTumorigenic stateCell divisionDNA methylationEpigenetic changesAge-related accumulationHuman cellsMultiple tissuesSomatic mutationsClinical tissuesTissue differencesEpigenomeCellsTissueNormal tissuesMethylationMutationsReplicationNormal breast tissueSignaturesVitroAccumulationDivisionPrincipal component analysis of synaptic density measured with [11C]UCB-J PET in early Alzheimer’s disease
O'Dell R, Higgins-Chen A, Gupta D, Chen M, Naganawa M, Toyonaga T, Lu Y, Ni G, Chupak A, Zhao W, Salardini E, Nabulsi N, Huang Y, Arnsten A, Carson R, van Dyck C, Mecca A. Principal component analysis of synaptic density measured with [11C]UCB-J PET in early Alzheimer’s disease. NeuroImage Clinical 2023, 39: 103457. PMID: 37422964, PMCID: PMC10338149, DOI: 10.1016/j.nicl.2023.103457.Peer-Reviewed Original ResearchConceptsCognitive domainsCognitive performanceSubjects' scoresCortical regionsNeuropsychological batteryEarly Alzheimer's diseaseAD groupBilateral regionsNormal participantsNegative loadingsCognitive impairmentCN participantsAlzheimer's diseaseParticipantsStructural correlatesStrong contributionParticipant characteristicsScoresPositive loadingsData-driven approachTotal variancePrincipal component analysisSpecific spatial patternsCellular allostatic load is linked to increased energy expenditure and accelerated biological aging
Bobba-Alves N, Sturm G, Lin J, Ware S, Karan K, Monzel A, Bris C, Procaccio V, Lenaers G, Higgins-Chen A, Levine M, Horvath S, Santhanam B, Kaufman B, Hirano M, Epel E, Picard M. Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging. Psychoneuroendocrinology 2023, 155: 106322. PMID: 37423094, PMCID: PMC10528419, DOI: 10.1016/j.psyneuen.2023.106322.Peer-Reviewed Original ResearchConceptsCellular agingCellular energy expenditureDNA methylation clockMitochondrial oxidative phosphorylationStress adaptationMtDNA instabilityOXPHOS activityMethylation clockOxidative phosphorylationMetabolic shiftEnergetic costHuman fibroblast lineCellular basisPhysiological responsesFibroblast linesStress triggersPotential driversBiological agingEnergy expenditureChronic activationLifespanDamaging effectsPrimary human fibroblast linesCytokine secretionPhosphorylationFrailty Resilience Score: A Novel Measure of Frailty Resilience Associated With Protection From Frailty and Survival
Milman S, Lerman B, Ayers E, Zhang Z, Sathyan S, Levine M, Ye K, Gao T, Higgins-Chen A, Barzilai N, Verghese J. Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated With Protection From Frailty and Survival. The Journals Of Gerontology Series A 2023, 78: 1771-1777. PMID: 37246648, PMCID: PMC10562888, DOI: 10.1093/gerona/glad138.Peer-Reviewed Original ResearchConceptsMultivariable-adjusted analysesHazard of mortalityPhenotypic frailtyBaseline frailtyOverall survivalEffective therapyHigh riskFrailtyResilience AssociatedOlder adultsGenetic riskIdentification of factorsReliable predictorMortalityResilience scoresSurvivalProteomic profilesRiskReliable measureDeviation increaseTherapyCohortThe Cutting Edge of Epigenetic Clocks: In Search of Mechanisms Linking Aging and Mental Health
Harvanek Z, Boks M, Vinkers C, Higgins-Chen A. The Cutting Edge of Epigenetic Clocks: In Search of Mechanisms Linking Aging and Mental Health. Biological Psychiatry 2023, 94: 694-705. PMID: 36764569, PMCID: PMC10409884, DOI: 10.1016/j.biopsych.2023.02.001.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsOxPhos 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
PCBrainAge: A Brain‐Specific AD‐Associated DNA Methylation Clock
Thrush K, Markov Y, Higgins‐Chen A, Morgan L. PCBrainAge: A Brain‐Specific AD‐Associated DNA Methylation Clock. Alzheimer's & Dementia 2022, 18 DOI: 10.1002/alz.069230.Peer-Reviewed Original ResearchΕ4 carrier statusAlzheimer's diseasePathogenesis of ADCarrier statusAPOE ε4 carrier statusAD diagnostic criteriaNeuropathological changesNeuropathological criteriaAD developmentBlood measuresDiagnostic criteriaAD riskBrain samplesBrain tissueClinical diagnosisNovel predictorCortical measuresDiseaseMolecular changesRecent evidenceSignificant differencesBlood tissueBloodDNA methylation agingDNA methylation clockAging 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 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 assessmentTick 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-TockTissue
2021
A 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 ResearchAging biomarkers and the brain
Higgins-Chen AT, Thrush KL, Levine ME. Aging biomarkers and the brain. Seminars In Cell And Developmental Biology 2021, 116: 180-193. PMID: 33509689, PMCID: PMC8292153, DOI: 10.1016/j.semcdb.2021.01.003.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2020
Schizophrenia 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 ResearchConceptsAge-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 Mortality