{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:06:48Z","timestamp":1789103208452,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"the National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01 HL118045"],"award-info":[{"award-number":["R01 HL118045"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R01 HL118045"],"award-info":[{"award-number":["R01 HL118045"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Child Health and Human Development","award":["R01 HD080749"],"award-info":[{"award-number":["R01 HD080749"]}]},{"name":"National Cancer Institute","award":["R01 CA220254"],"award-info":[{"award-number":["R01 CA220254"]}]},{"award":["R01 CA220254"],"award-info":[{"award-number":["R01 CA220254"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: DNA methylation (DNAm)-based aging measures are increasingly being used in biological aging, disease vulnerability, and cancer-related risk. However, it remains unclear whether these measures capture a single generalized aging process or separable biological domains relevant to cancer-relevant biological vulnerability. Methods: Using data from the Family and Community Health Study (FACHS), we examine whether blood-based DNAm scores capture two distinct biological domains relevant to cancer susceptibility: a replication\/mitotic domain, indexed by CellDRIFT, EpiTOC2, and MiAge, and an early-life systemic dysregulation domain, indexed by DunedinPACE, GrimAgeV2, and PhenoAge. Results: Regression results showed clear domain specificity. CRP, BMI, alcohol methylation, and AHRR\/cg05575921 were positively associated with the early-life systemic dysregulation domain but showed weak or null associations with the replication\/mitotic domain. Cross-domain tests confirmed significantly stronger associations for the early-life systemic dysregulation domain for CRP, BMI, and alcohol methylation, with a marginal difference for AHRR\/cg05575921. In contrast, telomere-related methylation and immune-cell composition showed a different pattern. DNAmTL was inversely associated with both domains and did not differ significantly across domains. Conclusions: These findings suggest that blood-based DNAm aging measures do not reflect a single aging process. Instead, they distinguish at least two cancer-relevant methylation domains: one reflecting replication-driven mitotic aging and hematopoietic cell-turnover biology, and another reflecting early-life systemic dysregulation vulnerability linked to inflammation, metabolic risk, smoking methylation, and alcohol-related methylation. This two-domain framework may help clarify how blood DNAm profiles capture complementary biological processes relevant to cancer susceptibility and guide future studies of methylation-based cancer risk.<\/jats:p>","DOI":"10.3390\/genes17091083","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:26:11Z","timestamp":1788956771000},"page":"1083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Two Separable Aging Domains in Blood DNA Methylation Scores Developed for Cancer Research: Mitotic Replication and Early-Life Systemic Dysregulation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8815-253X","authenticated-orcid":false,"given":"Katelyn N.","family":"Austin","sequence":"first","affiliation":[{"name":"Department of Sociology, The University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-6548","authenticated-orcid":false,"given":"Man-Kit","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Sociology, The University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s13059-019-1824-y","article-title":"DNA methylation aging clocks: Challenges and recommendations","volume":"20","author":"Bell","year":"2019","journal-title":"Genome Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e23488","DOI":"10.1002\/ajhb.23488","article-title":"\u201cEpigenetic clocks\u201d: Theory and applications in human biology","volume":"33","author":"Ryan","year":"2021","journal-title":"Am. J. Hum. Biol."},{"key":"ref_3","first-page":"3520","article-title":"Epigenetic clocks: Beyond biological age, using the past to predict the present and future","volume":"16","author":"Liang","year":"2024","journal-title":"Aging Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev-publhealth-060222-015657","article-title":"Quantification of epigenetic aging in public health","volume":"46","author":"Kusters","year":"2025","journal-title":"Annu. Rev. Public Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1158\/0008-5472.CAN-19-0924","article-title":"Epigenetic aging: More than just a clock when it comes to cancer","volume":"80","author":"Yu","year":"2020","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41576-022-00511-7","article-title":"Measuring biological age using omics data","volume":"23","author":"Rutledge","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eadf4163","DOI":"10.1126\/sciadv.adf4163","article-title":"More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome","volume":"9","author":"Minteer","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s13059-016-1064-3","article-title":"Correlation of an epigenetic mitotic clock with cancer risk","volume":"17","author":"Yang","year":"2016","journal-title":"Genome Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1080\/15592294.2017.1389361","article-title":"The MiAge Calculator: A DNA methylation-based mitotic age calculator of human tissue types","volume":"13","author":"Youn","year":"2018","journal-title":"Epigenetics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41588-018-0073-4","article-title":"DNA methylation loss in late-replicating domains is linked to mitotic cell division","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1038\/s41467-024-48649-8","article-title":"An improved epigenetic counter to track mitotic age in normal and precancerous tissues","volume":"15","author":"Zhu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/17501911.2025.2476391","article-title":"Immune cell composition is an important contributor to epigenetic age variation","volume":"17","author":"Marttila","year":"2025","journal-title":"Epigenomics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12414","DOI":"10.18632\/aging.206098","article-title":"A systematic review of phenotypic and epigenetic clocks used for aging and mortality quantification in humans","volume":"16","author":"Warner","year":"2024","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"573","DOI":"10.18632\/aging.101414","article-title":"An epigenetic biomarker of aging for lifespan and healthspan","volume":"10","author":"Levine","year":"2018","journal-title":"Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.18632\/aging.101684","article-title":"DNA methylation GrimAge strongly predicts lifespan and healthspan","volume":"11","author":"Lu","year":"2019","journal-title":"Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e54870","DOI":"10.7554\/eLife.54870","article-title":"Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm","volume":"9","author":"Belsky","year":"2020","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103041","DOI":"10.1016\/j.arr.2026.103041","article-title":"Epigenetic markers of ageing and cancer risk","volume":"117","author":"Li","year":"2026","journal-title":"Ageing Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1002\/ijc.33451","article-title":"DNA methylation age as a biomarker for cancer","volume":"148","author":"Lau","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13148-020-00905-6","article-title":"Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden","volume":"12","author":"Hillary","year":"2020","journal-title":"Clin. Epigenet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1007\/s11357-023-00941-z","article-title":"Sex differences in biological aging and the association with clinical measures in older adults","volume":"46","author":"Phyo","year":"2024","journal-title":"Geroscience"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Salameh, Y., Bejaoui, Y., and El Hajj, N. (2020). DNA methylation biomarkers in aging and age-related diseases. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00171"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1177\/0146167204264788","article-title":"Context and cognitions: Environmental risk, social influence, and adolescent substance use","volume":"30","author":"Gibbons","year":"2004","journal-title":"Personal. Soc. Psychol. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1177\/00221465211009309","article-title":"(Re) Setting epigenetic clocks: An important avenue whereby social conditions become biologically embedded across the life course","volume":"62","author":"Simons","year":"2021","journal-title":"J. Health Soc. Behav."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114654","DOI":"10.1016\/j.socscimed.2021.114654","article-title":"Neighborhood structural disadvantage and biological aging in a sample of Black middle age and young adults","volume":"293","author":"Lei","year":"2022","journal-title":"Soc. Sci. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1017\/S0954579421001541","article-title":"Childhood adversity predicts black young adults\u2019 DNA methylation-based accelerated aging: A dual pathway model","volume":"34","author":"Beach","year":"2022","journal-title":"Dev. Psychopathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5444","DOI":"10.1093\/nar\/19.19.5444","article-title":"A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies","volume":"19","author":"Lahiri","year":"1991","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Thrush, K.L., Higgins-Chen, A.T., Liu, Z., and Levine, M.E. (2022). R methylCIPHER: A methylation clock investigational package for hypothesis-driven evaluation & research. bioRxiv.","DOI":"10.1101\/2022.07.13.499978"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13073-020-00752-3","article-title":"A comparison of epigenetic mitotic-like clocks for cancer risk prediction","volume":"12","author":"Teschendorff","year":"2020","journal-title":"Genome Med."},{"key":"ref_30","first-page":"9484","article-title":"DNA methylation GrimAge version 2","volume":"14","author":"Lu","year":"2022","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e73420","DOI":"10.7554\/eLife.73420","article-title":"DunedinPACE, a DNA methylation biomarker of the pace of aging","volume":"11","author":"Belsky","year":"2022","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dogan, M.V., Shields, B., Cutrona, C., Gao, L., Gibbons, F.X., Simons, R., Monick, M., Brody, G.H., Tan, K., and Beach, S.R. (2014). The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-151"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Philibert, R., Dogan, M., Noel, A., Miller, S., Krukow, B., Papworth, E., Cowley, J., Long, J.D., Beach, S.R., and Black, D.W. (2018). Dose response and prediction characteristics of a methylation sensitive digital PCR assay for cigarette consumption in adults. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00137"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Beach, S.R., Ong, M.L., Gibbons, F.X., Gerrard, M., Lei, M.-K., Dawes, K., and Philibert, R.A. (2022). Epigenetic and proteomic biomarkers of elevated alcohol use predict epigenetic aging and cell-type variation better than self-report. Genes, 13.","DOI":"10.3390\/genes13101888"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1080\/15592294.2020.1834918","article-title":"A comparison of the predictive power of DNA methylation with carbohydrate deficient transferrin for heavy alcohol consumption","volume":"16","author":"Miller","year":"2021","journal-title":"Epigenetics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1080\/15592294.2022.2100684","article-title":"Digital methylation assessments of alcohol and cigarette consumption account for common variance in accelerated epigenetic ageing","volume":"17","author":"Lei","year":"2022","journal-title":"Epigenetics"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Houseman, E.A., Accomando, W.P., Koestler, D.C., Christensen, B.C., Marsit, C.J., Nelson, H.H., Wiencke, J.K., and Kelsey, K.T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-86"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Koestler, D.C., Jones, M.J., Usset, J., Christensen, B.C., Butler, R.A., Kobor, M.S., Wiencke, J.K., and Kelsey, K.T. (2016). Improving cell mixture deconvolution by id entifying o ptimal DNA methylation l ibraries (idol). BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-0943-7"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13059-018-1448-7","article-title":"An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray","volume":"19","author":"Salas","year":"2018","journal-title":"Genome Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10705519909540118","article-title":"Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives","volume":"6","author":"Hu","year":"1999","journal-title":"Struct. Equ. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1177\/0962280210395740","article-title":"Review of inverse probability weighting for dealing with missing data","volume":"22","author":"Seaman","year":"2013","journal-title":"Stat. Methods Med. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s40572-022-00338-8","article-title":"Integrating DNA Methylation Measures of Biological Aging into Social Determinants of Health Research","volume":"9","author":"Raffington","year":"2022","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Willems, Y.E., Rezaki, A.D., Aikins, M., Bahl, A., Wu, Q., Belsky, D.W., and Raffington, L. (2026). Social determinants of health and epigenetic clocks: A systematic review and meta-analysis of 140 studies. Nat. Hum. Behav., 1\u201313.","DOI":"10.1038\/s41562-026-02477-6"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.18632\/aging.102173","article-title":"DNA methylation-based estimator of telomere length","volume":"11","author":"Lu","year":"2019","journal-title":"Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev-med-070119-120305","article-title":"Biological aspects of cancer health disparities","volume":"72","author":"Freedman","year":"2021","journal-title":"Annu. Rev. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41416-020-01038-6","article-title":"Cancer health disparities in racial\/ethnic minorities in the United States","volume":"124","author":"Zavala","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1200\/OP.21.00297","article-title":"Calling attention to the role of race-driven societal determinants of health on aggressive tumor biology: A focus on Black Americans","volume":"18","author":"Ashing","year":"2022","journal-title":"JCO Oncol. Pract."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e13229","DOI":"10.1111\/acel.13229","article-title":"Underlying features of epigenetic aging clocks in vivo and in vitro","volume":"19","author":"Liu","year":"2020","journal-title":"Aging Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/acer.70020","article-title":"Alcohol and aging: Next-generation epigenetic clocks predict biological age acceleration in individuals with alcohol use disorder","volume":"49","author":"Perlstein","year":"2025","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e13149","DOI":"10.1111\/acel.13149","article-title":"Determinants of accelerated metabolomic and epigenetic aging in a UK cohort","volume":"19","author":"Robinson","year":"2020","journal-title":"Aging Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.canlet.2022.01.028","article-title":"Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics","volume":"531","author":"Lowder","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1634\/theoncologist.2013-0243","article-title":"Disparities in breast cancer treatment and outcomes: Biological, social, and health system determinants and opportunities for research","volume":"18","author":"Wheeler","year":"2013","journal-title":"Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1080\/17501911.2025.2550932","article-title":"DNA methylation-based health predictors: Advances, applications, and perspectives","volume":"17","author":"Xu","year":"2025","journal-title":"Epigenomics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13059-026-03952-z","article-title":"Sex-specific nonlinear DNA methylation aging trajectories reveal biomarkers of cancer risk and inflammation","volume":"27","author":"Grolaux","year":"2026","journal-title":"Genome Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Grolaux, R., Jacques, M., Jones-Freeman, B., Horvath, S., Teschendorff, A., and Eynon, N. (2025). Sex-specific non-linear DNA methylation trajectories across aging predict cancer risk and systemic inflammation. bioRxiv.","DOI":"10.1101\/2025.08.19.671184"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Chen, Y., Cheng, X., and Ji, S. (2025). DNA methylation and prediction of biological age. Front. Mol. Biosci., 12.","DOI":"10.3389\/fmolb.2025.1734464"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Beach, S.R., Lei, M.-K., Ong, M.L., Weaver, R.D., Carter, S.E., and Philibert, R.A. (2026). Genomic Markers of Heavy Alcohol Consumption Outperform Self-Report and Other Common Predictors of Mortality in Two Middle-Aged Samples of Black Americans. Genes, 17.","DOI":"10.3390\/genes17070799"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:27:18Z","timestamp":1789100838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":58,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091083"],"URL":"https:\/\/doi.org\/10.3390\/genes17091083","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}