{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T21:57:02Z","timestamp":1773093422588,"version":"3.50.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T00:00:00Z","timestamp":1704240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>Epigenetic clocks are DNA methylation-based chronological age prediction models that are commonly employed to study age-related biology. The difference between the predicted and observed age is often interpreted as a form of biological age acceleration, and many studies have measured the impact of environmental and disease-associated factors on epigenetic age. Most epigenetic clocks are fit using approaches that minimize the error between the predicted and observed chronological age, and as a result, they may not accurately model the impact of factors that moderate the relationship between the actual and epigenetic age. Here, we compare epigenetic clocks that are constructed using penalized regression methods to an evolutionary framework of epigenetic aging with the epigenetic pacemaker (EPM), which directly models DNA methylation as a function of a time-dependent epigenetic state. In simulations, we show that the value of the epigenetic state is impacted by factors such as age, sex, and cell-type composition. Next, in a dataset aggregated from previous studies, we show that the epigenetic state is also moderated by sex and the cell type. Finally, we demonstrate that the epigenetic state is also moderated by toxins in a study on polybrominated biphenyl exposure. Thus, we find that the pacemaker provides a robust framework for the study of factors that impact epigenetic age acceleration and that the effect of these factors may be obscured in traditional clocks based on linear regression models.<\/jats:p>","DOI":"10.3389\/fbinf.2023.1308680","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:34:51Z","timestamp":1704256491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Identifying epigenetic aging moderators using the epigenetic pacemaker"],"prefix":"10.3389","volume":"3","author":[{"given":"Colin","family":"Farrell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanyue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalsuda","family":"Lapborisuth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Pu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sagi","family":"Snir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Pellegrini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"689","DOI":"10.2217\/epi-2016-0179","article-title":"Aging, exceptional longevity and comparisons of the Hannum and Horvath epigenetic clocks","volume":"9","author":"Armstrong","year":"2017","journal-title":"Epigenomics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: archive for functional genomics data sets-update","volume":"41","author":"Barrett","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B4","article-title":"Reproducible research with jupyter notebooks","author":"Basu","year":"2023"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e14821","DOI":"10.1371\/journal.pone.0014821","article-title":"Epigenetic predictor of age","volume":"6","author":"Bocklandt","year":"2011","journal-title":"PloS one"},{"key":"B6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41398-019-0376-y","article-title":"Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals","volume":"9","author":"Braun","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/j.ajhg.2017.04.004","article-title":"CHARGE and kabuki syndromes: gene-specific DNAMethylation signatures identify EpigeneticMechanisms linking these clinically overlapping Conditions","volume":"100","author":"Butcher","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1080\/15592294.2019.1565590","article-title":"Exposure to polybrominated biphenyl (PBB) associates with genome-wide DNA methylation differences in peripheral blood","volume":"14","author":"Curtis","year":"","journal-title":"Epigenetics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12940-019-0509-z","article-title":"Thyroid hormone levels associate with exposure to polychlorinated biphenyls and polybrominated biphenyls in adults exposed as children","volume":"18","author":"Curtis","year":"","journal-title":"Environ. Health"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.21105\/joss.01277","article-title":"Tqdm: a fast, extensible progress meter for Python and cli","volume":"4","author":"Da Costa-Luis","year":"2019","journal-title":"JOSS"},{"key":"B11","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s00401-020-02224-9","article-title":"Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease","volume":"140","author":"Dabin","year":"2020","journal-title":"Acta Neuropathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.3390\/cancers12071799","article-title":"Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals","volume":"12","author":"D\u00e1maso","year":"2020","journal-title":"Cancers"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e79391","DOI":"10.1371\/journal.pone.0079391","article-title":"Methylome analysis and epigenetic changes associated with menarcheal age","volume":"8","author":"Demetriou","year":"2013","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1002\/ijc.31189","article-title":"DNA methylation-based biological aging and cancer risk and survival: pooled analysis of seven prospective studies","volume":"142","author":"Dugu\u00e9","year":"2018","journal-title":"Int. J. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4662","DOI":"10.1093\/bioinformatics\/btaa585","article-title":"The Epigenetic Pacemaker: modeling epigenetic states under an evolutionary framework","volume":"36","author":"Farrell","year":"2020","journal-title":"Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1126\/science.1136800","article-title":"Clustering by passing messages between data points","volume":"315","author":"Frey","year":"2007","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"105","DOI":"10.3109\/10408448509056268","article-title":"The PBB episode in Michigan: an overall appraisal","volume":"16","author":"Fries","year":"1985","journal-title":"Crit. Rev. Toxicol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.molcel.2012.10.016","article-title":"Genome-wide methylation profiles reveal quantitative views of human aging rates","volume":"49","author":"Hannum","year":"2013","journal-title":"Mol. Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/s41586-020-2649-2","article-title":"Array programming with NumPy","volume":"585","author":"Harris","year":"2020","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1097\/00001648-199807000-00005","article-title":"Cancer among a Michigan cohort exposed to polybrominated biphenyls in 1973","volume":"9","author":"Hoque","year":"1998","journal-title":"Epidemiology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"R115","DOI":"10.1186\/gb-2013-14-10-r115","article-title":"DNA methylation age of human tissues and cell types","volume":"14","author":"Horvath","year":"2013","journal-title":"Genome Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"15538","DOI":"10.1073\/pnas.1412759111","article-title":"Obesity accelerates epigenetic aging of human liver","volume":"111","author":"Horvath","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.18632\/aging.100861","article-title":"Decreased epigenetic age of PBMCs from Italian semi supercentenarians and their offspring","volume":"7","author":"Horvath","year":"2015","journal-title":"Aging"},{"key":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.18632\/aging.100859","article-title":"Increased epigenetic age and granulocyte counts in the blood of Parkinson\u2019s disease patients","volume":"7","author":"Horvath","year":"2015","journal-title":"Aging"},{"key":"B26","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/1471-2105-13-86","article-title":"DNA methylation arrays as surrogate measures of cell mixture distribution","volume":"13","author":"Houseman","year":"2012","journal-title":"BMC Bioinforma."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3012","DOI":"10.1210\/jc.2018-02076","article-title":"Epigenetic age acceleration in adolescence associates with BMI, inflammation, and risk score for middle age cardiovascular disease","volume":"104","author":"Huang","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: a 2D graphics environment","author":"Hunter","year":""},{"key":"B29","doi-asserted-by":"publisher","first-page":"097020","DOI":"10.1289\/EHP1302","article-title":"Serum polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) and thyroid function among Michigan adults several decades after the 1973-1974 PBB contamination of livestock feed","volume":"125","author":"Jacobson","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e67378","DOI":"10.1371\/journal.pone.0067378","article-title":"Continuous aging of the human DNA methylome throughout the human lifespan","volume":"8","author":"Johansson","year":"2013","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3721","DOI":"10.1038\/s41598-020-60758-0","article-title":"Longitudinal DNA methylation differences precede type 1 diabetes","volume":"10","author":"Johnson","year":"2020","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s13148-019-0614-4","article-title":"Epigenetic findings in periodontitis in UK twins: a cross-sectional study","volume":"11","author":"Kurushima","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/s42003-021-02935-z","article-title":"Epigenetic models predict age and aging in plains zebras and other equids","volume":"4","author":"Larison","year":"2021","journal-title":"Commun. Biol."},{"key":"B34","doi-asserted-by":"publisher","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":"B35","first-page":"142","article-title":"Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis","volume-title":"Nat Biotechnol","author":"Liu","year":"2013"},{"key":"B36","doi-asserted-by":"publisher","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":"B37","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.1038\/s41598-018-22686-y","article-title":"Author Correction: smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship","volume":"8","author":"Marabita","year":"2018","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13059-015-0584-6","article-title":"DNA methylation age of blood predicts all-cause mortality in later life","volume":"16","author":"Marioni","year":"2015","journal-title":"Genome Biol."},{"key":"B39","volume-title":"Python for Data Analysis: data Wrangling with Pandas, NumPy, and IPython","author":"McKinney","year":"2012"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2825","DOI":"10.48550\/arXiv.1309.0238","article-title":"Scikit-learn: machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s13148-016-0228-z","article-title":"Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort","volume":"8","author":"Perna","year":"2016","journal-title":"Clin. Epigenetics"},{"key":"B42","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13059-016-1066-1","article-title":"Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling","volume":"17","author":"Pidsley","year":"2016","journal-title":"Genome Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/s41559-022-01679-1","article-title":"Hibernation slows epigenetic aging in yellow-bellied marmots","volume":"6","author":"Pinho","year":"2021","journal-title":"Nat. Ecol. Evol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"319","DOI":"10.3109\/10408448409023762","article-title":"Polychlorinated biphenyls (PCBs) and polybrominated biphenyls(PBBs): biochemistry, toxicology, and mechanism of action","volume":"13","author":"Safe","year":"1984","journal-title":"Crit. Rev. Toxicol."},{"key":"B45","first-page":"61","article-title":"Econometric and statistical modeling with python in","volume":"57","author":"Seabold","year":"2010"},{"key":"B46","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1080\/15592294.2019.1623634","article-title":"Human epigenetic ageing is logarithmic with time across the entire lifespan","volume":"14","author":"Snir","year":"2019","journal-title":"Epigenetics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e1005183","DOI":"10.1371\/journal.pcbi.1005183","article-title":"A statistical framework to identify deviation from time linearity in epigenetic aging","volume":"12","author":"Snir","year":"2016","journal-title":"PLoS Comput. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1093\/hmg\/ddv493","article-title":"Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hy perglycemia","volume":"25","author":"Soriano-T\u00e1rraga","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1186\/1471-2164-15-1062","article-title":"Epigenetic signature of birth weight discordance in adult twins","volume":"15","author":"Tan","year":"2014","journal-title":"BMC Genomics"},{"key":"B50","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1136\/oemed-2015-103458","article-title":"Breast cancer among women in Michigan following exposure to brominated flame retardants: table\u00a01","volume":"73","author":"Terrell","year":"2016","journal-title":"Occup. Environ. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.18632\/aging.101590","article-title":"A multi-tissue full lifespan epigenetic clock for mice","volume":"10","author":"Thompson","year":"2018","journal-title":"Aging"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.18632\/aging.101211","article-title":"An epigenetic aging clock for dogs and wolves","volume":"9","author":"Thompson","year":"2017","journal-title":"Aging"},{"key":"B53","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1093\/nar\/gkt090","article-title":"Low-level processing of Illumina infinium DNA methylation BeadArrays","volume":"41","author":"Triche","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"13107","DOI":"10.1038\/srep13107","article-title":"Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes","volume":"5","author":"Tserel","year":"2015","journal-title":"Sci. Rep."},{"key":"B55","article-title":"Joblib: running python function as pipeline jobs","author":"Varoquaux","year":"2009"},{"key":"B56","doi-asserted-by":"publisher","first-page":"13507","DOI":"10.1038\/ncomms13507","article-title":"Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease","volume":"7","author":"Ventham","year":"2016","journal-title":"Nat. Commun."},{"key":"B57","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: fundamental algorithms for scientific computing in Python","volume":"17","author":"Virtanen","year":"2020","journal-title":"Nat. Methods"},{"key":"B58","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/ncomms13507","article-title":"Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers","volume":"7","author":"Voisin","year":"2015","journal-title":"Genome Med."},{"key":"B59","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: statistical data visualization","volume":"6","author":"Waskom","year":"2021","journal-title":"J. Open Source Softw."},{"key":"B60","doi-asserted-by":"publisher","first-page":"11370","DOI":"10.1073\/pnas.1816847116","article-title":"Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-\u03baB-driven inflammation and cardiovascular risk","volume":"116","author":"Zannas","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B61","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13073-019-0667-1","article-title":"Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing","volume":"11","author":"Zhang","year":"2019","journal-title":"Genome Med."}],"container-title":["Frontiers in Bioinformatics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2023.1308680\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:34:57Z","timestamp":1704256497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbinf.2023.1308680\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,3]]},"references-count":61,"alternative-id":["10.3389\/fbinf.2023.1308680"],"URL":"https:\/\/doi.org\/10.3389\/fbinf.2023.1308680","relation":{},"ISSN":["2673-7647"],"issn-type":[{"value":"2673-7647","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,3]]},"article-number":"1308680"}}