{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:09:49Z","timestamp":1792786189120,"version":"4.5.0"},"posted":{"date-parts":[[2025,8,27]]},"group-title":"Genomics","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"the Canadian Institutes of Health Research","award":["PAD 179760"],"award-info":[{"award-number":["PAD 179760"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"crossref"}]},{"name":"BC Cancer Foundation and BC Cancer Rising Stars Award","award":["F24-03198"],"award-info":[{"award-number":["F24-03198"]}],"id":[{"id":"https:\/\/ror.org\/03gqhbs95","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Intramural Research Program of the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Human aging does not follow a single trajectory. Epigenetic changes offer insight into the heterogeneity in aging by reflecting the combined influence of genetic, environmental, and lifestyle factors on the timing and progression of age-related changes beyond what chronological age alone can explain. Recent studies in cancer and aging underscore the importance of methylation variability as a marker of biological dysregulation. METHODS: We investigated the role of DNA methylation in aging heterogeneity by performing epigenome-wide differential methylation and variance association analyses in blood samples from 1,445 Canadians aged 45 to 85 from the Canadian Longitudinal Study on Aging.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>We identified 448 differentially methylated regions and 488 differentially variable regions associated with health decline as measured by the health deficit accumulation Frailty Index, cognitive function, and physical function. These two classes of regions showed minimal overlap, with distinct gene coverage, suggesting that variability contributes a complementary signal to aging heterogeneity. Genes overlapped by differentially methylated regions were enriched for immune and inflammation-related pathways, whereas differentially variable regions highlighted additional localized, CpG island\u2013enriched signals shared across health domains, consistent with regionally structured rather than diffuse dysregulation. By integrating significant CpGs from both analyses, we constructed an epigenetic biomarker. The biomarker was associated with all-cause mortality and showed higher discrimination than biomarkers constructed from differential methylation or variability alone, with a similar pattern reproduced in the Baltimore Longitudinal Study of Aging.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>These findings suggest that DNA methylation variability may provide a complementary dimension of epigenetic aging and support further evaluation in larger cohorts with more mortality events.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.25.671156","type":"posted-content","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T02:00:14Z","timestamp":1756346414000},"source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation variability provides a complementary epigenetic signature of aging heterogeneity: Findings from the Canadian Longitudinal Study on Aging and the Baltimore Longitudinal Study of Aging"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7707-4740","authenticated-orcid":false,"given":"Olga","family":"Vishnyakova","sequence":"first","affiliation":[{"name":"Department of Basic and Translational Research, BC Cancer, Vancouver, BC, Canada,"},{"name":"Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-5014","authenticated-orcid":false,"given":"Joosung","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Z.","family":"Moore","sequence":"additional","affiliation":[{"name":"Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Ferrucci","sequence":"additional","affiliation":[{"name":"Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada"},{"name":"Surrey Memorial Hospital, Fraser Health, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6674-995X","authenticated-orcid":false,"given":"Kenneth","family":"Rockwood","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine, Dalhousie University, Halifax, NS, Canada, and Frailty & Elder Care Network, Nova Scotia Health, Halifax, NS, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-6408","authenticated-orcid":false,"given":"Angela","family":"Brooks-Wilson","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Research, BC Cancer, Vancouver, BC, Canada,"},{"name":"Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-7314","authenticated-orcid":false,"given":"Lloyd T.","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092907401470000_2025.08.25.671156v3.1","doi-asserted-by":"publisher","DOI":"10.1186\/S13059-019-1824-Y"},{"key":"2026092907401470000_2025.08.25.671156v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2017.06.005"},{"key":"2026092907401470000_2025.08.25.671156v3.3","doi-asserted-by":"publisher","DOI":"10.1186\/GB-2011-12-1-R10"},{"key":"2026092907401470000_2025.08.25.671156v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/S42003-023-05725-X"},{"key":"2026092907401470000_2025.08.25.671156v3.5","doi-asserted-by":"crossref","unstructured":"Moylan C , Murphy S . 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