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However, before the use of aging biomarkers, such as epigenetic clocks, as surrogate endpoints, their responsiveness to interventions that target aging must be tested. Here we curate TranslAGE, a harmonized database of 51 public and private longitudinal interventional studies, and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 94 other DNA methylation (DNAm) biomarkers that can help explain the changes observed for each clock. Using this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging show the strongest responses across all interventions and show consistent results with one another; pharmacological and lifestyle interventions drive the strongest responses from DNAm biomarkers; and the characteristics of the study population and study duration are key factors in determining the responsiveness of DNAm biomarkers to an intervention. Moreover, clocks with multiple subscores (that is \u2018explainable clocks\u2019) provide specificity and greater mechanistic insight into the responsiveness of interventions than single-score clocks. These findings can help to design future clinical trials by guiding the choice of interventions and of specific subsets of DNAm biomarkers to minimize multiple testing, study duration, study population and sample size, with the eventual aim of uncovering DNAm biomarkers that can be used as surrogate aging endpoints.<\/jats:p>","DOI":"10.1038\/s41591-026-04562-9","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:01:53Z","timestamp":1787302913000},"page":"3477-3490","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Responsiveness of epigenetic aging biomarkers to longevity interventions in humans"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9387-1758","authenticated-orcid":false,"given":"Raghav","family":"Sehgal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Borrus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenel F.","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-8783","authenticated-orcid":false,"given":"John","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Kasamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslav","family":"Markov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahana","family":"Priyanka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7362-8753","authenticated-orcid":false,"given":"Ryan","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e0lia","family":"Carreras-Gallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6236-4705","authenticated-orcid":false,"given":"Jessica","family":"Lasky-Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun B.","family":"Dwaraka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8957-7153","authenticated-orcid":false,"given":"Michael J.","family":"Corley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2904-2741","authenticated-orcid":false,"given":"Albert","family":"Higgins-Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"4562_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/gerona\/glz267","volume":"75","author":"SB Kritchevsky","year":"2020","unstructured":"Kritchevsky, S. 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Sehgal and A.H.-C. are named as co-inventors of SystemsAge, which has been patented in the USA. A.H.-C. has received consulting fees from TruDiagnostic and FOXO Biosciences. R. Sehgal has received consulting fees from TruDiagnostic, LongevityTech.fund and Cambrian BioPharma. V.B.D., R. Smith and N.C.-G. are employees of TruDiagnostic and developed OMICmAge. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}