DNA Methylation Ageing Atlas Across 17 Human Tissues

DNA Methylation Ageing Atlas Across 17 Human Tissues | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Resource DNA Methylation Ageing Atlas Across 17 Human Tissues NIR EYNON, Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7184037/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD⁺ salvage metabolism supports therapeutic targeting of NAD⁺ in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies. Biological sciences/Molecular biology/Epigenetics/DNA methylation Health sciences/Biomarkers/Predictive markers Full Text Additional Declarations Yes there is potential Competing Interest. The Regents of the University of California are the sole owner of patents and patent applications directed at epigenetic biomarkers for which Steve Horvath is a named inventor; SH is a founder and paid consultant of the non-profit Epigenetic Clock Development Foundation that licenses these patents. SH is a Principal Investigator at the Altos Labs, Cambridge Institute of Science, a biomedical company that works on rejuvenation. The other authors declare no conflict of interests. Table 1 is available in the Supplementary Files section. Supplementary Files TablesandSupplementaryTables.xlsx Table 1 Top pan-tissue DMPs present in 13 or more tissues. Supplementary Table 1 Permutation-based sensitivity analysis for the overlap likelihood of VMPs and DMPs. Supplementary Table 2 Pan-tissue analysis of gene-gene networks Supplementary Table 3 In-silico perturbation analysis findings featuring key contributing genes and pathways Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7184037","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Resource","associatedPublications":[],"authors":[{"id":496646837,"identity":"4e98c1d2-1ece-43fb-81a5-0123b9b01f28","order_by":0,"name":"NIR 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\u003c/strong\u003ePan-tissue analysis of gene-gene networks\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Table 3 \u003c/strong\u003eIn-silico perturbation analysis findings featuring key contributing genes and pathways\u003c/p\u003e","description":"","filename":"TablesandSupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7184037/v1/d7391333057849c93fd42c00.xlsx"}],"financialInterests":"\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e there is potential Competing Interest. The Regents of the University of California are the sole owner of patents and patent applications directed at epigenetic biomarkers for which Steve Horvath is a named inventor; SH is a founder and paid consultant of the non-profit Epigenetic Clock Development Foundation that licenses these patents. SH is a Principal Investigator at the Altos Labs, Cambridge Institute of Science, a biomedical company that works on rejuvenation. The other authors declare no conflict of interests.\u003c/p\u003e\n\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"DNA Methylation Ageing Atlas Across 17 Human Tissues","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7184037/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7184037/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD⁺ salvage metabolism supports therapeutic targeting of NAD⁺ in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.","manuscriptTitle":"DNA Methylation Ageing Atlas Across 17 Human Tissues","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-07 08:19:42","doi":"10.21203/rs.3.rs-7184037/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-aging","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nataging","sideBox":"Learn more about [Nature Aging](https://www.nature.com/nataging/)","snPcode":"","submissionUrl":"","title":"Nature Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"586e8ca7-df07-455b-b5c9-5d14537aec70","owner":[],"postedDate":"August 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52755643,"name":"Biological sciences/Molecular biology/Epigenetics/DNA methylation"},{"id":52755644,"name":"Health sciences/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2026-04-13T16:18:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-07 08:19:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7184037","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7184037","identity":"rs-7184037","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}