Enhancing DNA Repair Prolongs Lifespan and Improves Healthspan in Mice

Enhancing DNA Repair Prolongs Lifespan and Improves Healthspan in Mice | 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 Biological Sciences - Article Enhancing DNA Repair Prolongs Lifespan and Improves Healthspan in Mice Zhiyong Mao, Weina Zhang, Huanyin Tang, Zhiwei Song, Junhao Xu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5846178/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 Impairments in DNA repair mechanisms undermine genomic integrity, accelerating the aging process and elevating the risk of age-related diseases in both murine models and humans. Despite the recognized link between DNA repair and aging, empirical evidence supporting the lifespan and healthspan extension through enhanced DNA repair is lacking. This knowledge gap is attributed to the complex interplay of numerous DNA repair genes involved in maintaining genomic stability, making it challenging to pinpoint specific pathways and factors that could be targeted for lifespan and healthspan improvements. In this study, we generated a knock-in mouse model overexpressing XRCC4 and DNA LIG4, key components of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks. Our findings reveal that augmenting NHEJ is a viable anti-aging strategy in mammals, as evidenced by extended lifespan and improved healthspan in both wild type mice and LmnaG609G/+ progeroid mice. Additionally, enhanced NHEJ activity improves cardiac, motor, and cognitive functions, as well as bone quality in aged mice. Transcriptomic and epigenetic analysis across different organs indicates significant downregulation in inflammatory responses and upregulation of pathways associated with maintaining organ homeostasis and function, further supporting the role of DNA repair in modulating aging and age-related diseases. Our data underscore the potential of targeting DNA repair pathways as a strategy to counteract aging and its associated health decline. Biological sciences/Physiology/Ageing Biological sciences/Molecular biology/DNA damage and repair/Non-homologous-end joining Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1SZWright.pdf Supplementary table 1 nreditorialpolicychecklist.pdf Checklist nrreportingsummary.pdf reporting summary Supplementaryfigure.pdf Supplementary figure 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5846178","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":577574704,"identity":"8e29bcf0-09e4-4598-8ee2-0d1eb4db0c22","order_by":0,"name":"Zhiyong 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Despite the recognized link between DNA repair and aging, empirical evidence supporting the lifespan and healthspan extension through enhanced DNA repair is lacking. This knowledge gap is attributed to the complex interplay of numerous DNA repair genes involved in maintaining genomic stability, making it challenging to pinpoint specific pathways and factors that could be targeted for lifespan and healthspan improvements. In this study, we generated a knock-in mouse model overexpressing XRCC4 and DNA LIG4, key components of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks. Our findings reveal that augmenting NHEJ is a viable anti-aging strategy in mammals, as evidenced by extended lifespan and improved healthspan in both wild type mice and LmnaG609G/+ progeroid mice. Additionally, enhanced NHEJ activity improves cardiac, motor, and cognitive functions, as well as bone quality in aged mice. Transcriptomic and epigenetic analysis across different organs indicates significant downregulation in inflammatory responses and upregulation of pathways associated with maintaining organ homeostasis and function, further supporting the role of DNA repair in modulating aging and age-related diseases. Our data underscore the potential of targeting DNA repair pathways as a strategy to counteract aging and its associated health decline.","manuscriptTitle":"Enhancing DNA Repair Prolongs Lifespan and Improves Healthspan in Mice","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-13 09:54:50","doi":"10.21203/rs.3.rs-5846178/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e74ddf73-9851-4a98-94db-837d03eca677","owner":[],"postedDate":"March 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61448510,"name":"Biological sciences/Physiology/Ageing"},{"id":61448511,"name":"Biological sciences/Molecular biology/DNA damage and repair/Non-homologous-end joining"}],"tags":[],"updatedAt":"2026-03-13T09:54:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-13 09:54:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5846178","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5846178","identity":"rs-5846178","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}