Modulation of the RNAse P/MRP complex and mitochondrial ribosome enhances cytosolic ribosome coordination and sustains longevity

Modulation of the RNAse P/MRP complex and mitochondrial ribosome enhances cytosolic ribosome coordination and sustains longevity | 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 Article Modulation of the RNAse P/MRP complex and mitochondrial ribosome enhances cytosolic ribosome coordination and sustains longevity Adam Antebi, Victoria Martinez-Miguel, Till Popkes-van Oepen, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9541370/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 is accompanied by declining protein synthesis and ribosome abundance, yet reduced translation can extend lifespan. Whether the age-associated decline is adaptive or reflects a pathological failure remains unclear. Here, we show that a breakdown in the coordination of ribosome biogenesis and assembly drives shortened lifespan. We identify the C. elegans ncl-1/BRAT tumor suppressor as a key coordinator of ribogenesis as well as cytosolic and mitochondrial ribosome production, whose loss leads to premature aging and proteostasis collapse. Importantly, we demonstrate that restoring cytosolic ribosomal homeostasis downstream of the nucleolus, by tamping down ribogenesis factor M/RNAse P and mitochondrial ribosomes, is sufficient to rescue cytosolic ribosomal coordination, proteostasis and longevity. Our findings identify age-associated ribosome dysfunction as a qualitative failure of ribosomal biogenesis, and show that restoring ribosomal homeostasis is sufficient to improve proteostasis and extend lifespan. Biological sciences/Molecular biology/Translation/Ribosome Biological sciences/Developmental biology/Ageing Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Table1Lifespans.xlsx Table 1 Table2BulkRNAseqProteomicsD1glp1glp1ncl1.xlsx Table 2 Table3davidbulkproteomicsglp1ncl1vsglp1D1.xlsx Table 3 Table4N2agingLFQquantarrayw.xlsx Table 4 Table5davidN2ageingtrajectories.xlsx Table 5 Table6TTGTTgenewise.csv Table 6 Table7glp1glp1ncl1gnmrps16gnpopl1D1LFQquantarrayw.xlsx Table 7 Table8glp1glp1ncl1gnmrps16gnpopl1D5LFQquantarrayw.xlsx Table 8 Table9davidSWproteomicsglp1ncl1vsglp1D5.xlsx Table 9 Table10davidSWproteomicsmrps16popl1combinedvsglp1ncl1D5.xlsx Table 10 Table11differentialtranslationD1.xlsx Table 11 Table12davidriboseqTEglp1ncl1vsglp1D1.xlsx Table 12 Table13davidriboseqTEmrsps16popl1combinedvsglp1ncl1D1.xlsx Table 13 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-9541370","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":638570082,"identity":"d0b88876-9a89-438b-af78-306fc0c25cdb","order_by":0,"name":"Adam 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longevity","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-9541370/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9541370/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Aging is accompanied by declining protein synthesis and ribosome abundance, yet reduced\r\ntranslation can extend lifespan. Whether the age-associated decline is adaptive or reflects a\r\npathological failure remains unclear. Here, we show that a breakdown in the coordination of\r\nribosome biogenesis and assembly drives shortened lifespan. We identify the C. elegans ncl-1/BRAT\r\ntumor suppressor as a key coordinator of ribogenesis as well as cytosolic and mitochondrial\r\nribosome production, whose loss leads to premature aging and proteostasis collapse. Importantly,\r\nwe demonstrate that restoring cytosolic ribosomal homeostasis downstream of the nucleolus, by\r\ntamping down ribogenesis factor M/RNAse P and mitochondrial ribosomes, is sufficient to rescue\r\ncytosolic ribosomal coordination, proteostasis and longevity. Our findings identify age-associated\r\nribosome dysfunction as a qualitative failure of ribosomal biogenesis, and show that restoring\r\nribosomal homeostasis is sufficient to improve proteostasis and extend lifespan.","manuscriptTitle":"Modulation of the RNAse P/MRP complex and mitochondrial ribosome enhances cytosolic ribosome coordination and sustains longevity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 10:05:23","doi":"10.21203/rs.3.rs-9541370/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0ace1c93-459c-490c-b4ef-dd3f027bf2d9","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-11T23:24:04+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"4","date":"2026-05-11T22:10:20+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67962499,"name":"Biological sciences/Molecular biology/Translation/Ribosome"},{"id":67962500,"name":"Biological sciences/Developmental biology/Ageing"}],"tags":[],"updatedAt":"2026-05-13T10:05:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 10:05:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9541370","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9541370","identity":"rs-9541370","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}