{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:56:00Z","timestamp":1790769360740,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,27]]},"group-title":"Genetics","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute on Aging","award":["R01AG075130"],"award-info":[{"award-number":["R01AG075130"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Aging","award":["R01AG083065"],"award-info":[{"award-number":["R01AG083065"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Aging","award":["F31AG084238"],"award-info":[{"award-number":["F31AG084238"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of General Medical Sciences","award":["R01GM124532"],"award-info":[{"award-number":["R01GM124532"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of General Medical Sciences","award":["R35GM133428"],"award-info":[{"award-number":["R35GM133428"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hevolution Foundation","award":["HF-AGE-23-1273964-51"],"award-info":[{"award-number":["HF-AGE-23-1273964-51"]}],"id":[{"id":"https:\/\/ror.org\/00kgc7526","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.754271","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:10:11Z","timestamp":1790503811000},"source":"Crossref","is-referenced-by-count":0,"title":["Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-1105","authenticated-orcid":false,"given":"Sarah J.","family":"Shemtov","sequence":"first","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Hwang","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire S.","family":"Chung","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Anson","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangmin","family":"Lee","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivetta","family":"Vorobyova","sequence":"additional","affiliation":[{"name":"Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxiang","family":"Wan","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4444-1145","authenticated-orcid":false,"given":"Scott R.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-9161","authenticated-orcid":false,"given":"Amy R.","family":"Vandiver","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert M.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitaker","family":"Cohn","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7401-4777","authenticated-orcid":false,"given":"B\u00e9r\u00e9nice A.","family":"Benayoun","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"},{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA"},{"name":"Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA"},{"name":"Cancer Biology Department, USC Keck School of Medicine, Los Angeles, CA, USA"},{"name":"USC Stem Cell Initiative, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max A.","family":"Thorwald","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinchas","family":"Cohen","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8460-8616","authenticated-orcid":false,"given":"Jonathan","family":"Wanagat","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Gout","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Mississippi State University, Starkville, MS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Vermulst","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026093004050741000_2026.09.24.754271v1.1","doi-asserted-by":"crossref","unstructured":"D. C. Wallace , Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51, 440\u2013450.","DOI":"10.1002\/em.20586"},{"key":"2026093004050741000_2026.09.24.754271v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1156906"},{"key":"2026093004050741000_2026.09.24.754271v1.3","doi-asserted-by":"crossref","first-page":"625020","DOI":"10.3389\/fcell.2021.625020","article-title":"mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology","volume":"9","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2026093004050741000_2026.09.24.754271v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-002-0893-7"},{"key":"2026093004050741000_2026.09.24.754271v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng0492-11"},{"key":"2026093004050741000_2026.09.24.754271v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng1778"},{"key":"2026093004050741000_2026.09.24.754271v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(89)92145-4"},{"key":"2026093004050741000_2026.09.24.754271v1.8","doi-asserted-by":"crossref","unstructured":"C. Lawless , L. Greaves , A. K. Reeve , D. M. Turnbull , A. E. Vincent , The rise and rise of mitochondrial DNA mutations. Open Biol 10, 200061 (2020).","DOI":"10.1098\/rsob.200061"},{"key":"2026093004050741000_2026.09.24.754271v1.9","doi-asserted-by":"crossref","first-page":"e1004620","DOI":"10.1371\/journal.pgen.1004620","article-title":"Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing","volume":"10","year":"2014","journal-title":"PLoS genetics"},{"key":"2026093004050741000_2026.09.24.754271v1.10","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1016\/S0021-9258(17)40396-6","article-title":"DNA polymerase of mitochondria is a gamma-polymerase","volume":"252","year":"1977","journal-title":"The Journal of biological chemistry"},{"key":"2026093004050741000_2026.09.24.754271v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112125"},{"key":"2026093004050741000_2026.09.24.754271v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature02517"},{"key":"2026093004050741000_2026.09.24.754271v1.13","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1038\/nprot.2014.170","article-title":"Detecting ultralow-frequency mutations by Duplex Sequencing","volume":"9","year":"2014","journal-title":"Nature protocols"},{"key":"2026093004050741000_2026.09.24.754271v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/ng.95"},{"key":"2026093004050741000_2026.09.24.754271v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/ng1988"},{"key":"2026093004050741000_2026.09.24.754271v1.16","doi-asserted-by":"crossref","unstructured":"C. Trumpff , Q. Huang , J. Michelson , C. C. Liu , D. Shire , C. G. Habeck , Y. Stern , M. Picard , Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging. bioRxiv, (2025).","DOI":"10.1101\/2025.01.28.635306"},{"key":"2026093004050741000_2026.09.24.754271v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.81"},{"key":"2026093004050741000_2026.09.24.754271v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/path.5084"},{"key":"2026093004050741000_2026.09.24.754271v1.19","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"2026093004050741000_2026.09.24.754271v1.20","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-052621-092014"},{"key":"2026093004050741000_2026.09.24.754271v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.05.018"},{"key":"2026093004050741000_2026.09.24.754271v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/348651a0"},{"key":"2026093004050741000_2026.09.24.754271v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1213-4"},{"key":"2026093004050741000_2026.09.24.754271v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13100"},{"key":"2026093004050741000_2026.09.24.754271v1.25","doi-asserted-by":"crossref","unstructured":"S. B. Hannah Tobias-Wallingford , Lauren Gaspar , Brian Gallagher , Carole Bassa , Emmanuel Sotirakis , Vincent Dubus , Christopher Hemme , Lars Olson , Giuseppe Coppotelli , Jaime M. Ross , A novel inducible mtDNA mutator mouse model to study mitochondrial dysfunction with temporal and spatial control. BioRxiv, (2025).","DOI":"10.1101\/2025.04.17.649454"},{"key":"2026093004050741000_2026.09.24.754271v1.26","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4777"},{"key":"2026093004050741000_2026.09.24.754271v1.27","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.822403"},{"key":"2026093004050741000_2026.09.24.754271v1.28","doi-asserted-by":"crossref","first-page":"e24","DOI":"10.1371\/journal.pgen.0030024","article-title":"The role of mitochondrial DNA mutations in mammalian aging","volume":"3","year":"2007","journal-title":"PLoS genetics"},{"key":"2026093004050741000_2026.09.24.754271v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nature05541"},{"key":"2026093004050741000_2026.09.24.754271v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.03.002"},{"key":"2026093004050741000_2026.09.24.754271v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.026"},{"key":"2026093004050741000_2026.09.24.754271v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24709"},{"key":"2026093004050741000_2026.09.24.754271v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab901"},{"key":"2026093004050741000_2026.09.24.754271v1.34","doi-asserted-by":"crossref","unstructured":"A. Seluanov , A. Vaidya , V. Gorbunova , Establishing primary adult fibroblast cultures from rodents. Journal of visualized experiments : JoVE, (2010).","DOI":"10.3791\/2033-v"},{"key":"2026093004050741000_2026.09.24.754271v1.35","doi-asserted-by":"crossref","unstructured":"C. Hernandez-Ainsa , E. Lopez-Gallardo , M. C. Garcia-Jimenez , F. J. Climent-Alcala , C. Rodriguez-Vigil , M. Garcia Fernandez de Villalta, R. Artuch , J. Montoya , E. Ruiz-Pesini , S. Emperador , Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome. Dis Model Mech 15, (2022).","DOI":"10.1242\/dmm.049083"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.24.754271","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:05:19Z","timestamp":1790766319000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.24.754271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":35,"URL":"https:\/\/doi.org\/10.64898\/2026.09.24.754271","relation":{},"subject":[],"published":{"date-parts":[[2026,9,27]]},"subtype":"preprint"}}