{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:59:35Z","timestamp":1791475175062,"version":"4.3.4"},"posted":{"date-parts":[[2026,10,4]]},"group-title":"Genomics","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["2U19AG023122"],"award-info":[{"award-number":["2U19AG023122"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1UH3AG064704-01"],"award-info":[{"award-number":["1UH3AG064704-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["N01:75N92025D00035"],"award-info":[{"award-number":["N01:75N92025D00035"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) resets epigenetic age, creating a major challenge for modeling age-associated cellular states and limiting the use of iPSCs in aging research beyond the genetic component. Recent work has shown that healthy organoids can re-accumulate age-associated epigenetic states over extended culture; whether disease-associated genetic states can directionally reshape these trajectories after reprogramming remains unknown. Here, we present a reproducible,\n                  <jats:italic>in-vitro<\/jats:italic>\n                  approach to re-establish epigenetic aging trajectories using iPSC-derived organoid systems, as quantified by multiple epigenetic clock models. We first demonstrate that epigenetic age progressively increases with serial passaging in a lung organoid model (alveolospheres). We then show that disease-associated mutations in multiple models drive additional, cell-intrinsic shifts in epigenetic age, implicating disease state as an independent modulator of epigenetic clocks. Together, these findings reinforce that iPSC-derived organoids recapitulate epigenetic aging trajectories over time, while highlighting disease state as a potent and potentially tractable modulator of epigenetic age\n                  <jats:italic>in vitro<\/jats:italic>\n                  . By enabling more faithful modeling of age-associated cellular states, this approach expands the utility of iPSC-based systems for dissecting the molecular mechanisms that regulate human aging.\n                <\/jats:p>","DOI":"10.64898\/2026.09.30.755445","type":"posted-content","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:50:13Z","timestamp":1791186613000},"source":"Crossref","is-referenced-by-count":0,"title":["Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3067-4458","authenticated-orcid":false,"given":"Nicholas J.","family":"Skvir","sequence":"first","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd W.","family":"Dowrey","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel F.","family":"Cranston","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Giadone","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA"},{"name":"Harvard Stem Cell Institute, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakota","family":"Jones","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly S.","family":"Golden","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Braden","family":"Pate","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Labott","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Serrano","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, USA"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, 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