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Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.<\/jats:p>","DOI":"10.1101\/2023.02.15.528714","type":"posted-content","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T22:35:12Z","timestamp":1676500512000},"source":"Crossref","is-referenced-by-count":1,"title":["Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging"],"prefix":"10.64898","author":[{"given":"James R.","family":"Occean","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marshall 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