biostudies-literatureMinetti ADeutsche ForschungsgemeinschaftElse Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)Deutsche Forschungsgemeinschaft (German Research Foundation)NIDDK NIH HHSFoundation for the National Institutes of HealthFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)NCI NIH HHSElse Kröner-Fresenius-Stiftung2063-2077https://www.ebi.ac.uk/biostudies/studies/S-EPMC12717014biostudies-literatureUnknown27(12)Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo furthNature cell biologyPolyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis.PMC12717014NE 2144/5-1467788900R01 CA257523R01 CA211184U54 CA224068R01 CA034992R01CA211184, R01CA034992, R01CA257523, R01DK126545, U01CA250554 and U54CA2240682019_A79R01 DK126545U01 CA250554Omrani OKhawaled SImada SCirri ETasdogan AMeckelmann SWMinetti AYilmaz OOri ASpengler KHeller RNeri FHeinze IAllies GRasa MBrenner CLu JGebert NRahnis NCansiz FRosler JfalsePolyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis.Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo furth2025-01-01T00:00:00Z2025 Dec2026-06-06T05:23:41.565Z2026-05-26T03:12:14.749ZS-EPMC127170144128644110.1038/s41556-025-01804-9