Polyamines 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 further delays regeneration in old mice, whereas its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight the promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with ageing.
Authors
- Saleh Khawaled (ORCID: https://orcid.org/0000-0002-2315-3697)
- Norman Rahnis (ORCID: https://orcid.org/0000-0001-8424-9919)
- Jonas Rösler
- Omid Omrani (ORCID: https://orcid.org/0000-0002-9902-3477)
- Emilio Cirri (ORCID: https://orcid.org/0000-0001-9618-661X)
- Katrin Spengler (ORCID: https://orcid.org/0000-0001-9611-7841)
- Shinya Imada
- Alessandro Ori (ORCID: https://orcid.org/0000-0002-3046-0871)
- Alpaslan Tasdogan (ORCID: https://orcid.org/0000-0003-2543-852X)
- Feyza Cansiz (ORCID: https://orcid.org/0009-0006-6526-990X)
- Sven W. Meckelmann (ORCID: https://orcid.org/0000-0002-0407-7879)
- Francesco Neri (ORCID: https://orcid.org/0000-0003-3903-1974)
- Ivonne Heinze
- Gabriele Allies (ORCID: https://orcid.org/0009-0000-0784-9021)
- Regine Heller (ORCID: https://orcid.org/0000-0002-1703-1925)
- Nadja Gebert (ORCID: https://orcid.org/0000-0002-7659-3426)
- Alberto E. Minetti (ORCID: https://orcid.org/0000-0002-0120-4406)
- Jing Lü (ORCID: https://orcid.org/0000-0001-6017-326X)
- Christiane Brenner
- Mahdi Rasa
- Ömer Yilmaz (ORCID: https://orcid.org/0000-0002-7577-4612)
Institutions
- Broad Institute (US)
- Beth Israel Deaconess Medical Center (US)
- University Hospital Bonn (DE)
- Beth Israel Deaconess Hospital (US)
- Essen University Hospital (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Leibniz University of Applied Sciences (DE)
- Jena University Hospital (DE)
- Allen Institute (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Technische Universität Berlin (DE)
- University of Turin (IT)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41556-025-01804-9
- Citations
- 4
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Alexander and Margaret Stewart Trust
- Dana-Farber/Harvard Cancer Center
- Australian Government
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Deutsche Forschungsgemeinschaft
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Ricerca Molinette
- National Institutes of Health
- Leibniz-Gemeinschaft