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<p>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.</p>

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Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月24日

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  • Alberto Minetti,
  • Omid Omrani,
  • Christiane Brenner,
  • Feyza Cansiz,
  • Shinya Imada,
  • Jonas Rösler,
  • Saleh Khawaled,
  • Gabriele Allies,
  • Sven W. Meckelmann,
  • Nadja Gebert,
  • Ivonne Heinze,
  • Norman Rahnis,
  • Jing Lu,
  • Katrin Spengler,
  • Mahdi Rasa,
  • Emilio Cirri,
  • Regine Heller,
  • Ömer Yilmaz,
  • Alpaslan Tasdogan,
  • Francesco Neri,
  • Alessandro Ori

摘要

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.