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Polyamines sustain epithelial regeneration of aged intestine

ABSTRACT: Aging reduces the regenerative capacity of the intestinal epithelium in different species including humans. The causes of delayed regeneration in the elderly remain unclear. Here, we used proteomic and metabolomic profiling of intestinal tissues together with functional assays to characterize the dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent. Comparison of regeneration dynamics in mice of different ages revealed emergence of a proteostasis stress signature and increased levels of polyamines following injury exclusively in old epithelia. Mechanistically, we show that delayed regeneration is a cell-intrinsic feature of old epithelial cells that display reduced protein synthesis and accumulation of ubiquitylated proteins. We demonstrate that an intervention based on dietary restriction followed by re-feeding prior to injury elevates intracellular polyamine levels, alleviates proteostasis stress and restores the regenerative capacity of the old intestines. Our work provides novel targets and strategies to improve intestinal regeneration in the elderly.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Alessandro Ori

PROVIDER: MSV000094212 | MassIVE | Fri Mar 01 04:54:00 GMT 2024

SECONDARY ACCESSION(S): PXD050266

REPOSITORIES: MassIVE

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