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Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis

ABSTRACT: Aging hampers the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here, using proteomic and metabolomic profiling of intestinal tissues together with functional assays, we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent. 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 accumulation of ubiquitylated proteins. Inhibition of the polyamine pathway in vivo further delays regeneration in old mice, while its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with aging.

INSTRUMENT(S): Orbitrap Exploris 480

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

SUBMITTER: Alessandro Ori

PROVIDER: MSV000098281 | MassIVE | Mon Jun 23 09:33:00 BST 2025

SECONDARY ACCESSION(S): PXD065348

REPOSITORIES: MassIVE

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Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis

Project description:Aging hampers the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here, using proteomic and metabolomic profiling of intestinal tissues together with functional assays, we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent. 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 accumulation of ubiquitylated proteins. Inhibition of the polyamine pathway in vivo further delays regeneration in old mice, while its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with aging.

2025-06-23 | MSV000098282 | MassIVE

Polyamines sustain epithelial regeneration of aged intestine

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