Polyamines Rescue Aged Gut Regeneration by Fixing Protein Quality Control
A 2025 Nature Cell Biology study reveals polyamines counteract proteostasis breakdown in aging intestines, restoring regenerative capacity after injury.
Summary
As the gut ages, its ability to repair itself after injury declines partly because protein homeostasis breaks down. Researchers at the Leibniz Institute on Aging used 5-fluorouracil injury in young and old mice to map regeneration dynamics via proteomics and metabolomics. They found old intestines uniquely accumulate ubiquitylated proteins and show reduced protein synthesis after injury, hallmarks of proteostasis stress. Critically, old intestines also upregulate polyamine metabolism as a compensatory response. Blocking the polyamine pathway worsened regeneration in old mice, while activating it through dietary restriction followed by refeeding or direct polyamine supplementation restored regenerative capacity. The findings identify the polyamine–proteostasis axis as a targetable pathway for improving gut repair in elderly individuals.
Detailed Summary
Aging progressively impairs the small intestine's remarkable capacity to regenerate its epithelial lining, a process driven by intestinal stem cells. While prior work identified changes in stem cell niche signaling and systemic inflammation as contributors, the molecular dynamics underlying delayed repair in old tissue remained poorly understood. This study provides a detailed, time-resolved picture of those dynamics and pinpoints the polyamine–proteostasis axis as a central regulator.
The researchers administered a single dose of 5-fluorouracil (5-FU), a chemotherapeutic that disrupts DNA replication, RNA synthesis, and ribosome function, to young (3–5 month) and old (20–24 month) male mice. Intestinal tissues were harvested at 2, 5, and 7 days post-injection and subjected to quantitative proteomics and metabolomics, complemented by histology, organoid assays, and functional readouts. Young mice recovered fully within 5–7 days, while old mice showed sustained reductions in crypt number, villus cell density, proliferating cells, and body weight, confirming delayed regeneration.
Proteomic profiling revealed that old intestinal epithelia uniquely accumulate ubiquitylated proteins and exhibit reduced ribosomal protein abundance and protein synthesis rates following injury—clear signatures of proteostasis stress. These deficits were shown to be cell-intrinsic: aged intestinal organoids (enteroids) displayed the same impairments in protein synthesis and ubiquitylated protein clearance independent of systemic factors. Strikingly, the metabolomic data showed that polyamine levels (spermidine, spermine, and related metabolites) rose specifically in old intestines after 5-FU injury, suggesting a compensatory activation of the polyamine biosynthetic pathway.
To test whether polyamines are functionally important, the team pharmacologically inhibited the pathway in vivo using DFMO (difluoromethylornithine), an inhibitor of ornithine decarboxylase. DFMO treatment further delayed regeneration specifically in old mice, confirming that endogenous polyamine induction is a beneficial adaptive response. Conversely, enhancing polyamine availability—either via dietary supplementation or through a dietary restriction followed by refeeding (DR/RF) protocol shown previously to boost polyamine metabolism—was sufficient to accelerate intestinal regeneration in old mice, improving crypt recovery, proliferation markers, and tissue architecture. The mechanism involves spermidine-driven hypusination of the translation factor EIF5A, which relieves ribosomal stalling and improves translation efficiency, thereby alleviating the proteostasis burden that accumulates in aged epithelia under stress.
These findings position polyamines not merely as metabolic byproducts but as essential modulators of epithelial resilience during aging. The identification of a dietary intervention (DR/RF) that recapitulates the benefits of polyamine supplementation is particularly relevant, as it suggests actionable and potentially translatable strategies for improving gut recovery in elderly patients undergoing chemotherapy or other intestinal injury.
Key Findings
- Old mouse intestines show unique proteostasis stress after 5-FU injury: reduced protein synthesis and accumulation of ubiquitylated proteins.
- Polyamine levels rise specifically in aged intestinal epithelia post-injury, representing a compensatory adaptive response.
- Inhibiting polyamine biosynthesis (DFMO) worsens regeneration in old mice, confirming polyamines are functionally required.
- Dietary restriction followed by refeeding or direct polyamine supplementation restores regenerative capacity in aged intestines.
- Proteostasis deficits in aged intestines are cell-intrinsic, replicated in aged organoids without systemic factors.
Methodology
Male young (3–5 month) and old (20–24 month) mice received a single intraperitoneal 5-FU injection; intestinal tissues were collected at 2, 5, and 7 days for quantitative proteomics and metabolomics. Functional validation used aged intestinal organoids, in vivo pharmacological inhibition of polyamine synthesis (DFMO), dietary restriction/refeeding protocols, and exogenous polyamine supplementation.
Study Limitations
The study used only male mice, limiting generalizability across sexes. All experiments were conducted in rodent models, and whether the polyamine–proteostasis axis operates identically in human aged intestines requires direct validation. The long-term safety of polyamine supplementation in elderly cancer patients, who may have elevated cancer risk, warrants careful evaluation.
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