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Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging

Saeedi Saravi, Seyed Soheil, Pugin, Benoit, Constancias, Florentin, Shabanian, Khatereh, Spalinger, Marianne, Thomas, Aurélien, Le Gludic, Sylvain, Shabanian, Taraneh, Karsai, Gergely, Colucci, Manuel, Menni, Cristina, Attaye, Ilias, Zhang, Xinyuan, Allemann, Meret Sarah, Lee, Pratintip, Visconti, Alessia, Falchi, Mario, Alimonti, Andrea, Ruschitzka, Frank, Paneni, Francesco, Beer, Jürg H.·2025·Nature Aging
DOI 10.1038/s43587-025-00864-8PMC PMC12176623

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Abstract

Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 ( Clos ). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H 2 O 2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut–vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.

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Metadata

Authors
Saeedi Saravi, S. S., Pugin, B., Constancias, F., Shabanian, K., Spalinger, M., Thomas, A., Le Gludic, S., Shabanian, T., Karsai, G., Colucci, M., Menni, C., Attaye, I., Zhang, X., Allemann, M. S., Lee, P., Visconti, A., Falchi, M., Alimonti, A., Ruschitzka, F., Paneni, F., & Beer, J. H.
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2025-05-12
Volume
5
Issue
6
Pages
1025-1045
ISSN
2662-8465
DOI
10.1038/s43587-025-00864-8
PMC
PMC12176623
Cited by
68
References
12
Language
en
Licence
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (#310030_21A053, #CRSK-3_229134)
  • Schweizerische Herzstiftung
  • Novartis Stiftung für Medizinisch-Biologische Forschung (#21A053)

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