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

Seyed Soheil Saeedi Saravi; Benoit Pugin; Florentin Constancias; Khatereh Shabanian; Marianne Spalinger; Aurélien Thomas; Sylvain Le Gludic; Taraneh Shabanian; Gergely Karsai; Manuel Colucci; Cristina Menni; Ilias Attaye; Xinyuan Zhang; Meret Sarah Allemann; Pratintip Lee; Alessia Visconti; Mario Falchi; Andrea Alimonti; Frank Ruschitzka; Francesco Paneni; Jürg H Beer

doi:10.1038/s43587-025-00864-8

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

Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco PaneniJürg H Beer

Twin Research & Genetic Epidemiology

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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 H2O2 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.

Original language	English
Pages (from-to)	1025-1045
Number of pages	21
Journal	Nature Aging
Volume	5
Issue number	6
Early online date	12 May 2025
DOIs	https://doi.org/10.1038/s43587-025-00864-8
Publication status	Published - Jun 2025

Keywords

Gastrointestinal Microbiome/physiology
Animals
Phenylacetates/metabolism
Cellular Senescence/physiology
Aging/metabolism
Humans
Mice
Endothelial Cells/metabolism
Male
Clostridium/metabolism
Mice, Inbred C57BL
Hydrogen Peroxide/metabolism
Female
Glutamine/analogs & derivatives
Feces/microbiology
Aged
Mitochondria/metabolism
Sirtuin 1/metabolism

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10.1038/s43587-025-00864-8Licence: CC BY

Gut microbiota-dependent_SARAVI_Publishedonline12May2025_GOLD_VoR (CC BY)Final published version, 9.12 MBLicence: CC BY

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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., ... Beer, J. H. (2025). Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nature Aging, 5(6), 1025-1045. https://doi.org/10.1038/s43587-025-00864-8

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title = "Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging",

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 H2O2 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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author = "{Saeedi Saravi}, {Seyed Soheil} and Benoit Pugin and Florentin Constancias and Khatereh Shabanian and Marianne Spalinger and Aur{\'e}lien Thomas and {Le Gludic}, Sylvain and Taraneh Shabanian and Gergely Karsai and Manuel Colucci and Cristina Menni and Ilias Attaye and Xinyuan Zhang and Allemann, {Meret Sarah} and Pratintip Lee and Alessia Visconti and Mario Falchi and Andrea Alimonti and Frank Ruschitzka and Francesco Paneni and Beer, {J{\"u}rg H}",

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year = "2025",

month = jun,

doi = "10.1038/s43587-025-00864-8",

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Saeedi Saravi, SS, 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, MS, Lee, P, Visconti, A , Falchi, M, Alimonti, A, Ruschitzka, F, Paneni, F & Beer, JH 2025, 'Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging', Nature Aging, vol. 5, no. 6, pp. 1025-1045. https://doi.org/10.1038/s43587-025-00864-8

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T1 - Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging

AU - Saeedi Saravi, Seyed Soheil

AU - Pugin, Benoit

AU - Constancias, Florentin

AU - Shabanian, Khatereh

AU - Spalinger, Marianne

AU - Thomas, Aurélien

AU - Le Gludic, Sylvain

AU - Shabanian, Taraneh

AU - Karsai, Gergely

AU - Colucci, Manuel

AU - Menni, Cristina

AU - Attaye, Ilias

AU - Zhang, Xinyuan

AU - Allemann, Meret Sarah

AU - Lee, Pratintip

AU - Visconti, Alessia

AU - Falchi, Mario

AU - Alimonti, Andrea

AU - Ruschitzka, Frank

AU - Paneni, Francesco

AU - Beer, Jürg H

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/6

Y1 - 2025/6

N2 - 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 H2O2 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.

AB - 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 H2O2 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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KW - Animals

KW - Phenylacetates/metabolism

KW - Cellular Senescence/physiology

KW - Aging/metabolism

KW - Humans

KW - Mice

KW - Endothelial Cells/metabolism

KW - Male

KW - Clostridium/metabolism

KW - Mice, Inbred C57BL

KW - Hydrogen Peroxide/metabolism

KW - Female

KW - Glutamine/analogs & derivatives

KW - Feces/microbiology

KW - Aged

KW - Mitochondria/metabolism

KW - Sirtuin 1/metabolism

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DO - 10.1038/s43587-025-00864-8

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C2 - 40355758

SN - 2662-8465

VL - 5

SP - 1025

EP - 1045

JO - Nature Aging

JF - Nature Aging

IS - 6

ER -

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

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