The balance of microbial populations making up the gut microbiome shifts with age. Inflammatory species and those generating harmful metabolites increase in number at the expense of species that generate beneficial metabolites. This is why approaches that rejuvenate the gut microbiome, forcing it back into a more youthful balance of populations, produce significant gains in health and life span in animal studies conducted to date. Here, researchers focus on just one aspect of gut microbiome aging, identifying a specific microbial metabolite that harms the vascular endothelium by provoke cellular senescence. The endothelium is in the inner lining of blood vessels. Damage and dysfunction in the endothelium is one of the early contributing causes of a range of vascular dysfunction, from the development of atherosclerotic lesions to leakage of the blood-brain barrier.
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.
Link: https://doi.org/10.1038/s43587-025-00864-8
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