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

Endothelial cell (EC) senescence plays a crucial role in the development ofcardiovascular diseases in aging population. Gut microbiota alterations are emergingas significant factors present in cellular senescence associated with aging. However,little is known about how aging-related changes in gut microbiota are causallyimplicated in EC senescence. Here we show that gut microbiota-dependentphenylacetic acid (PAA) and its derivative, phenylacetylglutamine (PAGln), areelevated in a human aging cohort (TwinsUK, n=7,303) and in aged mice.Metagenomic analyses revealed a marked increase in the abundance of PAA-producing microbial pathways (PPFOR and VOR), which were positively associatedwith the abundance of Clostridium sp. ASF356, higher circulating PAAconcentrations, and endothelial dysfunction in old mice. We found that PAA potentlyinduces EC senescence and attenuates angiogenesis. Mechanistically, PAAincreases mitochondrial H2 O 2 generation, which aggravates IL6-mediated HDAC4translocation and thereby upregulates VCAM1. In contrast, exogenous acetate,which was reduced in old mice, rescues the PAA-induced EC senescence andrestores angiogenic capacity through markedly alleviating the SASP and epigeneticalteration. Our studies provide direct evidence of PAA-mediated crosstalk betweenaging gut microbiota and EC senescence and suggest a microbiota-based therapyfor promoting healthy aging.