Abstract Body (Do not enter title and authors here): Background: The microbially produced phenylalanine–derived metabolite Phenylacetic acid (PAA) contributes to endothelial senescence in aging. However, the effects of PAA on perivascular adipose tissue (PVAT) physiology and its role in atherosclerosis are unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis.
Methods: To address the knowledge gap, plasma PAA levels were measured by LC-MS/MS, coupled with fecal shotgun metagenomics in the TwinsUK Aging Cohort (n=2,953) and Aging Heart Zurich Cohort (ASCVD patients; n=105). In a mouse model of chronological aging, the impact of PAA on PVAT senescence and dysfunction was examined. Additionally, atheroprone Ldlr^−/− mice fed a high-fat diet were treated with and without PAA (50 mg/kg/d), and aortic atherosclerotic lesion area was evaluated after 12 weeks.
Results: Here, we show that the gut microbial metabolite phenylacetic acid (PAA) drives aortic PVAT senescence and dysfunction in both chronological aging and atherosclerotic states. Our findings indicate that PAA production increases with age, which is positively associated with the abundance of gut bacterium Clostridium sp. ASF356 in aged mice. The bacterium- and PAA-induced senescence phenotype was verified in both cellular and mouse models. In atheroprone Ldlr^-/- mice with an ABx-suppressed intestinal microbiota, daily supplementation with PAA increased atherosclerotic lesion size in vivo. Mechanistically, senescence-messaging secretome, including IL6, from senescent endothelial cells induces a senescence-like state and disrupted insulin and metabolic signaling through Notch1 activation in adipocytes, leading to vascular dysfunction. Our senolytic D+Q therapy impeded PAA-induced cellular senescence in vivo, restoring PVAT function.
Conclusions: Our findings uncover a gut-vascular axis whereby gut microbiota metabolite PAA causally exacerbates aortic PVAT dysfunction through endothelial senescence. Furthermore, these mechansisms accelerate the development of atherosclerosis in aging, suggesting that PAA metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.