Time‐Restricted Feeding Delays Cardiovascular Aging by Increasing Acetic Acid Through Remodeling Gut Microbiota

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Abstract
Time‐restricted feeding (TRF) restricts food intake to daily windows, yet its efficacy against vascular aging and underlying mechanisms remain unclear. Here, we demonstrate that TRF attenuates angiotension II ‐induced accelerated vascular aging by reshaping gut microbiota, stabilizing microbial diversity, and elevating the Firmicutes/Bacteroidetes ratio. TRF preserved intestinal barrier integrity, upregulated tight junction proteins (Occludin, ZO‐1, MUC2), reduced serum lipopolysaccharide, and suppressed systemic inflammation. These benefits translated into alleviated hypertension, aortic stiffness (reflected by pulse wave velocity), and pathological cardiac remodeling. Fecal microbiota transplantation recapitulated these effects, whereas antibiotic‐induced microbiota depletion abolished TRF protection; importantly, exogenous acetate supplementation fully restored the phenotypes, establishing acetic acid as the critical downstream mediator. Mechanistically, acetic acid bound to GPR43, inhibited HDAC3, increased H4K8ac acetylation, blocked NLRP3‐mediated pyroptosis, and reduced senescence markers (p53, p21, p16) in human umbilical vein endothelial cells, aorta, and heart. 16S rRNA sequencing and short ‐ chain fatty acids metabolomic profiling further identified Limosilactobacillus as the primary acetic acid‐producing bacterium enriched by TRF. Together, we uncover a Limosilactobacillus ‐acetic acid‐GPR43/HDAC3/H4K8ac/NLRP3 axis, offering mechanistic insights into TRF as a non‐pharmacological strategy against age‐related cardiovascular diseases.

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