PPARγ/P21 Signaling Mediates Butyrate-Driven Protection against Aging-Related Endothelial Dysfunction: A Novel Effect of Soybean Polysaccharide via the Gut-Vascular Axis

Abstract Aging-induced endothelial dysfunction is a core driver of age-related cardiovascular diseases (CVDs). In 20-month-old naturally aged mice, 12-week soybean polysaccharide (SP) supplementation restored endothelium-dependent relaxation, reduced aortic reactive oxygen species and VCAM-1 in the aortic endothelium, and attenuated colon senescence, improved gut barrier integrity, and reduced systemic inflammation, as shown by decreased serum LPS, IL-1β, TNF-α, and fecal and serum TMA/TMAO levels. SP enriched butyrate-producing gut bacteria, including Lachnospiraceae_NK4A136_group, and increased gut and serum butyrate, consistent with enhanced microbial short-chain fatty acid biosynthesis capacity predicted by PICRUSt2. Direct butyrate supplementation reproduced these vascular and colonic benefits. It activated PPARγ signaling and downregulated p21, ICAM-1, VCAM-1, and p16, whereas PPARα and PPARδ remained unchanged. These findings support a gut microbiota–butyrate–PPARγ/p21 axis through which SP protects against aging-related endothelial dysfunction, providing a nutritional basis for targeting the gut–vascular axis in cardiovascular aging.