Gut microbiota-derived caproic acid attenuates aging-associated arteriosclerosis

Aim: Aging is an irreversible primary risk factor for arteriosclerosis, causing high cardiovascular morbidity-mortality in the elderly via vascular remodeling and cellular senescence. Gut microbiota-derived short-chain fatty acids (SCFAs) exert cardiovascular protective effects, yet cross-species functional SCFAs counteracting age-related arteriosclerosis remain unclear. This study aimed to identify conserved SCFAs linked to vascular aging and validate caproic acid’s protective function against AngII-induced arteriosclerosis. Methods: We assessed vascular aging phenotypes in young (8-week) and aged (24-month) mice and a human cohort (97 young < 65 years, 30 old ≥ 65 years). Serum SCFAs were quantified by targeted GC-MS. Correlation and mediation analyses evaluated relationships between caproic acid, pulse pressure (PP), and pulse wave velocity (PWV). Caproic acid protection was validated in AngII-induced arteriosclerosis mice and MOVAS cells. Results: Circulating SCFAs declined with aging in humans and mice. Caproic acid and butyric acid were the two shared significantly down-regulated SCFAs. Serum caproic acid negatively correlated with human PP, and with both PP and aortic PWV in mice. Mediation analysis showed caproic acid directly ameliorated age-related vascular dysfunction. In AngII-treated mice, caproic acid reduced systolic blood pressure, PP and aortic PWV, mitigated aortic remodeling and elastic fiber damage, and suppressed vascular senescence protein upregulation. Gpr41 knockdown in MOVAS cells eliminated caproic acid’s anti-senescence effect, confirming GPR41-dependent protection. Conclusion: Caproic acid acts as a conserved metabolite against age-related arteriosclerosis by inhibiting vascular cell senescence and improving hemodynamics, representing a promising therapeutic target for arteriosclerosis.