Aging-driven metabolic abnormalities remodel intercellular communication through the gut-liver-heart axis and may promote coronary artery disease: the key role of bile acid metabolism.

摘要

Coronary artery disease (CAD) remains the leading cause of cardiovascular mortality worldwide and shows a strong age-dependence that classical risk-factor models do not fully explain. A growing body of work indicates that aging is closely associated with CAD and, in preclinical models, can promote it through immunometabolic remodeling of the gut-liver-heart axis, in which bile acid metabolism is proposed to act as a central molecular link. Here we integrate cellular, molecular, and clinical evidence to outline how aging perturbs this axis and sustains chronic vascular inflammation. At the cellular level, senescent cells in the intestinal, hepatic, and vascular compartments generate the senescence-associated secretory phenotype (SASP) - a process linked to cGAS-STING and NLRP3 inflammasome activation, mitochondrial dysfunction, and decline of the NAD+-SIRT3 axis - and help establish the systemic state of inflammaging. In the gut, age-related dysbiosis lowers bile salt hydrolase and 7α-dehydroxylase activities, contracts the secondary bile acid pool, weakens epithelial barrier integrity, and triggers metabolic endotoxemia that maintains LPS-TLR4-NF-κB signaling. In the liver, Kupffer cell M1 polarization, attenuated farnesoid X receptor (FXR) signaling, and altered exosomal cargo amplify systemic inflammatory output. Reduced FXR and Takeda G-protein-coupled receptor 5 (TGR5) signaling weakens the endogenous restraint of macrophage activation, vascular smooth muscle cell phenotypic switching, and cardiomyocyte metabolic protection. The downstream result is endothelial dysfunction, foam cell formation, plaque instability, and adverse cardiac remodeling. We then appraise emerging immune-metabolic interventions - microbiota remodeling, FXR/TGR5 agonists, senolytic therapies, metformin, and integrated biomarker frameworks for early risk stratification - while noting that most are currently supported only by preclinical or early-phase human data. By placing bile acid signaling at the interface of innate immunity, microbial ecology, and metabolic homeostasis, this review offers an immunological framework for aging-associated CAD and identifies candidate immune-metabolic targets for prevention and therapy in older adults.