Bile acids as a “new hormone” in aging-related liver disease

Abstract

Bile acids (BAs) have evolved from their classical definition as digestive surfactants to be recognized as potent endocrine signaling molecules that orchestrate systemic metabolism. Through activation of nuclear receptors such as farnesoid X receptor (FXR) and membrane receptors such as G protein-coupled BA receptor 1 (GPBAR1/TGR5), BAs regulate glucose, lipid, immune, and energy homeostasis. Aging reshapes BA synthesis, enterohepatic circulation, hydrophobicity, microbial biotransformation, and receptor responsiveness, thereby linking BA metabolism to hepatic senescence, inflammaging, and age-associated liver vulnerability. In turn, dysregulated BA signaling can amplify mitochondrial stress, endoplasmic reticulum stress, impaired autophagy, immune dysfunction, and senescence-associated secretory phenotypes, suggesting a bidirectional relationship between BA remodeling and aging progression. This review critically examines the role of BAs as hormone-like mediators within the aging liver microenvironment, summarizes major BA species and receptor preferences, integrates gut microbiota–BA crosstalk, and evaluates the therapeutic potential and caveats of targeting the BA–FXR–TGR5 axis in aging-related liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), autoimmune liver diseases (AILDs), chronic hepatitis B (CHB), and hepatocellular carcinoma (HCC).