Bile acid signaling, metabolism, and aging

Bile acids (BAs) serve not only as key facilitators of lipid absorption but also as crucial signaling molecules regulating glucose and lipid metabolism, inflammation, and overall energy homeostasis. Aging profoundly alters BA metabolism, characterized by shifts in biosynthetic pathways, compositional changes, disrupted receptor-mediated signaling, and alterations in gut microbiota interactions. These age-related changes contribute to the onset and progression of metabolic conditions, including type 2 diabetes, obesity, metabolic dysfunction-associated fatty liver disease, and neurodegenerative disorders. An increased abundance of hydrophobic and cytotoxic BAs has been associated with systemic inflammation, metabolic rigidity (disruption of metabolic flexibility), and organ dysfunction. Targeting BA signaling-through pharmacological modulation of farnesoid X receptor and Takeda G protein-coupled receptor 5 or microbiota-directed therapies-offers promising strategies to mitigate aging-related metabolic decline. A deeper understanding of how BA metabolism evolves over the lifespan may unveil novel interventions to promote healthy aging and prevent age-related disease.