Aging Triggers an Intestinal Energy Crisis and HDL3 Deficiency Disrupting Gut–Liver Axis Homeostasis

ABSTRACT During aging, decreased intestinal barrier function and its ability to synthesize metabolites are closely associated with various age‐related diseases. However, the mechanism by which impaired intestinal synthesis contributes to gut–liver axis aging remains unclear. This study reveals that aging induces a mitochondrial energy crisis and defective membrane localization of ABCA1, significantly inhibiting the biosynthesis of high‐density lipoprotein 3 (HDL3) in the intestine. Exogenous supplementation with β‐nicotinamide mononucleotide (NMN) restores intestinal NAD + homeostasis, enhances oxidative phosphorylation efficiency, and promotes ATP‐dependent lipid transport, thereby rejuvenating the production of gut‐derived HDL3. Further investigations demonstrate that gut‐originated HDL3 neutralizes lipopolysaccharide (LPS) in the liver and attenuates TLR4‐mediated inflammatory cascades, ultimately ameliorating age‐related liver injury. These findings elucidate a novel mechanism whereby NMN modulates the NAD + –mitochondria–ABCA1–HDL3 axis to preserve gut–liver axis function, offering a promising therapeutic strategy for mitigating aging‐related pathologies in this metabolic cross‐talk.