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

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.

NAD+; NMN; aging; gut‐derived HDL3; gut–liver axis; mitochondrial function.