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

Aging induces a mitochondrial energy crisis in the intestine that significantly inhibits biosynthesis of high-density lipoprotein 3 (HDL3).

• Aging was associated with decreased mitochondrial oxidative phosphorylation efficiency in intestinal tissue.
• The energy crisis impaired ATP-dependent lipid transport processes necessary for HDL3 production.
• Intestinal HDL3 biosynthesis was found to be substantially reduced in aged compared to young subjects/animals.

Aging causes defective membrane localization of ABCA1 in intestinal cells, further inhibiting HDL3 biosynthesis.

• ABCA1 (ATP-binding cassette transporter A1) is responsible for ATP-dependent lipid transport required for HDL3 formation.
• In aged intestine, ABCA1 failed to properly localize to the cell membrane, disrupting its lipid transport function.
• Defective ABCA1 localization was identified as a key mechanism linking the energy crisis to reduced HDL3 production.

Exogenous supplementation with β-nicotinamide mononucleotide (NMN) restores intestinal NAD+ homeostasis and rejuvenates gut-derived HDL3 production.

• NMN supplementation restored NAD+ levels in aged intestinal tissue.
• Restored NAD+ enhanced oxidative phosphorylation efficiency in intestinal mitochondria.
• Improved mitochondrial function promoted ATP-dependent lipid transport, thereby increasing gut-derived HDL3 production.
• NMN was described as modulating the NAD+-mitochondria-ABCA1-HDL3 axis.

Gut-originated HDL3 neutralizes lipopolysaccharide (LPS) in the liver and attenuates TLR4-mediated inflammatory cascades.

• HDL3 produced in the intestine traveled to the liver where it bound and neutralized LPS.
• Neutralization of LPS by HDL3 attenuated TLR4 (Toll-like receptor 4)-mediated inflammatory signaling cascades.
• This mechanism ultimately ameliorated age-related liver injury.
• The findings identify a novel gut-liver axis communication pathway mediated by intestinal HDL3.

Decreased intestinal barrier function and impaired intestinal metabolite synthesis during aging are closely associated with age-related diseases and gut-liver axis disruption.

• The mechanism by which impaired intestinal synthesis contributes to gut-liver axis aging was previously unclear.
• Aging was found to disrupt gut-liver axis homeostasis through the energy crisis and HDL3 deficiency.
• The study positions intestinal HDL3 deficiency as a key mediator of age-related liver pathology.

NMN modulation of the NAD+-mitochondria-ABCA1-HDL3 axis represents a therapeutic strategy for mitigating aging-related pathologies in the gut-liver metabolic cross-talk.

• The NAD+-mitochondria-ABCA1-HDL3 axis was described as a novel mechanistic pathway preserving gut-liver axis function.
• NMN supplementation was identified as a 'promising therapeutic strategy for mitigating aging-related pathologies.'
• The findings connect NAD+ metabolism, mitochondrial function, lipid transport, and innate immune signaling in a unified aging pathway.