Gut microbial load mediates the longevity effect of Korean red ginseng in Drosophila melanogaster.

Korean red ginseng (KRG) has been reported to modulate gut microbiota and extend lifespan. However, whether the gut microbiota contributes to the longevity effect of KRG remains unclear. Here, using axenic flies and fecal microbiota transplantation, we showed that the lifespan-extending effect of KRG depends on the gut microbiota. Further analyses revealed that KRG exerted minimal effects on microbial diversity and composition, but significantly reduced microbial load. Moreover, gnotobiotic and antibiotic treatment experiments revealed that overall microbial load, rather than any individual dominant taxon, is the key mediator of KRG-mediated longevity. Mechanistically, KRG-mediated regulation of the canonical longevity pathways, IIS and Sir2, was dependent on microbial load. Specifically, the effects of KRG on AKT phosphorylation, FOXO nuclear translocation, and the expression of FOXO target genes and Sir2, observed in conventional flies, were abolished in axenic and antibiotic-treated flies. In addition, neither KRG nor antibiotic treatment extended lifespan in chico or Sir2 mutant flies, and KRG conferred no additional benefit in antibiotic-treated mutants. Collectively, these findings demonstrate that KRG extends lifespan by reducing gut microbial load, thereby modulating the IIS and Sir2 pathways, and highlight microbial load as a key mediator of KRG-induced longevity.