How the INDY gene rebalances gut microbiota and extends lifespan

Reducing INDY, a plasma membrane citrate transporter, keeps heterozygous flies with significantly lower bacterial loads and greater microbial diversity during aging compared to wild-type controls. The mechanism operates through modulation of JAK/STAT signaling—specifically Upd3 and Upd2 in the young midgut, and Stat92E in aged flies—without affecting other pathway components. Though the microbiota proved unnecessary for INDY-mediated lifespan extension, microbe removal amplified its longevity effects, revealing synergistic interaction: double heterozygotes for INDY and upd3 outlived single heterozygotes. For the longevity-focused reader, this signals an emerging principle: the goal is not simply to suppress pathogenic microbes or reinforce intestinal barriers in isolation, but to orchestrate gut metabolism such that microbial composition naturally rebalances toward less inflammatory states.