<i>Indy</i> reduction decreases aging-related dysbiosis in <i>Drosophila</i>.

Reduction in the <i>Indy (I'm not dead yet)</i> gene, a plasma membrane citrate transporter, in <i>Drosophila</i> and its homolog in worms extends lifespan by promoting metabolic homeostasis. <i>Indy</i> reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear. Here we show that <i>Indy</i> heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiota was not required for <i>Indy</i> lifespan extension, though removal of microbes did enhance the effects of <i>Indy</i> reduction on longevity, suggesting potential interactions between the microbiota and <i>Indy</i>. <i>Indy</i> down-regulation was linked to reduced expression of Upd3 and Upd2 in the midgut of young flies and Stat92E in old <i>Indy</i> flies, while no change in other members of the JAK/STAT signaling pathway observed. Furthermore, flies double heterozygous for <i>Indy²⁰⁶/+</i> and <i>upd3^Delta</i>/+ alleles lived longer than single heterozygous flies, suggesting synergistic effects on longevity of <i>Indy</i> and upd3 pathways. Altogether, our results suggest that <i>Indy</i> reduction impacts microbiota load and composition, which together with effects of <i>Indy</i> on midgut metabolism contributes to preserved gut homeostasis and extended lifespan.