Indy reduction decreases aging-related dysbiosis in Drosophila.

Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy 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 Indy 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 Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiota and Indy. Indy down-regulation was linked to reduced expression of Upd3 and Upd2 in the midgut of young flies and Stat92E in old Indy flies, while no change in other members of the JAK/STAT signaling pathway observed. Furthermore, flies double heterozygous for Indy206/+ and upd3Delta/+ alleles lived longer than single heterozygous flies, suggesting synergistic effects on longevity of Indy and upd3 pathways. Altogether, our results suggest that Indy reduction impacts microbiota load and composition, which together with effects of Indy on midgut metabolism contributes to preserved gut homeostasis and extended lifespan.