Old fruit flies generally die from intestinal dysfunction; intestinal aging is the most important aspect of aging in this species. INDY is a longevity associated gene that has been shown to have important effects on intestinal health in flies. Upregulation of INDY expression extends life in flies. Here, researchers show that a part of this effect results from a reduction in harmful age-related changes in the composition of the gut microbiome. A growing body of evidence shows that the gut microbiome is influential on long-term health and the pace of aging, particularly via its contribution to the chronic inflammation of aging. With age, beneficial microbial species are reduced in number while inflammatory microbial species grow in number. At the same time, the intestinal barrier becomes leaky, allowing more unwanted cells and metabolites into the body. This is detrimental to tissue function in all organs, and a contribution to degenerative aging.
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.
Link: https://doi.org/10.18632/aging.206408
View the full article at FightAging
