Gut Microbial Genetic Variation Prolongs Host Healthy Longevity and Remodels Metabolome and Proteome in Drosophila Melanogaster

Abstract Microbial genetic variation plays a crucial role in shaping host‐microbe interactions; however, its impact on healthy aging remains largely unexplored. This study investigates how genetic variations in gut‐residing Saccharomyces cerevisiae affect the health and lifespan of Drosophila melanogaster . This study identifies 14 yeast mutants that significantly extended the lifespan of D. melanogaster , with 13 mutants enhancing locomotor function in aged flies and two mutants improving reproductive capacity. Metabolomic and proteomic analyses reveal that these mutant yeasts rejuvenate the metabolic state of the aging gut and alter protein levels in tissues outside the gut. Most of the proteins with at least a two‐fold change are upregulated. The data also highlights mitochondrial energy metabolism as a key anti‐aging mechanism driven by the yeast. Notably, terpenoid metabolites such as ergosterol acetate showed strong lifespan‐extending effects and may influence energy metabolism. In conclusion, these findings establish a strong link between gut metabolic status and healthy aging, underscoring the significance of the microbial‐host mitochondrial axis as a key mechanism by which gut microbes promote host health and longevity. Furthermore, genetically engineered probiotics in model organisms offer a promising potential strategy for extending healthy lifespan, thus meriting further investigation in translational research models.