E. coli metabolism raw data for research.

The human microbiome can modulate the efficacy of therapeutic drugs, but the role of bacteria-drug interactions in longevity is poorly understood. Here, we performed a large-scale drug screen using a splicing aging marker and identified a fluoropyrimidine derivative, doxifluridine, that extends lifespan and healthspan in <i>C. elegans</i> and attenuates human cellular senescence. Interestingly, the effect of doxifluridine on lifespan extension was dependent on bacterial strains. Using a four-way screen strategy that combined the bacteria <i>E. coli</i> and the nematode <i>C. elegans</i> model, we elucidated the interaction between doxifluridine, nutrient, microbe, and host longevity. We demonstrated that bacterial ribonucleotide metabolism modulated doxifluridine conversion and regulated host lifespan. Moreover, doxifluridine altered bacterial metabolites, such as linoleic acid and agmatine, which also affected host lifespan. These findings reveal the potential role of bacteria in mediating the anti-aging effect of fluoropyrimidine drugs.