Metformin-induced longevity is associated with retrotransposon dynamics in yeast chronological aging

The widely used antidiabetic drug metformin extends lifespan across diverse model organisms, from yeast to primates. However, the cellular mechanisms underlying its anti-aging effects remain only partially understood. Here, we combined large-scale genetic screening and high-resolution lifespan phenotyping with transcriptomic and proteomic analyses to provide a systems view of metformin's impact on the chronological lifespan of Saccharomyces cerevisiae. Unexpectedly, we uncovered pronounced gene-drug interactions between metformin and chromatin-modifying factors. Specifically, deletions of Set3C histone deacetylation complex subunits phenocopied the longevity effect of metformin, with no additive benefit when combined, suggesting convergence 10 on shared pathways. Transcriptome profiling further revealed that metformin reprogrammed stationary-phase gene expression, with Ty1-copia retrotransposons emerging as a consistently induced signature, thereby suggesting a possible mechanism for the observed interactions with Set3C regulation. Overall design: We performed RNAseq analysis comparing populations of WT cells in mid exponential and late stationary phase with or without metformin.