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

The widely used antidiabetic drug metformin promotes longevity across diverse model organisms, from yeast to primates, yet the cellular mechanisms by which it acts are not fully resolved. Here, we use high-resolution genetic profiling to define metformin's impact on the chronological lifespan of Saccharomyces cerevisiae. Unexpectedly, our analyses uncover pronounced gene-drug interactions between metformin and chromatin modification. In particular, impairment of the histone deacetylase Set3C phenocopies the effects of metformin, suggesting convergence on a shared pathway. Consistent with this genetic interaction, transcriptome sequencing shows that metformin reprograms stationary-phase gene expression, with Ty1-copia retrotransposons emerging as a dominant signature. Notably, targeted analysis of Ty1 expression reveals that Set3C perturbation reproduces the metformin-induced Ty1 response, directly linking chromatin regulation to the observed lifespan phenotypes. Despite this transcriptional activation, metformin reduces TYA Gag-like protein levels without increasing insertion frequency, revealing an uncoupling between retrotransposon expression and mobility. In parallel, proteome analysis identifies increased mitochondrial and stress-response proteins as early outcomes of metformin exposure, both known modulators of Ty1 dynamics and potential mediators of this response. Together, our findings position chromatin regulation and retrotransposon expression as integral components of metformin's effects on longevity, expanding its influence beyond signaling, metabolism, and stress response.