Meneses-Plascencia, J. | bioRxiv Science

bioRxiv2025

SWR1C loss promotes longevity through tRNA-mediated proteostasis

The conserved SWR1C chromatin remodeling complex promotes cellular aging, yet the mechanisms linking its activity to lifespan control remain poorly defined. Although SWR1C shapes chromatin architecture and regulates non-coding RNA expression, how these activities relate to its role in aging remains unclear. Here, we combine genetic and lifespan-epistasis analyses to identify the cellular processes that underlie SWR1C-dependent chronological longevity in Saccharomyces cerevisiae. Loss of subunits specifically required for H2A.Z deposition robustly extends longevity, and this effect is functionally linked to cytosolic translation and proteostasis pathways. Lifespan profiling of ncRNA deletions reveals a substantial fraction of aging phenotypes and prevalent genetic interactions with SWR1, with tRNAs emerging as key determinants of its long-lived phenotype. The expression of specific tRNA genes is dysregulated in swr1{Delta} cells, and interactions with tyrosine-decoding tRNA genes are linked to ER proteotoxic stress, suggesting that altered tRNA pools affect proteostasis during aging. These findings establish tRNAs as central mediators of SWR1C-associated longevity, revealing a fundamental connection between chromatin remodeling, RNA biology, and proteostasis stress responses in lifespan regulation.

cell biology↗

bioRxiv2025

Metformin-induced longevity is associated with retrotransposon dynamics in yest 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 metformins 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 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. Paradoxically, TYA Gag-like protein levels and retrotransposition frequency were modestly reduced, indicating an uncoupling between transcriptional activation and retromobility. Proteome analysis revealed increased abundance of mitochondrial and stress-response proteins as primary outcomes of metformin exposure, both known modulators of Ty1 dynamics in yeast. Together, our findings position chromatin regulation and retrotransposon expression as integral components of metformins pro-longevity mechanisms, expanding its influence beyond signaling, metabolism, and stress response. HighlightsO_LILarge-scale genetic screening reveals that deletions of Set3C histone deacetylase phenocopy metformin-induced longevity. C_LIO_LIMetformin consistently induces Ty1 retrotransposon transcription but reduces Gag protein abundance and retromobility. C_LIO_LIProteomic changes highlight mitochondrial and stress-response proteins as primary outcomes of metformin exposure. C_LIO_LIRetrotransposon dynamics emerge as a key component associated with metformin-induced longevity. C_LI

cell biology↗