Exposing the core genetic drivers of chronological aging in yeast cells

Abstract

The chronological lifespan of Saccharomyces cerevisiae has been pivotal in advancing our understanding of aging in eukaryotic cells. However, gaining a genome-wide perspective of this trait remains challenging due to substantial discrepancies observed across large-scale gene-deletion screens. In this study, we performed a meta-analysis to compile a ranked catalog of key processes and regulators driving chronological longevity in yeast, ensuring their robustness across diverse experimental setups. These consistent chronological aging factors were enriched in genes associated with yeast replicative lifespan and orthologs implicated in aging across other model organisms. Functional analysis revealed that the downstream cellular mechanisms underlying chronological longevity in yeast align with well-established, universal hallmarks of aging, underscoring the potential of the yeast chronological aging model to investigate conserved aging processes. Additionally, we identified transcriptional regulators associated with these consistent genetic factors, uncovering potential global and local modulators of chronological aging. Among these, Tec1, a key regulator of the filamentous growth pathway, emerged as a central hub connected to multiple aging pathways. To further elucidate the functional role of this regulator, we conducted a high-resolution lifespan-epistasis screen, demonstrating that TEC1 and mitochondrial machinery promote chronological longevity in parallel, compensating for each other\'s impaired functions. Our findings provide an integrated view of the core genetic and functional landscape underlying aging in yeast cells.