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Thiolutin Extends Replicative Lifespan by Rewiring Yeast Transcription and Metabolism

ABSTRACT: This study examines the global transcriptomic response of Saccharomyces cerevisiae strain BY4741 to short-term exposure to thiolutin, a transcriptional inhibitor. Exponentially growing cells were treated with 3 µg/mL thiolutin for 3 hours and compared with untreated controls. RNA sequencing was performed using paired-end libraries prepared with the MGIEasy RNA Library Prep Set and sequenced on the BGISEQ-500 platform. Three independent biological replicates were analyzed per condition. Differential expression analysis using DESeq2 (Benjamini–Hochberg false discovery rate < 0.05) revealed extensive transcriptional remodeling affecting pathways related to ribosome biogenesis, oxidative phosphorylation, proteostasis, stress response, and aging-associated processes.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE320120 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.

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Thiolutin Extends Replicative Lifespan by Rewiring Yeast Transcription and Metabolism

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