Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae

• Published in: PLoS genetics Vol. 7; no. 9; p. e1002253
• Main Authors: Kruegel, Undine, Robison, Brett, Dange, Thomas, Kahlert, Günther, Delaney, Joe R, Kotireddy, Soumya, Tsuchiya, Mitsuhiro, Tsuchiyama, Scott, Murakami, Christopher J, Schleit, Jennifer, Sutphin, George, Carr, Daniel, Tar, Krisztina, Dittmar, Gunnar, Kaeberlein, Matt, Kennedy, Brian K, Schmidt, Marion
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2011; Public Library of Science (PLoS)
• Subjects: Age; Aging; Biology; Brewer's yeast; Cytoplasm; DNA Replication - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Experiments; Gene Expression Regulation, Fungal; Genetic aspects; Homeostasis; Humans; Oxidative Stress - genetics; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein folding; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics; Silent Information Regulator Proteins, Saccharomyces cerevisiae - metabolism; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Software; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-proteasome system; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002253

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.