title: Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.
abstract: 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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Undine
authors.initials: U
authors.lastname: Kruegel
authors.forename: Brett
authors.initials: B
authors.lastname: Robison
authors.forename: Thomas
authors.initials: T
authors.lastname: Dange
authors.forename: Günther
authors.initials: G
authors.lastname: Kahlert
authors.forename: Joe R
authors.initials: JR
authors.lastname: Delaney
authors.forename: Soumya
authors.initials: S
authors.lastname: Kotireddy
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Scott
authors.initials: S
authors.lastname: Tsuchiyama
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murakami
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schleit
authors.forename: George
authors.initials: G
authors.lastname: Sutphin
authors.forename: Daniel
authors.initials: D
authors.lastname: Carr
authors.forename: Krisztina
authors.initials: K
authors.lastname: Tar
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Marion
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056565:Sirtuin 2; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C119430:RPN4 protein, S cerevisiae; C086677:YAP1 protein, S cerevisiae; C496536:Ubr2 protein, S cerevisiae; C083324:TOR1 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae