Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae

Undine Kruegel, Brett Robison, Thomas Dange, Günther Kahlert, Joe R. Delaney, Soumya Kotireddy, Mitsuhiro Tsuchiya, Scott Tsuchiyama, Christopher J. Murakami, Jennifer Schleit, George Sutphin, Daniel Carr, Krisztina Tar, Gunnar Dittmar, Matt Kaeberlein, Brian K. Kennedy, Marion Schmidt

Research output: Contribution to journalArticle

132 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1002253
JournalPLoS Genetics
Volume7
Issue number9
DOIs
StatePublished - Sep 2011

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proteasome endopeptidase complex
Proteasome Endopeptidase Complex
Saccharomyces cerevisiae
yeast
ubiquitin
Ubiquitin
epistasis
protein
detoxification
rodent
repair
turnover
Yeasts
Poisons
yeasts
Mole Rats
Heterocephalus glaber
cells
dietary restriction
neurodegenerative diseases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Kruegel, U., Robison, B., Dange, T., Kahlert, G., Delaney, J. R., Kotireddy, S., ... Schmidt, M. (2011). Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae. PLoS Genetics, 7(9), [e1002253]. https://doi.org/10.1371/journal.pgen.1002253

Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae. / 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.

In: PLoS Genetics, Vol. 7, No. 9, e1002253, 09.2011.

Research output: Contribution to journalArticle

Kruegel, U, Robison, B, Dange, T, Kahlert, G, Delaney, JR, Kotireddy, S, Tsuchiya, M, Tsuchiyama, S, Murakami, CJ, Schleit, J, Sutphin, G, Carr, D, Tar, K, Dittmar, G, Kaeberlein, M, Kennedy, BK & Schmidt, M 2011, 'Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae', PLoS Genetics, vol. 7, no. 9, e1002253. https://doi.org/10.1371/journal.pgen.1002253
Kruegel U, Robison B, Dange T, Kahlert G, Delaney JR, Kotireddy S et al. Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae. PLoS Genetics. 2011 Sep;7(9). e1002253. https://doi.org/10.1371/journal.pgen.1002253
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. / Elevated proteasome capacity extends replicative lifespan in saccharomyces cerevisiae. In: PLoS Genetics. 2011 ; Vol. 7, No. 9.
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