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A Suppressor Screen for the Characterization of Genetic Links Regulating Chronological Lifespan in Saccharomyces cerevisiae
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Caffeine extends yeast lifespan by targeting TORC1.

Valeria Wanke1, Elisabetta Cameroni, Aino Uotila

  • 1Department of Microbiology and Molecular Medicine, University of Geneva Medical School CH-1211 Geneva, Switzerland.

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Dietary restriction extends lifespan by regulating nutrient-sensitive kinases. Inhibiting the TORC1-Sch9 pathway with rapamycin or caffeine releases Rim15, promoting longevity in yeast and potentially other eukaryotes.

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Area of Science:

  • Molecular biology
  • Genetics
  • Biochemistry

Background:

  • Dietary restriction (DR) is a known lifespan-extending intervention across diverse organisms.
  • The precise molecular mechanisms linking DR to longevity remain incompletely understood.
  • Nutrient-sensitive kinases like TORC1, Sch9, PKA, and Rim15 are implicated in DR's effects in yeast.

Purpose of the Study:

  • To elucidate the molecular pathway connecting nutrient-sensitive kinases to lifespan extension.
  • To investigate the inhibitory relationship between Sch9 and Rim15.
  • To determine the effect of TORC1 inhibition on this pathway and organismal lifespan.

Main Methods:

  • Utilized the model eukaryote Saccharomyces cerevisiae.
  • Investigated direct phosphorylation events between kinases using biochemical assays.
  • Administered specific inhibitors: rapamycin (TORC1 inhibitor) and caffeine.
  • Monitored lifespan changes in response to inhibitor treatments.

Main Results:

  • Confirmed TORC1 directly phosphorylates and activates Sch9.
  • Demonstrated that Sch9 directly phosphorylates and inhibits Rim15.
  • Showed that rapamycin or caffeine treatment disrupts TORC1-Sch9-mediated inhibition of Rim15.
  • Observed a consequent increase in yeast lifespan upon pathway inhibition.

Conclusions:

  • A conserved kinase cascade involving TORC1, Sch9, and Rim15 mediates lifespan regulation in response to nutrient availability.
  • Inhibition of this pathway, notably via caffeine, can extend lifespan.
  • Caffeine's potential to promote longevity may extend to other eukaryotes, including humans.