Abstract
Upon starvation for glucose or any other macronutrient, yeast cells exit from the mitotic cell cycle and acquire a set of characteristics that are specific to quiescent cells to ensure longevity. Little is known about the molecular determinants that orchestrate quiescence entry and lifespan extension. Using starvation-specific gene reporters, we screened a subset of the yeast deletion library representing the genes encoding ‘signaling’ proteins. Apart from the previously characterised Rim15, Mck1 and Yak1 kinases, the SNF1/AMPK complex, the cell wall integrity pathway and a number of cell cycle regulators were shown to be necessary for proper quiescence establishment and for extension of chronological lifespan (CLS), suggesting that entry into quiescence requires the integration of starvation signals transmitted via multiple signaling pathways. The CLS of these signaling mutants, and those of the single, double and triple mutants of RIM15, YAK1 and MCK1 correlates well with the amount of storage carbohydrates but poorly with transition-phase cell cycle status. Combined removal of the glycogen and trehalose biosynthetic genes, especially GSY2 and TPS1, nearly abolishes the accumulation of storage carbohydrates and severely reduces CLS. Concurrent overexpression of GSY2 and TSL1 or supplementation of trehalose to the growth medium ameliorates the severe CLS defects displayed by the signaling mutants (rim15Δyak1Δ or rim15Δmck1Δ). Furthermore, we reveal that the levels of intracellular reactive oxygen species are cooperatively controlled by Yak1, Rim15 and Mck1, and the three kinases mediate the TOR1-regulated accumulation of storage carbohydrates and CLS extension. Our data support the hypothesis that metabolic reprogramming to accumulate energy stores and the activation of anti-oxidant defence systems are coordinated by Yak1, Rim15 and Mck1 kinases to ensure quiescence entry and lifespan extension in yeast.
Highlights
Studies in invertebrates and rodents have consistently shown that dietary intervention mimicking calorie restriction (CR) or mutations in nutrient and growth signalling pathways can increase longevity by 30–50%, accompanied by reduced or delayed morbidity in most cases [1]
We reveal that the levels of intracellular reactive oxygen species are cooperatively controlled by Yak1, Rim15 and Mck1, and the three kinases mediate the TOR1-regulated accumulation of storage carbohydrates and chronological lifespan (CLS) extension
Chronological Lifespan Is Dependent on Storage Carbohydrates
Summary
Studies in invertebrates and rodents have consistently shown that dietary intervention mimicking calorie restriction (CR) or mutations in nutrient and growth signalling pathways can increase longevity by 30–50%, accompanied by reduced or delayed morbidity in most cases [1]. Among the nutrient signalling pathways, the conserved TOR pathway regulates lifespan from simple eukaryotes to mammals [2,3]. Feeding mice with the TOR inhibitor rapamycin, even late in life, extends lifespan, representing the first pharmacological anti-aging regime in mammals [4]. The TOR pathway controls many aspects of cell physiology, promoting ribosome biogenesis, translation and cell growth and proliferation, and inhibiting autophagy and the stress response [6,7]. It remains unclear which aspects of TOR signalling contribute most significantly or to aging and lifespan regulation [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
