Chronological Lifespan in Yeast Is Dependent on the Accumulation of Storage Carbohydrates Mediated by Yak1, Mck1 and Rim15 Kinases

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.

Context-dependent deposition and regulation of mRNAs in P-bodies

“…Puf5 promotes chronological lifespan (Stewart et al, 2007), which is dependent on the 294 accumulation of carbohydrates such as glycogen (Cao et al, 2016). Likewise, a ∆atp11 strain 295…”

The Small Yeast GTPase Rho5 and Its Dimeric GEF Dck1/Lmo1 Respond to Glucose Starvation

“…This adds yet another important physiological function to what has already been reported for its role in CWI signaling [4], the responses to high medium osmolarity (HOG pathway [6]) and oxidative stress, including the consequences for mitophagy and apoptosis [9,10], and the maintenance of chronological lifespan [24]. The notion that Rho5 fulfils the role of a central hub that integrates signals from different stress response and survival pathways [10] is further supported by the new findings presented herein.…”

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

“…However, regulation of the cell cycle shows poor correlation with the short‐lived phenotype of Rim15‐deficient cells; other TOR/Rim15‐dependent mechanisms such as carbohydrate storage seem to play a more important role (Cao et al., 2016). In agreement, we found that Ste12 regulation of cell cycle is not under the control of the TOR pathway, as rapamycin treatment did not affect G1 arrest in a ste12 ∆ background, suggesting that Ste12 controls cell cycle transitions in response to nutrients in a TOR‐independent manner.…”

“…Hence, it is possible that Ste12 regulates lifespan through other mechanisms. Noteworthy, STE11 , an upstream component of the pheromone pathway, is also implicated in cell cycle and lifespan regulation (Cao et al., 2016). This supports the idea that Ste12 controls cell cycle transitions in response to nutrients and that the emergence of a G1‐arrested population is necessary for lifespan extension.…”