Starvation signals in yeast are integrated to coordinate metabolic reprogramming and stress response to ensure longevity

Studies on replicative and chronological aging in Saccharomyces cerevisiae have greatly advanced our understanding of how longevity is regulated in all eukaryotes. Chronological lifespan (CLS) of yeast is defined as the age-dependent viability of non-dividing cell populations. A number of nutrient sensing and signal transduction pathways (mainly TOR and PKA) have been shown to regulate CLS, yet it is poorly understood how the starvation signals transduced via these pathways lead to CLS extension. Using reporters whose expressions are induced by glucose starvation, we have screened the majority of the ‘signaling’ mutants in the yeast genome and identified many genes that are necessary for stress response. Subsequent analyses of the ‘signaling’ mutants not only revealed novel regulators of CLS, such as the GSK-3 ortholog Mck1, but also demonstrated that starvation signals transmitted by SNF1/AMPK, PKC1 and those negatively regulated by TOR/PKA, including Rim15, Yak1 and Mck1 kinases, are integrated to enable metabolic reprogramming and the acquisition of stress resistance. Coordinated metabolic reprogramming ensures the accumulation of storage carbohydrates for quiescent cells to maintain viability. We provide new evidence that Yak1, Rim15 and Mck1 kinases cooperate to activate H2O2-scanvenging activities, thus limiting the levels of ROS in cells entering quiescence. These findings support the recent advances in higher organisms that the flexibility of metabolic reprogramming and the balance between energetics and stress resistance are the unifying principles of lifespan extension. Future work to reveal how the metabolic switch and stress response is coordinated will help delineate the molecular mechanisms of aging in yeast and shed novel insight into aging/anti-aging principles in higher organisms.