Yeast chronological aging is linked to cell cycle regulation

Cells of the budding yeast Saccharomyces cerevisiae cultured in a nutrient-rich liquid medium initially containing 2% glucose as the sole carbon source are not limited in calorie supply [1]. When these cells consume glucose, they employ an intricate signaling network to elicit cell cycle arrest at the checkpoint START A in late G1, stimulate the differentiation of a chronologically aging yeast culture into quiescent (Q) and non-quiescent (NQ) cell populations, and allow to maintain a niche of Q cells [2,3]. Caloric restriction (CR) without malnutrition is a diet that extends longevity and postpones the onset of age-related pathologies in yeasts, nematodes, fruit flies, fishes, dogs, rodents and primates [1,4]. It was unknown if the aging-delaying effect of CR diet in S. cerevisiae relates to changes in the regulation of cell cycle and/or cell differentiation. Our recent study has revealed that CR prolongs chronological lifespan of S. cerevisiae via a mechanism linking cellular aging to cell cycle regulation, maintenance of a Q state, entry into an NQ state and survival in the NQ state [5]. Using centrifugation in Percoll density gradient, we purified populations of Q and NQ cells from CR and non-CR yeast cultures of different chronological ages [5]. Our comparative analyses of physical, morphological, reproductive and biochemical properties of these cell populations have revealed the existence of a ̋stem ̋ cell niche subpopulation in both CR and non-CR cultures. This subpopulation consists of nondifferentiated Q cells of high density that are viable, unbudded, arrested at the G1 phase of the cell cycle and exist in a specialized non-proliferative state called G0 (Figure 1) [5]. Our findings indicate that CR delays yeast chronological aging by modulating four cellular processes schematically depicted in Figure 1. First process: CR creates a stem cell niche subpopulation of non-differentiated Q cells by arresting the cell cycle and causing an entry into the G0 state at a checkpoint in early G1 [5]; in contrast, the arrest of the cell cycle, entry into the G0 state and formation of a stem cell niche subpopulation under non-CR conditions occur in late G1 [2]. Second process: non-differentiated Q cells of high density become committed to entry into the differentiation program that yields Q cells of low density as early as in logarithmic growth phase of a yeast culture under CR conditions; in contrast, non-differentiated Q cells of high density differentiate into Q cells of low density only in stationary phase of a yeast culture under non-CR conditions [5]. Third process: CR decelerates the progression of Q cells of low density through the differentiation program leading to the formation of NQ cells of low density [5]. Fourth process: CR slows the advancement of Q cells of high density through the maintenance program that yields NQ cells of high density [5]. CR delays the conversion of lowand high-density Q cells into lowand high-density NQ cells (respectively) because this diet elicits changes in a discrete set of morphological, reproductive, biochemical and physiological traits of Q cells that have low and high densities [5]. These traits of Q cells include the reproductive competence of these cells and their ability to synchronously re-enter the mitotic cell cycle when nutrients become available, glycogen and trehalose concentrations, the concentrations of triacylglycerols and cardiolipins, mitochondrial functionality, reactive oxygen species concentrations and the extent of oxidative molecular damage, cell resistance to long-term thermal and oxidative stresses, and cell susceptibility to the apoptotic and liponecrotic modes of regulated cell death [5]. The CR-driven changes in all these traits of Q cells constitute a mechanism responsible for the delay of yeast chronological aging when calorie supply is limited. In sum, we demonstrated that that CR prolongs yeast chronological lifespan through a mechanism that relates cellular aging and cellular longevity to cell cycle regulation, maintenance of a Q state, entry into an NQ state and survival in the NQ state. This mechanism underlies the CR-dependent delay of cellular aging and extension of cellular longevity in S. cerevisiae. The population of non-differentiated Q cells of high density in yeast cultures exhibits the following two aging-related features characteristic of adult stem cell populations in various tissues of metazoans: 1) the ability to self-renew and differentiate into several cell types; and 2) the ability of CR to increase the abundance, improve the function and/or stimulate the selfrenewal of these cell populations by modulating TOR (target of rapamycin), PKA (protein kinase A) and AMPK (AMPactivated protein kinase) signaling [6,7]. Because aging of adult stem cells essentially contributes to organismal aging, health and longevity in metazoans [6,7], the population of non-differentiated Q cells of high density in yeast is a