Chronological life span is defined by how long a cell can survive in a non-dividing state. In yeast, it is measured by viability after entry into stationary phase. To date, some factors affecting chronological life span have been identified; however, the molecular details of how these factors regulate chronological life span have not yet been elucidated clearly. Because life span is a complicated phenomenon and is supposedly regulated by many factors, it is necessary to identify new factors affecting chronological life span to understand life span regulation. To this end, we have screened for long-lived mutants and identified Pma1, an essential P-type proton ATPase, as one of the determinants of chronological life span. We show that partial loss of Pma1 activity not only by mutations but also by treatment with the Pma1 inhibitory chemical vanadate resulted in the longlived phenotype in Schizosaccharomyces pombe. These findings suggest a novel way to manipulate chronological life span by modulating Pma1 as a molecular target.In the natural environment, most microorganisms exhibit only brief periods of rapid growth. Nutrient starvation is the most common natural situation, so the ability to adapt to nutrient limitation is crucial for microorganisms. Cells respond to starvation by ceasing growth and entering stationary phase and differentiate in ways that allow them to maintain viability for extended periods in the absence of nutrients (1). In yeast, the period in which the cells keep their viability after entry into stationary phase is recognized as the chronological life span (2).In Saccharomyces cerevisiae, two of the major pathways that control chronological life span have been identified: the Ras-PKA-Msn2/4 pathway and the Sch9 pathway (3, 4). The downregulation of either pathway promotes life span extension. Importantly, similar pathways (insulin/insulin-like growth factor I-like) regulate longevity in higher eukaryotes, suggesting a common evolutionary origin for the life span regulatory mechanisms (5, 6).In Schizosaccharomyces pombe, Pka1 and Sck2 are regulators of chronological life span; each mutant shows a long-lived phenotype, and the pka1 sck2 double mutant displays an additive effect on chronological life span extension, suggesting that these two factors regulate related but independent pathways (7). We reported previously that a mutant of lcf1 ϩ , which encodes a long-chain fatty acyl-CoA synthetase, showed rapid loss of viability after entry into stationary phase and suggested that fatty acid utilization and/or metabolism is important to determine viability in stationary phase in fission yeast (8,9). Recently, we identified a novel gene, ecl1 ϩ , which extends the chronological life span of S. pombe when overexpressed (10). In addition, we also identified two paralogs and one ortholog of ecl1 ϩ in S. pombe and S. cerevisiae, respectively (11, 12). On the basis of these observations, we proposed that Ecl1 family proteins are novel regulators for chronological life span in yeast. Ecl1 family proteins ...

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The Ecl1 family genes extend the lifespan of fission yeast when overexpressed. They also cause resistance against H(2)O(2) stress. In this study, we found that the bZip transcription factor Atf1 is a direct activator of the induction of extender of chronological lifespan (ecl1 (+)) by H(2)O(2) stress. Based on ChIP analysis, we identified that Atf1 binds to the upstream DNA region of ecl1(+). Previously, we reported that overexpression of ecl1(+) increased the expression of the catalase-encoding ctt1(+). This ecl1(+)-dependent increase of ctt1(+) expression occurred in ∆atf1 mutant. On the other hand, the activation of ctt1 (+) caused by the ∆pyp1 mutation, which enhances Sty1-Atf1 activity, could occur in ∆ecl1 mutant. Based on these results, we propose that Atf1 can regulate ctt1(+) in both an Ecl1-dependent and an Ecl1-independent manner.

Ecl1 family genes (ecl1 (+), ecl2 (+), and ecl3 (+)) have been identified as extenders of the chronological lifespan in Schizosaccharomyces pombe. Here, we found that the triple-deletion mutant (∆ecl1/2/3) had a defect in sexual development after entry into the stationary phase, although the mutant essentially showed normal mating and sporulation under nitrogen starvation or carbon limitation. In this study, we showed that limitation of zinc or iron can be a signal for sexual development of S. pombe cells grown in Edinburgh minimal medium until the stationary phase and that Ecl1 family genes are important for this process. Because the ∆ecl1/2/3 mutant diminishes the zinc depletion-dependent gene expression, Ecl1 family proteins may function as zinc sensors in the process of sexual development.

Overexpression of Ecl1-family genes (ecl1 , ecl2, and ecl3 ) results in the extension of the chronological life span in Schizosaccharomyces pombe. However, the mechanism for this extension has not been defined clearly. Ecl1-family proteins consist of approximately 80 amino acids, and four cysteine residues are conserved in their N-terminal domains. This study focused on the Ecl1 protein, mutating its cysteine residues sequentially to confirm their importance. As a result, all mutated Ecl1 proteins nearly lost the function to extend the chronological life span, suggesting that these four cysteine residues are essential for the Ecl1 protein. Utilizing ICP-AES (inductively coupled plasma atomic emission spectroscopy) analysis, we found that wild-type Ecl1 proteins contain zinc, while cysteine-mutated Ecl1 proteins do not. We also analyzed the effect of environmental zinc on the chronological life span. We found that zinc limitation extends the chronological life span, and this extension depends on the Ecl1-family proteins.