The yeast chronological life span (CLS) model has led to the identification of the pro-aging effects of the TOR-Sch9 /S6K and Ras-Adenylate cyclase-PKA pathways, components of which play conserved role in nutrient sensing and aging in mammals [1-4]. One of the early changes that occurs in yeast cells grown in media containing 2% glucose and excess amino acids is the production of acetic acid and acidification of the medium to below pH 4. This acidification has been shown to accelerate yeast aging [5-9]. However, it is clear that it does not explain the effect of the TOR-Sch9/S6K and Ras-AC-PKA pathways on aging since their inhibition extends chronological life span in media that is not acidified and that does not contain acetic acid [10]. The assumption that acetic acid is an organic toxin, which is the key mediator of chronological aging under standard conditions, is probably not true for most genetic backgrounds, since under physiological conditions acetic acid is generated at low levels compared to another metabolite, ethanol [6-7, 11]. Additionally, acetic acid, in spite of its potential toxicity, represents one among several carbon sources that can be utilized by Saccharomyces cerevisiae for growth and metabolism [12-15].

In previous issue of Aging, Leontieva and Blagosklonny describe a yeast-like chronological senescence (CS) model in mammalian cells (Leontieva and Blagosklonny). They show that human tumor cells maintained in stationary culture lose their viability (colony forming units) and that this process is accelerated by medium acidification caused in part by lactate accumulation, which mirrors the accumulation of ethanol and some acetic acid, and the acidification of the medium in S. cerevisiae [5-7, 9]. In yeast, the ethanol accumulated during the growth phase can be used as carbon source during the diauxic shift and the post-diauxic phase, when cells stop dividing and switch from a fermentation- to a respiration-based metabolism [5, 16-17]. Long-lived mutants with deficiencies in the TOR- Sch9/S6K and Ras-AC-PKA pathways deplete ethanol, show a reduced accumulation of extracellular acetic acid [6, 11](M. Wei unpublished results) as well as activate glycerol biosynthesis [11]. As opposed to glucose and ethanol and, possibly, acetic acid, glycerol does not elicit adverse effects on cellular protection and life span suggesting that the Tor1/Sch9-regulated glycerol biosynthesis results in the removal of pro-aging carbon sources [11].

Leontieva and Blagosklonny show that the “yeast-like” chronological senescence in mammalian cells is delayed and attenuated by the inhibition of the mTOR and PI3K signaling pathways, both of which have been implicated in longevity regulation in organisms ranging from yeast to mice. Conditioned medium produced by rapamycin-treated cells was less toxic in inducing CS. However, the addition of rapamycin did not protect fibrosarcoma cells from high concentration of lactate suggesting that rapamycin did not protect cells from CS per se. Rather, inhibition of mTOR affected cellular metabolism and inhibited lactate production during the early phase of stationary survival, which led to a reduced initial lactate accumulation and delayed CS (Leontieva and Blagosklonny). Interestingly, mTOR was spontaneously inactivated after one day in culture, possibly a protective response to lactate accumulation and medium acidification. These results suggest that mTOR promotes CS by favoring lactate production and medium acidification in agreement with the role for TOR-Sch9/S6K in promoting ethanol and acetic acid accumulation in yeast [5, 11, 18]. By contrast, the deletion of either TOR1 or SCH9/S6K are known to extend yeast chronological life span in part by depleting ethanol and acetic acid but largely by mechanisms that are cell autonomous [10-11, 19-21].

It has been argued that acidification of the culture medium and the accumulation of non-fermentable carbon sources such as ethanol and acetic acid render the CLS a paradigm for the identification of “private” mechanisms specific for yeast chronological aging [7, 22-23]. However, not only the yeast CLS method has been remarkably effective in discovering genes later shown to promote aging in mammals [4], it has also revealed the multi-factorial nature of yeast chronological senescence and points to the involvement of diverse cellular processes, such as mitochondrial respiration, reactive oxygen species signaling [1, 19, 24-27], stress response [3, 10, 28], autophagy [29-30], and genome maintenance, in the regulation of life span [31-35]. Although, accumulation of toxic metabolic byproducts may not represent a mechanism of aging in yeast [5-8] or mammalian cells (Leontieva and Blagosklonny [36]), chronological senescence provides a simple model for probing the roles of genes and signaling pathways that affect aging and a powerful platform for high-throughput screening of agents that modulate aging and age-related disease progression.

References

  • 1. Longo VD, Gralla EB, Valentine JS. Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J Biol Chem. 1996; 271:12275-12280. [PubMed]
  • 2. Longo VD. Mutations in signal transduction proteins increase stress resistance and longevity in yeast, nematodes, fruit flies, and mammalian neuronal cells. Neurobiol Aging. 1999; 20:479-486. [PubMed]
  • 3. Fabrizio P, et al. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001; 292:288-290. [PubMed]
  • 4. Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010; 328:321-326. [PubMed]
  • 5. Fabrizio P, et al. Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J Cell Biol. 2004; 166:1055-1067. [PubMed]
  • 6. Fabrizio P, et al. Sir2 blocks extreme life-span extension. Cell. 2005; 123:655-667. [PubMed]
  • 7. Burtner CR, et al. A molecular mechanism of chronological aging in yeast. Cell Cycle. 2009; 8:1256-1270. [PubMed]
  • 8. Burtner CR, et al. A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle. 2011; 10:1385-1396. [PubMed]
  • 9. Murakami CJ, et al. Composition and acidification of the culture medium influences chronological aging similarly in vineyard and laboratory yeast. PloS one. 2011; 6:e24530 [PubMed]
  • 10. Wei M, et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008; 4:e13 [PubMed]
  • 11. Wei M, et al. Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet. 2009; 5:e1000467 [PubMed]
  • 12. Weinhouse S and Millington RH. Acetate metabolism in yeast, studied with isotopic carbon. J Am Chem Soc. 1947; 69:3089-3093. [PubMed]
  • 13. Gilvarg C and Bloch K. The utilization of acetic acid for amino acid synthesis in yeast. J Biol Chem. 1951; 193:339-346. [PubMed]
  • 14. Brown HD. Biosynthesis of branched-chain amino acids in yeast: effect of carbon source on leucine biosynthetic enzymes. J Bacteriol. 1975; 121:959-969. [PubMed]
  • 15. Dickinson JR, et al. NMR studies of acetate metabolism during sporulation of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1983; 80:5847-5851. [PubMed]
  • 16. Werner-Washburne M, et al. Stationary phase in Saccharomyces cerevisiae. Mol Microbiol. 1996; 19:1159-1166. [PubMed]
  • 17. Gray JV, et al. “Sleeping beauty”: quiescence in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2004; 68:187-206. [PubMed]
  • 18. Burtner CR, Murakami CJ, Kaeberlein M. A genomic approach to yeast chronological aging. Methods Mol Biol. 2009; 548:101-114. [PubMed]
  • 19. Bonawitz ND, et al. Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 2007; 5:265-277. [PubMed]
  • 20. Pan Y, et al. Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell metabolism. 2011; 13:668-678. [PubMed]
  • 21. Pan Y and Shadel GS. Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging. 2009; 1:131-145. [PubMed]
  • 22. Kaeberlein M. Lessons on longevity from budding yeast. Nature. 2010; 464:513-519. [PubMed]
  • 23. Burhans WC and Weinberger M. Acetic acid effects on aging in budding yeast: are they relevant to aging in higher eukaryotes? Cell cycle. 2009; 8:2300-2302. [PubMed]
  • 24. Herker E, et al. Chronological aging leads to apoptosis in yeast. J Cell Biol. 2004; 164:501-507. [PubMed]
  • 25. Aerts AM, et al. Mitochondrial dysfunction leads to reduced chronological lifespan and increased apoptosis in yeast. FEBS Lett. 2009; 583:113-117. [PubMed]
  • 26. Bonawitz ND, Rodeheffer MS, Shadel GS. Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. Mol Cell Biol. 2006; 26:4818-4829. [PubMed]
  • 27. Goldberg AA, et al. Effect of calorie restriction on the metabolic history of chronologically aging yeast. Exp Gerontol. 2009; 44:555-571. [PubMed]
  • 28. Cheng C, et al. Significant and systematic expression differentiation in long-lived yeast strains. PLoS One. 2007; 2:e1095 [PubMed]
  • 29. Eisenberg T, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11:1305-1314. [PubMed]
  • 30. Fabrizio P, et al. Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet. 2010; 6:e1001024 [PubMed]
  • 31. Maclean MJ, et al. Base excision repair activities required for yeast to attain a full chronological life span. Aging cell. 2003; 2:93-104. [PubMed]
  • 32. Madia F, et al. Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism. J Cell Biol. 2009; 186:509-523. [PubMed]
  • 33. Madia F, et al. Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. J Cell Biol. 2008; 180:67-81. [PubMed]
  • 34. Qin H M, Lu M, Goldfarb DS. Genomic instability is associated with natural life span variation in Saccharomyces cerevisiae. PloS one. 2008; 3:e2670 [PubMed]
  • 35. Weinberger M, et al. DNA replication stress is a determinant of chronological lifespan in budding yeast. PLoS One. 2007; 2:e748 [PubMed]
  • 36. Leontieva OV and Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging. 2011; 3:1078-1091. [PubMed]