Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.
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This study was funded by the NIH/NIA grant AG024377 to RCD and by the National Institute of General Medical Sciences grant P20GM103486 to Louis Hersh. The funders had no role in the study design, data collection and analysis, decisions to publish, or preparation of the manuscript.
This study was also supported by the Fundamental Research Funds for the Central Universities of China grant 2682014RC14 to XH.
This article was corrected in "Correction: Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan," published in PLOS One, v. 10, no. 4, article e0125857, p. 1. DOI: http://dx.doi.org/10.1371/journal.pone.0125857
A copy of this correction is available as supplemental content.
Huang, Xinhe; Leggas, Markos; and Dickson, Robert C., "Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan" (2015). Pharmaceutical Sciences Faculty Publications. 46.
Correction: Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan
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S1 Fig. Effect of individual drugs on cell growth.
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S2 Fig. Effect of ComboDT on cell growth.
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S3 Fig. Determination of EC50 for individual drugs.
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S4 Fig. Glucose utilization during the first 48 hrs of culture incubation.
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S1 Table. Strains used in this study.
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S2 Table. Statistical analysis of CLS data.