title: Drug synergy drives conserved pathways to increase fission yeast lifespan.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.  nc.ude.utjws.emoh@gnauhehnix.
authors.forename: Xinhe
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences and the Lucille Markey Cancer Center, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.affiliation: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dickson
mesh_terms: D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004357:Drug Synergism; D008136:Longevity / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D013312:Stress, Physiological / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe