title: TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast.
abstract: Target of rapamycin complex 1 (TORC1) is implicated in growth control and aging from yeast to humans. Fission yeast is emerging as a popular model organism to study TOR signaling, although rapamycin has been thought to not affect cell growth in this organism. Here, we analyzed the effects of rapamycin and caffeine, singly and combined, on multiple cellular processes in fission yeast. The two drugs led to diverse and specific phenotypes that depended on TORC1 inhibition, including prolonged chronological lifespan, inhibition of global translation, inhibition of cell growth and division, and reprograming of global gene expression mimicking nitrogen starvation. Rapamycin and caffeine differentially affected these various TORC1-dependent processes. Combined drug treatment augmented most phenotypes and effectively blocked cell growth. Rapamycin showed a much more subtle effect on global translation than did caffeine, while both drugs were effective in prolonging chronological lifespan. Rapamycin and caffeine did not affect the lifespan via the pH of the growth media. Rapamycin prolonged the lifespan of nongrowing cells only when applied during the growth phase but not when applied after cells had stopped proliferation. The doses of rapamycin and caffeine strongly correlated with growth inhibition and with lifespan extension. This comprehensive analysis will inform future studies into TORC1 function and cellular aging in fission yeast and beyond.
authors.affiliation: Department of Genetics, Evolution & Environment and Institute of Healthy Ageing, University College London, Gower Street - Darwin Building, London, WC1E 6BT, UK.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Rallis
authors.forename: Sandra
authors.initials: S
authors.lastname: Codlin
authors.forename: Jürg
authors.initials: J
authors.lastname: Bähler
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D049109:Cell Proliferation; D003470:Culture Media / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D006863:Hydrogen-Ion Concentration; D000076222:Mechanistic Target of Rapamycin Complex 1; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics; D009584:Nitrogen / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013997:Time Factors
chemical_list: D002110:Caffeine; D003470:Culture Media; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009584:Nitrogen; D019869:Phosphatidylinositol 3-Kinases; D029702:Schizosaccharomyces pombe Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C513100:tor2 protein, S pombe
keywords: Schizosaccharomyces pombe; Target of Rapamycin; cell proliferation; chronological aging; gene regulation; translation
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