Lifespan extension by calorie restriction relies on the Sty1 MAP kinase stress pathway.
Either calorie restriction, loss-of-function of the nutrient-dependent PKA or TOR/SCH9 pathways, or activation of stress defences improves longevity in different eukaryotes. However, the molecular links between glucose depletion, nutrient-dependent pathways and stress responses are unknown. Here, we show that either calorie restriction or inactivation of nutrient-dependent pathways induces lifespan extension in fission yeast, and that such effect is dependent on the activation of the stress-dependent Sty1 mitogen-activated protein (MAP) kinase. During transition to stationary phase in glucose-limiting conditions, Sty1 becomes activated and triggers a transcriptional stress programme, whereas such activation does not occur under glucose-rich conditions. Deletion of the genes coding for the SCH9-homologue, Sck2 or the Pka1 kinases, or mutations leading to constitutive activation of the Sty1 stress pathway increase lifespan under glucose-rich conditions, and importantly such beneficial effects depend ultimately on Sty1. Furthermore, cells lacking Pka1 display enhanced oxygen consumption and Sty1 activation under glucose-rich conditions. We conclude that calorie restriction favours oxidative metabolism, reactive oxygen species production and Sty1 MAP kinase activation, and this stress pathway favours lifespan extension.
Zuin
Alice
A
Universitat Pompeu Fabra, Barcelona, Spain.
Carmona
Mercè
M
Morales-Ivorra
Isabel
I
Gabrielli
Natalia
N
Vivancos
Ana P
AP
Ayté
José
J
Hidalgo
Elena
E
D051697:Activating Transcription Factor 1 / Q000378:metabolism; D015152:Blotting, Northern; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*; D010101:Oxygen Consumption; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology*
C479693:1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine; D051697:Activating Transcription Factor 1; D010750:Phosphoproteins; D011720:Pyrazoles; D011743:Pyrimidines; D029702:Schizosaccharomyces pombe Proteins; C106740:atf1 protein, S pombe; D006861:Hydrogen Peroxide; C113036:Sck2 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D005947:Glucose