Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression.
The relationships between mitochondrial respiration, reactive oxygen species (ROS), and life span are complex and remain controversial. Inhibition of the target of rapamycin (TOR) signaling pathway extends life span in several model organisms. We show here that deletion of the TOR1 gene extends chronological life span in Saccharomyces cerevisiae, primarily by increasing mitochondrial respiration via enhanced translation of mtDNA-encoded oxidative phosphorylation complex subunits. Unlike previously reported pathways regulating chronological life span, we demonstrate that deletion of TOR1 delays aging independently of the antioxidant gene SOD2. Furthermore, wild-type and tor1 null strains differ in life span only when respiration competent and grown in normoxia in the presence of glucose. We propose that inhibition of TOR signaling causes derepression of respiration during growth in glucose and that the subsequent increase in mitochondrial oxygen consumption limits intracellular oxygen and ROS-mediated damage during glycolytic growth, leading to lower cellular ROS and extension of chronological life span.
Bonawitz
Nicholas D
ND
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Chatenay-Lapointe
Marc
M
Pan
Yong
Y
Shadel
Gerald S
GS
D019069:Cell Respiration / Q000235:genetics; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D030781:Organisms, Genetically Modified; D010101:Oxygen Consumption; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D000099156:Superoxide Dismutase 2
D005947:Glucose; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C083324:TOR1 protein, S cerevisiae