Manganese superoxide dismutase (MnSOD or SOD2) is a mitochondrial detoxification enzyme that catalyzes the conversion of superoxide to hydrogen peroxide. Hydrogen peroxide is then decomposed to water by catalase, glutathione peroxidase, or peroxiredoxins. MnSOD/SOD2 and other enzymes involved in antioxidant defense protect cells from reactive oxygen species (ROS). Calorie restriction leads to SIRT3-mediated deacetylation of MnSOD/SOD2 and the subsequent increase of its antioxidant activity. MnSOD/SOD2 also plays an essential role in mediating the protective effect of mTOR inhibition to reduce epithelial stem cell senescence.