Figure 6.

The NADH shuttle systems and life span regulation. (A) Mdh1 and Aat1 overexpressions extend CLS. (B) The malate–aspartate shuttle is required for maximum CLS extension induced by CR. Fractions of viable wild-type, Mdh1-oe, Aat1-oe, Gut2-oe, mdh1Δaat1Δ double mutant, and gut2Δ single mutant cells were determined from cultures grown to stationary phase. One representative set of three independent experiments, each conducted in triplicate, is shown. Error bars denote standard deviations. (WT) BY4742 wild type; (CR) 0.5% glucose; (v) empty vector control; (oe) overexpression. (C) A model for the role of the NADH shuttle in CR. Multiple CR pathways act to affect longevity in yeast. CR activates mitochondrial respiration, which is required for 0.5% CR and CR mimic-induced life span extension. A functional malate–aspartate shuttle is also required for CR-induced life span extension. We propose that under CR, the malate–aspartate shuttle transmits the increase in the NAD/NADH ratio from the mitochondrial pool to the cytosolic/nuclear pool. The increased NAD/NADH ratio in the cytosolic/nuclear pool then activates other longevity factors such as the Sir2 family to extend life span. Overexpression of the shuttle components (such as Gut2) may also extend life span by maintaining mitochondrial activity, thereby increasing metabolic fitness of the cell.