A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction.

Caloric restriction (CR) of laboratory rodents, which extends their maximum lifespan, only transiently reduces the specific metabolic rate of highly oxidative tissues. However, superoxide production by mitochondria of those tissues is greatly reduced by CR. This is probably a major contributor to the slowed aging seen in CR, but its mechanism is unknown. Here it is proposed that the major metabolic shift enabling reduced superoxide production is a diversion of much of the electron flux generated by glycolysis and the TCA cycle away from its usual destination, Complex I, and to the plasma membrane redox system. The cell's ATP synthesis capacity is thereby diminished, but so is its ATP demand, due to reduced turnover of the Na+/K+-ATPase. Direct tests of this hypothesis are proposed.