Recent studies have shown that alpha-ketoglutarate (AKG), an important cellular intermediate, prolongs lifespan and delays the onset of age-related decline in a dose-dependent manner in several model organisms such as nematodes, fruit flies, yeasts and mice. Mimicking a state of caloric restriction and acting as a hormesis-inducing agent are proposed to be possible mechanisms underlying lifespan-extending effects of dietary AKG. Here, we analyze potential molecular mechanisms by which AKG can imitate a state of caloric restriction and stimulate production of reactive oxygen species (ROS) in mitochondria. According to hormesis, moderate increase in ROS levels induces defensive mechanisms resulting in biologically beneficial effects, such as healthier and longer lifespan. Herewith, a strong oxidative stress by high AKG concentrations may be responsible for lifespan-shortening effects of this metabolite. Limitations of dietary restriction hypothesis as a mechanism of AKG action are also discussed.
