In many multicellular eukaryotes--including mammals--reduced caloric intake is associated with increased life span. It has been postulated that this might result from a decrease in the metabolically dependent production of reactive oxygen species (ROS). However, whether reduced ROS production translates into increased life span has been a subject of debate. Schulz et al. exposed the nematode Caenorhabditis elegans to 2-deoxy-D-glucose (DOG)--which isn’t metabolized beyond the initial phosphorylation by hexokinase--to create a metabolic state similar to that elicited by glucose deprivation. Although glucose metabolism was decreased, mitochondrial respiration was increased, as was life span. Knockdown of a glycolytic enzyme also increased respiration and extended life span, whereas increased glucose availability led to a decrease in both parameters. DOG failed to increase oxygen consumption or life span in worms lacking AAK-2 (the C. elegans homolog of AMP-dependent kinase). DOG elicited an increase in ROS production after 48 hours and an increase in catalase activity after 6 days. Moreover, worms treated with DOG for 6 days were resistant to paraquat and sodium azide, stressors that can increase mitochondrial ROS production. Pretreatment with the ROS scavenger N-acetylcysteine reduced the DOG-dependent increases in ROS and life span, and in resistance to azide and paraquat, as did treatment with ascorbic acid (vitamin C) and trolox (a vitamin E derivative). The authors propose that glucose restriction may increase life span through a mechanism that depends on an AAK-dependent increase in ROS production--and thereby stress resistance--and raise questions about the desirability of antioxidant supplements.
T. J. Schulz, K. Zarse, A. Voigt, N. Urban, M. Birringer, M. Ristow, Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell. Metab. 6, 280-293 (2007). [PubMed]