Bart P Braeckman et al. (2003) International Worm Meeting "Caloric restriction and Ins/IGF-1 like signalling have divergent effects on metabolism in C. elegans."

Thomas E Johnson, Annemie De Vreese, Jacques R Vanfleteren, Sylvie Vaneygen, Kristel Brys, Koen Houthoofd, Bart P Braeckman, Isabelle Lenaerts

[International Worm Meeting, 2003]

Several genes that affect life span in C. elegans act in a common signalling pathway that shows homology to the mammalian insulin and IGF-1 signalling pathways and also controls dauer formation in C. elegans. Both constitutive dauer formation and extended life span of these mutants can be suppressed by mutation in the daf-16 gene, which encodes a forkhead transcription factor that is inactive and resides in the cytoplasm when phosphorylated by the Ins/IGF-1 signal, and relocates to the nucleus and controls transcription of a life maintenance program when dephosphorylated. Longevity mutants with reduced activities of the Ins/IGF-1 pathway were recently discovered in Drosophila and mice, suggesting that this pathway for life span control is evolutionary conserved. A nutritionally complete, but calorie restricted, diet can significantly extend life span in many species, pointing to another conserved mechanism of life-span determination. The mechanism by which caloric restriction prolongs life span is still unknown, however. Caloric restriction has been achieved in C. elegans by using diluted E. coli concentrations, eat-mutants, and axenic medium. Calorically restricted worms show elevated metabolic rates, increased XTT-reduction capacity, lower ATP levels and increased activities of the antioxidant enzymes SOD and catalase. Insulin production is regulated by the metabolic status in mammalian species. It was therefore assumed that caloric restriction would cause longevity by decreasing the insulin/IGF-1 production, resulting in the expression of the life maintenance program specified by the Ins/IGF-1 pathway. Our results suggest that caloric restriction influences the metabolism of C. elegans independently from the Ins/IGF-1 pathway. Indeed, we found that caloric restriction and deficiencies in the Ins/IGF pathway caused effects on oxygen consumption and XTT-reduction activity that were additive, and both life span controlling mechanisms have divergent effects on the heat output and ATP stores. Furthermore the C/R ratio is fundamentally altered in daf-2, daf-16, daf-2; daf-16 and daf-2; daf-12, but caloric restriction has no effect. In addition, metabolic alterations that are caused by caloric restriction are also seen in daf-16 mutants, suggesting that caloric restriction does not need intact daf-16 activity. These conclusions are consistent with two separate pathways that control the metabolism and life span of C. elegans.