Coenzyme Q and Aging in Caenorhabditis elegans

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The nematode Caenorhabditis elegans is an excellent model for genetic studies of the aging process. Gene mutations that increase life span have been identified in C. elegans that have homologs in vertebrates and appear to act by highly conserved mechanisms, and in pathways that parallel those present in humans. Mutations in the C. elegans clk-1 gene result in an extended life span, slowed development and sluggish behavior. Homology of clk-1 and COQ7 suggested that the long-lived C. elegans clk-1 mutants are defective in ubiquinone (coenzyme Q or CoQ) biosynthesis. Normally nematodes are provided a diet of CoQ-replete E. coli. In the absence of dietary CoQ, the clk-1 mutants display their true phenotype - growth arrest in early development and sterility when emerging from the dauer stage. These results suggest that clk-1 is essential for coenzyme Q biosynthesis, and that the aging and developmental phenotypes previously described may be attributed to CoQ levels. CoQ functions in cells as a redox-active coenzyme of both mitochondria and plasma membrane electron transport, as an essential lipid soluble antioxidant, and plays a role in thermogenesis (uncoupling) and apoptosis. Our recent studies indicate that both mean and maximum life span of wild-type nematodes fed Q-less diets is extended 60 percent. This life span extension is quite robust and is observed in all Age mutants tested so far, when transferred to the Q-less diet as adults. A compelling hypothesis for this life extension is that the standard E. coli Q8-replete diet affects the amount and type of quinones present, which in turn affects reactive oxygen species production by modulating the state of mitochondrial respiration in the nematode. We propose to evaluate the relationship between Q metabolism and aging by employing biochemistry and molecular genetics. It is likely that the studies proposed here will define the metabolic alterations resulting from dietary CoQ, and will help determine how diet/environment and genotype interact to change longevity. Based on the strong conservation of CoQ function, our findings will be very relevant to aging in other organisms.