Senior Scholar Award in Aging
Catherine F. Clarke, Ph.D., co-PI
University of California - Los Angeles
Pamela L. Larsen, Ph.D., co-PI
University of Texas Health Science Center - San Antonio

Intersection of two pathways in control of aging: nutritional coenzyme Q and DAF-2 signaling

The nematode Caenorhabditis elegans is an excellent model for genetic studies of the aging process. Mutations in the clk-1 gene of C. elegans result in an extended life span, slowed development and sluggish behavior. Our studies of the clk-1 mutants suggest that the slowed rates of aging, development and behavior are due to a biochemical defect in Coenzyme Q (Q) biosynthesis. Q 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. Nematodes are routinely fed E. coli, so to remove the dietary source of Q we used an unconventional approach and altered the genotype of the E. coli. This Q-less food exposed the true phenotype of the clk-1 mutants, which is growth arrest in early development. Our approach to experimentally vary the food has opened up new avenues of investigation of the interplay between nematode genotypes and the environment. Recently, we examined the effect of Q-less food on adult life span. Strikingly, the N2 wild-type adults fed the Q-less E. coli have a mean life span of 34.0 + 0.59 days (n=74) while those fed the standard Q-replete E. coli have a mean life span of 20.9 + 0.36 days (n=137). These data indicate that a dietary source of Q has a profound life shortening effect on the wild-type animals.

The life span extension generated by the Q-less E. coli diet was observed for all of C. elegans genotypes tested. Thus, the daf-2, daf-12, and daf-16 gene products, involved in an insulin-like signaling pathway, are not required for the longevity effect. Our results suggest that the Q-less food effect is the same longevity mechanism as mutation of the clk-1 gene, namely decreased levels of Q. However, the longevity mechanism of the daf-2 mutants is distinct from that of decreased Q. We have developed a model in which alterations in dietary Q and DAF-2 signaling intersect at the mitochondria and result in substantial life span extension in the nematode, via a concerted decrease in reactive oxygen species (ROS) production and enhanced scavenging of ROS. Our goal is to define the metabolic alterations resulting from dietary Q, and to determine how diet/environment and genotype interact to change longevity.

Contact Dr. Clarke.

Contact Dr. Larsen.