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Pamela L.
Larsen,
Ph.D., co-PI
University of California Los Angeles
Catherine F.
Clarke,
Ph.D., co-PI
University of California Los Angeles
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.
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