Deletion of NAD+-dependent isocitrate dehydrogenases extends lifespan.
Trey Powers (1), Stan Fields(1) (2)
(1) University of Washington, Departments of Genome Sciences and Medicine;
(2) Howard Hughes Medical Institute
S. cerevisiae has been a useful model organism in studies of the basic mechanisms of aging. This utility is largely due to mounting evidence that similar genetic and environmental interventions can extend lifespan in taxonomically diverse organisms. Aging in yeast is measured in two distinct ways: chronological lifespan, a measure of the ability of cells to survive long periods in liquid media; and replicative lifespan, a measure of the number of times a cell can replicate. In order to elucidate novel genetic mechanisms implicated in lifespan regulation, we screened the yeast deletion mutants for those that extend chronological lifespan. Of several deletions identified, Δidh2 and Δidh1 also extend replicative lifespan by 18 and 30 percent, respectively. IDH1 and IDH2 encode the mitochondrial NAD+-dependent isocitrate dehydrogenases, which compete for their substrate with the mitochondrial Idp1, an NADP-dependent isocitrate dehydrogenase. Our current model to explain this lifespan extension proposes that diminished formation of NADH in favor of NADPH results in increased efficiency of reductive repair processes, and thereby forestalls the aging process in the deletion mutants. Future experiments to test this model involve overproducing NADP-reducing metabolic enzymes to determine whether increased cellular NADPH production may explain some aspects of the lifespan extension afforded by caloric restriction.
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