Identification of new genes and pathways that act to delay C. elegans aging
Massachusetts Institute of Technology. Dept. of Biology.
H. Robert Horvitz and Leonard Guarente.
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Aging of an organism is determined by both stochastic and genetic components. The importance of genes is illustrated by the discovery of single gene mutations that alter lifespans of species ranging from invertebrates C. elegans and D. melanogaster to mice. To better understand the mechanisms underlying genetic regulation of the rate of aging, we have studied aging and lifespan determination in C. elegans. We have investigated the mechanism of action of the sir-2.1 gene, which extends C. elegans lifespan when overexpressed. We discovered that sir-2.1 acts to promote longevity in parallel to low insulin signaling, in a stress-dependent pathway that converges with the insulin-like pathway on a forkhead transcription factor DAF-16. We discovered that 14-3-3 proteins play a role in C. elegans lifespan determination. 14-3-3 proteins interact with the SIR-2.1 protein, and the 14-3-3 genes par-5 andftt-2 are required for the longevity mediated by sir-2. I1 overexpression, indicating that 14-3-3 proteins act to delay C. elegans aging in the sir-2. I1-dependent longevity pathway. To identify new genes that act to delay C. elegans aging we developed a genetic screen for mutants that prematurely accumulate the age-related fluorescent pigment lipofuscin. In this screen, we isolated loss-of-function mutations in the gene kat-1. These mutations confer increased lipofuscin accumulation, short lifespan, and other abnormalities characteristic of premature aging. kat-1 encodes a ketoacyl thiolase involved in fatty acid beta-oxidation, suggesting that defects in fat metabolism can affect the regulation of aging.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2008.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology