RNAi Mediated Gene Disruption in Caenorhabditis Elegans

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Application in response to research objective 21 "Genetics, Behavior, Social Factors and Aging" of the NIA pilot research grant program. While the mechanisms that cause aging have recently become the subject of an intensive research effort, the multi-factorial nature of aging makes it difficult to disentangle the factors responsible for senescence. A powerful method towards identifying the causal mechanisms of aging is to study genetic mutations or manipulations that extend longevity using an intensively analyzed model organism, such as the nematode Caenorhabditis elegans. A new method for identifying genes affecting longevity in C. elegans is the use of RNA-mediated inference (RNAi). RNAi silences gene expression through the use of double-stranded RNA that target specific mRNAs for degradation. RNAi has proven itself to be a valuable tool to study aging in C. elegans and has been used to identify hundreds of genes that influence longevity in C. elegans. However, to provide true insight into the aging process, studies of C. elegans and aging must also assay other measures of physiological function such as metabolic rates, in addition to chronological life span. Measures of physiological processes are especially important when considering factors that increase longevity in an ectothermic (poikilothermic) organism such as C. elegans because factors that reduce the metabolic rate of ectotherms also tend to increase their longevity. This research will use RNAi to manipulate gene function in C. elegans and to combine these manipulations with metabolic rate measurements on these animals. Ultimately one of the most interesting outcomes of such an analysis will be to reveal whether any of the longlived RNAi treated worms also retain normal metabolic rates. Such worms could identify candidate genes affecting processes that act "downstream" from the metabolic rate and provide valuable insights into the causes of aging and mechanisms by which it can be attenuated.