Dietary restriction (DR) has been reproducibly found to increase life span and delay age-associated diseases in many organisms, including mammals. The mechanism(s) by which DR promotes health, however, remain poorly understood. The overarching goal of this proposal is to fully characterize the genetic and molecular basis of life span extension and disease prevention from DR in the nematode Caenorhabditis elegans. These studies are likely to be highly relevant for human health and will identify candidate genetic targets for a variety of age-associated diseases, such as diabetes, heart disease, cancer, and Alzheimer's disease. C. elegans has served as one of the premier invertebrate models for characterizing pathways that modulate longevity. At least four methods of DR have been reported to increase life span in C. elegans;however, none has become widely accepted. This lack of consensus has impeded progress in understanding how DR relates to known modifiers of longevity. We have recently developed a novel DR method in C. elegans where adult animals are maintained on a nutrient-agar surface without bacterial food source (dietary deprivation = DD). DD increases adult life span by more than 50% and dramatically reduces disease phenotypes associated with expression of at least three different toxic peptides, including proteotoxic peptides implicated in the pathogenesis of Huntington's disease and Alzheimer's disease. Here we propose phenotypic, genetic, and genomic experiments to characterize life span extension and disease prevention by DD in C. elegans. One aim of this work is to carry out a comprehensive comparative analysis (including global gene expression profiling) of DD with prior methods of DR in C. elegans. These experiments are important both because they will elucidate the relationship between different DR methods in C. elegans, and because they will improve confidence in future studies of DR in this organism. In subsequent aims, we will use information from this comparative analysis as a starting point for identifying genetic targets of DR. We will determine which of these targets are necessary and/or sufficient for life span extension and/or suppression of proteotoxic disease using a combination of RNAi knock-down and transgenic overexpression. Genetic and biochemical interactions between these targets of DR will be explored in follow-up studies. PUBLIC HEALTH RELEVANCE: Dietary restriction has been shown to increase longevity and delay a wide range of age-associated diseases in many different organisms. We have developed a novel method for studying dietary restriction, and we have found that our method dramatically improves health in invertebrate models of Huntington's disease and Alzheimer's diseases. The goal of this proposal is to understand how dietary restriction increases longevity and retards disease. These studies will identify candidate therapeutic targets for several age-associated human diseases, including cancer, heart disease, diabetes, and Alzheimer's disease.
NIH ExPorter
NIH ExPorter