[
International Worm Meeting,
2007]
Single-gene mutants have elucidated genetic pathways regulating worm lifespan, and further provided both the general understanding of genetic components programming human aging as well as a tool set for the characterization of age-related disease states and their associated treatments. Variations in longevity phenotypes are expected and observed in our library of recombinant inbred lines (RILs) and are attributed to natural sequence variation, more specifically single nucleotide polymorphisms (SNPs). Here we present our investigation on how the novel longevity mutants with non-mutagenized genomes age, providing a unique perspective on the underlying mechanisms. At the previous International C. elegans Meeting, we reported the generation of 400 RILs by crossing the geographically isolated Bristol N2 and Hawaiian CB4856 strains, and inbreed each progeny for multiple generations to ensure a homozygous genome. To date, an additional set of 400 or so RILs have been generated and we genotypically characterized the entire library using evenly distributed SNP markers. As expected in shuffled genomes, the majority of RILs assayed age similarly to the parental strains. However, a small fraction of the RILs have significant variations in lifespan. Age-associated phenotypes are further characterized in these natural aging mutants, and we present here the status of using multi-factorial analysis to tease out the contributions of these seemingly distinct but related biological processes to the overall lifespan. Evolutionarily conserved genetic pathways that ensure successful aging have been well characterized in worms. Using a candidate gene approach in combination with transcriptional perturbation, we aim to determine how these pathways behave in a completely natural, yet novel genetic background. Each RIL has a unique mosaic genome with random combinations of N2 and CB4856 DNA. This provides a collection of novel genetic backgrounds that cannot be recreated by a single-gene mutation, thus is distinct from one created artificially via chemical mutagenesis. We expect unexpected changes in age-related processes, providing a unique perspective to understanding the molecular mechanisms of aging and a novel approach to studying human aging and age-associated diseases attributed to natural sequence variations among individuals.