A Metabolomic Approach to Assessing Life-History Traits in Caenorhabditis elegans

Abstract

The proximate causes of ageing and the biological processes that determine lifespan are still unclear. However, many studies using model organisms have led to the identification of genes associated with longevity. While there is a clear link between changes in metabolism and changes in longevity, there has been relatively little ageing-related research that has measured metabolites directly. Metabolic profiling of low molecular weight metabolites (metabolomics) has an advantage over other 'omics' techniques, in that it directly samples the metabolic changes in an organism, and integrates information from changes at the gene, transcript and protein levels, as well as post-translational modification. This thesis demonstrates that metabolic profiling provides a new and useful phenotyping tool for studying ageing in the nematode Caenorhabditis elegans. Using both nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS), I have identified metabolites that are linked with long life. I have carried out the first characterisation of the C. elegans metabolome throughout both development and ageing. Comparing these metabolic changes in wild type worms with those seen in a long-lived mutant aid the understanding of when and how mutant worms acquire their long-lived phenotype. In addition to this, I have examined the effects on metabolism of a commonly used technique in C. elegans ageing research: the inhibition of DNA synthesis to maintain synchronous ageing populations. This provided a way to control for the effects of this technique when used in my work, but also demonstrated that its use may result in artefacts in data. I have also investigated the effect of mutation accumulation on the C. elegans metabolic profile. I have shown that metabolomics provides a way to obtain new phenotypes in this type of study, and novel information about the variation that occurs as a result of spontaneous mutation.