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
