Investigating the roles of SKN-1B and RNA polymerase III in ageing

The diseases of ageing represent an increasingly severe threat to human health, and most societies are experiencing an unprecedented demographic shift towards an older population. In this thesis the nematode worm C. elegans is used to examine two aspects of the ageing process. Firstly, it investigates the function of skn-1b. skn-1 is the C. elegans orthologue of mammalian NRF proteins and is required for normal longevity and stress resistance. The skn-1b isoform is expressed in two ASI neurons and is known to be required for the longevity resulting from the life-extending intervention dietary restriction, however little is known about the mechanisms by which this is possible. This study shows that skn-1b expression peaks at the L2 stage and that its levels and patterns are modulated by food levels in the external environment with daf-11 being an important mediator of this. Signalling from ASI neurons via secreted ILPs and TGF-β ligand appears disrupted in animals lacking skn-1b, and animals lacking skn-1b display a cell non-autonomous failure to properly activate the UPRER when challenged with tunicamycin. It also reports that the SKN-1B protein is a functional transcription factor, but that skn-1b is not required for oxidative stress resistance, normal lifespan or brood size. In the second part of this thesis we identify RNA polymerase III as limiting lifespan in C. elegans, showing that knockdown of Pol III function using rpc-1 RNAi can extend lifespan either when active in the whole worm or just the intestine. Inhibition of Pol III protects the C. elegans intestine showing that at least one ageing pathology is delayed. Finally, this thesis shows that this lifespan extension is separable from that resulting from inhibition of 12 Ribosomal Protein S6 Kinase (rsks-1). Taken together, the findings presented here shed more light on the role of transcriptional regulators in the ageing process.