Changes in RNA regulatory processes during mammalian ageing

Abstract

Ageing is defined as a system-wide, gradual loss in overall organ and tissue function across the lifespan of an organism, and in humans is the single largest risk factor for most chronic diseases. Thanks to ongoing improvements in healthcare, human life expectancy is steadily rising, but the proportion of life spent free of chronic disease (known as healthspan) is not extending concurrently in our increasingly aged population. Socio-economic costs are growing, both in terms of healthcare spending and quality of life. A central goal of ageing research therefore is to find methods of extending healthspan. However, ageing is a complex, heterogeneous process and the underlying mechanisms of ageing and determinants of lifespan/healthspan are still not well understood. RNA regulators of gene expression are important factors in the ageing process, and I hypothesise that they may have potential to affect healthspan, or act as biomarkers of ageing. In this thesis, I have examined some of these RNA regulatory factors and their associations with ageing and lifespan in mammals. In order to do this, I assessed the expression patterns of RNA regulatory factors in two mouse models and a human cohort. In one mouse model, I found that both mRNA splicing regulatory factors and microRNAs are associated with strain-specific longevity during normal ageing, and that it is possible that these regulators play a causal role in determining strain lifespan. In the second mouse model, I showed these splicing factors to be associated with dietary restriction (a known treatment for extension of lifespan) and provided evidence that they could be mechanistically involved in the lifespan response to dietary restriction. I also showed that expression levels of these splicing factors were associated with cognitive decline and reduction in physical ability in humans. These results indicate that correct RNA regulation is a key component of the ageing process and suggests that the factors that govern these processes may represent useful future targets for healthpan intervention in ageing people.