RNA Polymerase III in healthy ageing: Consolidating the mechanisms of longevity from worms and flies to mice

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Ageing and its associated functional decline are of growing medical, social and economic importance. Ageing can be modulated by nutritional, genetic and pharmacological interventions whose effects are highly conserved across animal taxa. These interventions are often focused on inhibiting the nutrient signalling pathways, such as those delineated by the Target of Rapamycin kinase Complex I (TORC1). However, due to the complexities in the outputs of these pathways, we still do not understand the end-point mechanisms of these interventions that impact animal ageing.

We have recently described that partial inhibition of RNA polymerase III is an evolutionarily conserved longevity intervention acting downstream of TORC1. Hence, understanding Pol III action presents an exciting opportunity to identify the end-point mechanisms that drive age-related decline.

This project exploits the evolutionary conservation of Pol III transcriptional machinery, as well as the documented conservation of longevity mechanisms, to address this question concertedly across worms, flies and mice. Using genomic techniques in all three organisms, we will identify the features of Pol III transcriptome that underlie longevity. We will exploit the strong genetic tools in the worm and the fly to determine which specific Pol III-transcribed genes are mediating the effect of Pol III inhibition on lifespan. In all three organisms, we will extensively survey health benefits arising in later-life upon knockdown of Pol III. Importantly, using the mouse, we will establish for the first time the role of Pol III in mammalian ageing.

This tight collaboration, together with data integration using machine learning, will allow us to elucidate conserved mechanisms whereby Pol III impacts on ageing. In turn, this knowledge will help devise interventions that can improve human health and wellbeing throughout the life course.

Potential beneficiaries of this research, in the short and long-term, include:

1) Public care and healthcare services (Societal and economic impact).
A substantial and ever-increasing amount of care efforts are targeted at older people. In the long-term, this basic research has the potential to result in treatments that reduce the occurrence of ageing-related health and fitness issues, and hence will reduce the overall cost of care, including healthcare, in today's society, increasing effectiveness of a public service. There is evidence that inhibiting the TORC1 pathway in adulthood is sufficient to improve health. So, there is a possibility that an intervention that allows for increased health and wellbeing of the aged, and alleviates the effects of an inappropriate early-lifestyle choices preventing multiple, detrimental manifestations of ageing, ultimately results from this research. Such new treatments/interventions, including preventative approaches, aimed to increase the health and wellbeing at later ages, have the potential to decrease overall treatment costs and improve the quality of the care system.

2) Older people (Societal and economic impact).
Older people represent an ever-increasing portion of our society and often face immense personal costs due to ageing-related loss of function, decreased overall health and wellbeing, and increased occurrence of ageing-related conditions. The final aim of this research is to provide a basis for development of treatments for age-related conditions. As Pol III itself is druggable, this is a real possibility. In the long-term, this will result in tangible benefits in terms of increased quality of life, health, wellbeing and creativity and decrease in emotional and physical suffering for older people. This effect will not just be national but international. The research will also increase the awareness of others to the problems of ageing.

3) Economy (Economic impact).
This project will have an impact on the UK economy in several ways, both in short and long-term. Firstly, in the short-term, the project will create three new jobs across the UK as well as provide training thus creating highly skilled workers for e.g. the pharmaceutical industry. The PDRAs will receive multidisciplinary research training focusing on in vivo biological mechanisms of ageing, incorporating bioinformatics and machine learning and also assessment of potential targets for therapeutic intervention. They will develop expertise in project management of collaborative research and oral and written presentation. These transferable skills will promote their development as independent scientists and facilitate future employability. In the long-term, reduction in public care costs will liberate funds for investment into the economy. New interventions for treatment of ageing-related disease that will be developed as a result of research initiated in this project will benefit the pharmaceutical industry and hence the economy. Treatments that extend health into old age will provide more work force aiding the economy. The project will raise the research profile of the UK leading to more investments by the pharmaceutical industry. All of these will have an effect of increasing the economic performance, competitiveness and reputation of the UK.

4) Government policy (Societal and economic impact).
This project will have an impact on the UK government and its policy. In the short term, this research will provide insight into new ways in which age related health could be improved, remedied or prevented, thus informing government policy on the feasibility of this approach and whether further funding in this area of scientific enquiry is required and justified. In the long-term, the effects on the health of older people may inform government policy in numerous important areas such as healthcare and pensions.