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

The proportion of older individuals is steadily increasing in our societies. Since age is the main risk factor for a number of debilitating, chronic diseases and comorbidities, this demographic change is resulting in ever-increasing human and socioeconomic costs. Understanding the biology of ageing is a key research priority because it has the potential to provide us with means to maintain health into old age.

Research in biogerontology has firmly shown that animal ageing is modifiable by identifying a suite of nutritional, genetic and pharmacological interventions capable of extending lifespan and improving health in older ages. The beneficial effects of these interventions are strongly conserved between animal species. Down-regulation of nutrient sensing signalling pathways, such as those governed by the Target of Rapamycin kinase Complex 1 (TORC1) either by genetic or pharmacological means, is an excellent example of this: its health and survival benefits can be observed in species ranging from worms to mice. However, we still do not have a full understanding of the processes that drive ageing, and this knowledge is necessary if we are to design treatments capable of improving late-life health and wellbeing in humans.

We have recently shown that partially inhibiting the evolutionarily conserved enzyme, RNA polymerase III (Pol III), can extend lifespan in yeast, worms and flies. Importantly, Pol III inhibition can recapitulate the effect of systemic TORC1 inhibition on lifespan, revealing Pol III as a key mechanism driving ageing downstream of TORC1. Pol III is one of three RNA polymerases functioning in the eukaryotic nucleus. Historical focus on protein coding genes, solely transcribed by Pol II, has left the roles of Pol III relatively unexplored despite its fundamental cellular function. Here, we propose to pursue our efforts to understand the role of this understudied enzyme in the biology of ageing.

The strength of this proposal arises from its co-ordinated approach using three distinct model organisms. We will examine the activity and role of Pol III in worms, flies and mice. We will exploit the advantages of each animal model. All three will be used to probe into genome-wide expression of Pol III-transcribed genes and the ability of Pol III inhibition to improve age-related health, by comparing control and long-lived animals. The strong genetic tools in worms and flies will be employed to gain a mechanistic insight into the longevity achieved by Pol III inhibition by identifying the relevant downstream genes and processes, while the mouse will be used to establish the role of Pol III in modulating mammalian ageing. Close collaboration between the three laboratories will foster continuous integration of experimental outcomes and, aided by machine learning approaches, will achieve a comprehensive understanding of the role of Pol III in ageing.

Both the TORC1 pathway and Pol III itself are susceptible to pharmacological inhibition. Thus, consolidated knowledge of Pol III's conserved functions, in the long-term, has the potential to provide us with means to ensure human health and wellbeing throughout the life course.

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.