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

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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.