Award details

Ribosome biogenesis as a central driver of animal ageing - a mechanistic study in the fruit fly.

Reference	BB/W013525/1
Principal Investigator / Supervisor	Dr Nazif Alic
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Genetics Evolution and Environment
Funding type	Research
Value (£)	630,431
Status	Current
Type	Research Grant
Start date	08/08/2022
End date	07/08/2025
Duration	36 months

Abstract

Ageing and the associated functional decline are of growing medical, social and economic importance. The rate of ageing can be modulated by fundamental cellular processes. However, the basic understanding of mechanisms is often lacking. Ribosomes are macromolecular machines composed of rRNAs and ribosomal proteins (RPs) that are universally used by cells to translate mRNA. Studies in yeast and worms have demonstrated that reduced provision of some RPs can promote healthy ageing. We have recently shown that a partial reduction in the activity of RNA polymerase I (Pol I), the enzyme dedicated solely to catalysing the rate-limiting step in ribosome biogenesis, the generation of the rRNA precursor, improves old-age health and survival in fruit flies. Additionally, our human population genetic analysis indicates the conservation of the role of Pol I in human ageing. In this study, we propose to elucidate the mechanisms that underlie longevity resulting from partial Pol I inhibition, thus providing a broader understanding of how ribosome biogenesis impacts adult physiology, health and ageing. Using tools in fly genetics, genomics and physiology, we will answer three independent but interlinked questions: Is rRNA transcription mediating the longevity effects of key ageing pathways? What is the relationship between rRNA synthesis and provision of RPs in the context of ageing? What are the molecular mechanisms underlying longevity from reduced rRNA synthesis; do they involve improvements in general proteostasis and/or specific translational regulation? Answering these questions will give us a unique insight into the role of ribosome biogenesis in animal physiology and life-long health. In turn, this knowledge will deepen our understanding of the fundamental mechanisms of animal ageing with relevance to humans, which can be harnessed to ensure human health and wellbeing throughout the life course.

Summary

The proportion of older people in our societies is rapidly increasing. For many, older age comes with increased frailty, impaired function and increased susceptibility to disease. Indeed, this increased disease susceptibility was starkly illustrated during the current pandemic with substantially worse outcomes of Covid-19 in older people. The ageing of our populations is incurring massive personal and socioeconomic costs that need to be urgently addressed. Ageing itself is plastic - it can be shaped by a number of fundamental cellular processes. Understanding how ageing is modulated presents us with an opportunity to devise interventions to improve human health into old age. Importantly, directly targeting ageing has the potential for broad health improvements not limited to a single disease. Ribosomes are macromolecular machines composed of proteins and RNA that are universally used by cells to perform the fundamental task of translation, whereby the information contained in a messenger RNA is used to synthesise a protein. Translation is essential for expression of all protein-coding genes. Interestingly, previous work has shown that reducing the provision of ribosomal proteins (RP), which are constituents of the ribosome, can extend lifespan of yeast and worms, thus revealing ribosome biogenesis as an evolutionarily-conserved, fundamental cellular process that promotes ageing. Indeed, reduced size of the cellular factories where ribosomes are made, the nucleoli, are a hallmark of longevity in a number of species. However, a comprehensive understanding of the role of ribosomes and their biogenesis in ageing is lacking. RNA polymerase I (Pol I) is the essential eukaryotic enzyme dedicated solely to producing ribosomal RNA (rRNA), which is the rate-limiting step for ribosome biogenesis. In a recent, pioneering study, we reported that reducing rRNA synthesis by partially inhibiting Pol I can improve old-age health and extend lifespan in the fruit fly. Our subsequent examination of human population genetic data uncovered that variation in expression of Pol I subunits is causally associated with human longevity. Hence, in addition to discovering the role of Pol I in againg, our work has extended the evolutionary conservation of ribosome biogenesis as a fundamental cellular process promoting ageing from yeast and worms to flies and likely humans. The fruit fly is a small animal but a powerful, easily manipulated experimental model that has proven utility in understanding the basic biology of animal, including human, ageing. In this project, we propose to capitalise on the strength of the fruit fly models of reduced Pol I activity to understand how ribosome biogenesis promotes animal ageing. Firstly, we will examine if rRNA synthesis is mediating the effects of several key ageing pathways, establishing rRNA transcription as a central ageing process. Secondly, we will elucidate the relationship between rRNA synthesis and provision of ribosomal proteins in ageing. Thirdly, we will discover the molecular mechanisms underlying longevity from reduced rRNA synthesis. Specifically, we will determine if longevity results from general improvements in cellular protein quality control and / or if it is a result of altered translation of specific mRNAs. The outcomes of the project will provide us with a better understanding of the role of ribosomes and their biogenesis in animal ageing, the role of RNA polymerase I in adult physiology and the fundamental cellular mechanisms that promote health in older ages. In turn, this knowledge will inform interventions aimed at ensuring human health throughout the life course.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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