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

老年人在我们社会中的比例正在迅速增加。对许多人来说，老年人身体虚弱，功能受损，对疾病的易感性增加。事实上，这种疾病易感性的增加在当前的大流行中得到了鲜明的体现，老年人的新冠肺炎后果严重恶化。我们的人口老龄化正在造成巨大的个人和社会经济代价，需要紧急加以解决。老龄化本身是可塑性的-它可以由一些基本的细胞过程塑造。了解衰老是如何调节的，为我们提供了一个机会，可以设计干预措施，改善人类进入老年的健康状况。重要的是，直接针对衰老有可能带来广泛的健康改善，而不仅仅局限于一种疾病。核糖体是由蛋白质和RNA组成的大分子机器，细胞普遍使用它们来执行基本的翻译任务，从而使用信使RNA中包含的信息来合成蛋白质。翻译对于所有蛋白质编码基因的表达至关重要。有趣的是，以前的工作表明，减少核糖体蛋白（RP）的提供，这是核糖体的组成部分，可以延长酵母和蠕虫的寿命，从而揭示核糖体生物合成是一个进化保守的，基本的细胞过程，促进衰老。事实上，在许多物种中，制造核糖体的细胞工厂--核仁--的缩小是长寿的标志。RNA聚合酶I（RNA polymerase I，Pol I）是真核生物合成核糖体RNA（ribosomal RNA，rRNA）的关键酶，是核糖体生物合成的限速步骤。在最近的一项开创性研究中，我们报告说，通过部分抑制Pol I来减少rRNA合成可以改善果蝇的老年健康并延长寿命。我们随后对人类群体遗传数据的研究发现，Pol I亚基表达的变化与人类寿命有因果关系。因此，除了发现Pol I在衰老中的作用外，我们的工作还扩展了核糖体生物合成的进化保守性，作为促进衰老的基本细胞过程，从酵母和蠕虫到苍蝇和可能的人类。果蝇是一种小动物，但它是一种功能强大、易于操作的实验模型，已被证明可用于了解动物（包括人类）衰老的基本生物学。在这个项目中，我们建议利用果蝇模型减少Pol I活性的优势来了解核糖体生物合成如何促进动物衰老。首先，我们将研究rRNA合成是否介导几个关键衰老途径的影响，建立rRNA转录作为一个中心的衰老过程。其次，我们将阐明衰老过程中rRNA合成和核糖体蛋白供应之间的关系。第三，我们将从减少rRNA合成中发现长寿的分子机制。具体来说，我们将确定长寿是否是由于细胞蛋白质质量控制的总体改善和/或是否是特定mRNAs翻译改变的结果。该项目的结果将使我们更好地了解核糖体及其生物发生在动物衰老中的作用，RNA聚合酶I在成人生理学中的作用以及促进老年人健康的基本细胞机制。反过来，这种知识将为旨在确保人类一生健康的干预措施提供信息。

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.