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

核糖体生物发生作为动物衰老的核心驱动因素——果蝇的机制研究。

• 批准号: BB/W013525/1
• 负责人: Nazif Alic
• 金额: $ 80.33万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW013525%2F1
• 关键词: Ribosome; biogenesis; central; driver; animal

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.

老年人在我们社会中的比例正在迅速增加。对许多人来说，老年伴随着虚弱、功能受损和疾病易感性的增加。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证明，新冠肺炎在老年人中的结果要糟糕得多。我们的人口老龄化正在招致巨大的个人和社会经济成本，这些成本亟待解决。老龄化本身是塑料的--它可以由许多基本的细胞过程塑造。了解老龄化是如何调节的，为我们提供了一个机会来设计干预措施，以改善进入老年的人类健康。重要的是，直接针对衰老具有广泛改善健康的潜力，而不仅仅限于一种疾病。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，信使RNA中包含的信息被用来合成蛋白质。翻译对于所有蛋白质编码基因的表达都是必不可少的。有趣的是，以前的工作表明，减少核糖体组成成分核糖体蛋白(RP)的供应可以延长酵母和蠕虫的寿命，从而揭示核糖体生物发生是一种进化保守的促进衰老的基本细胞过程。事实上，制造核糖体的细胞工厂--核仁--的规模缩小，是许多物种长寿的标志。然而，对核糖体及其生物发生在衰老中的作用缺乏全面的了解。RNA聚合酶I(Pol I)是一种重要的真核酶，专门用于产生核糖体RNA(RRNA)，而rRNA是核糖体生物发生的限速步骤。在最近的一项开创性研究中，我们报告了通过部分抑制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，POLI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发生的进化保守，将其作为促进从酵母和蠕虫到苍蝇和可能的人类的一个基本细胞过程。果蝇是一种小动物，但它是一种强大的、易于操作的实验模型，已被证明在理解动物的基本生物学方面是有用的，包括人类的衰老。在这个项目中，我们建议利用Pol I活性降低的果蝇模型的优势来了解核糖体生物发生如何促进动物衰老。首先，我们将检查rRNA合成是否介导了几个关键的衰老途径的影响，将rRNA转录确立为中心衰老过程。其次，我们将阐明在衰老过程中rRNA合成和核糖体蛋白供应之间的关系。第三，我们将通过减少rRNA的合成来发现长寿的分子机制。具体地说，我们将确定长寿是否是细胞蛋白质质量控制的普遍改善和/或特定mRNA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在成年生理中的作用，以及促进老年人健康的基本细胞机制。反过来，这些知识将为旨在确保人类整个生命过程健康的干预措施提供信息。

项目成果

Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.

• DOI: 10.1073/pnas.2311313121
• 发表时间: 2024-01-23
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Urena, Enric;Xu, Bowen;Regan, Jennifer C.;Atilano, Magda L.;Minkley, Lucy J.;Filer, Danny;Lu, Yu-Xuan;Bolukbasi, Ekin;Khericha, Mobina;Alic, Nazif;Partridge, Linda
• 通讯作者: Partridge, Linda