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.

我们社会中老年人的比例正在迅速增加。对于许多年龄较大，脆弱，功能受损和对疾病的易感性提高。的确，在当前大流行期间，这种疾病的易感性提高得到了明显的说明，而老年人的Covid-19结果差得多。我们人口的衰老是要紧急解决的巨大个人和社会经济成本。生气本身是塑料的 - 可以通过许多基本的蜂窝过程来塑造它。了解衰老的调制如何使我们有机会设计干预措施，以改善人类健康到老年。重要的是，直接靶向衰老的潜力不限于单一疾病。透视体是由蛋白质和RNA组成的大分子机器，这些机器由细胞普遍使用，这些机器被细胞普遍使用，以执行翻译的基本任务，其中包含在Messenger RNA中的信息可用于合成蛋白质。翻译对于所有蛋白质编码基因的表达至关重要。有趣的是，先前的工作表明，核糖体蛋白（RP）的提供（RP）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发生是一种进化保存的，基本的细胞过程，从而促进衰老。实际上，核糖体制作的细胞工厂的大小减小了核仁，是许多物种寿命的标志。然而，缺乏对核糖体及其在衰老中的生物发生作用的全面理解。RNA聚合酶I（POLI）是仅致力于产生核糖体RNA（RRNA）的必需真核酶，这是核糖体生物发生的速率限制步骤。在最近的一项开创性研究中，我们报道说，通过部分抑制pol I减少rRNA合成可以改善老年健康并延长果蝇中的寿命。我们随后对人口遗传数据的检查发现，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againg中的作用外，我们的工作还扩大了核糖体生物发生的进化保护，作为一种基本的细胞过程，促进了从酵母菌和蠕虫到苍蝇和可能人类的衰老的基本细胞过程。果蝇是一种小动物，但是一种强大的，易于操纵的实验模型，在了解动物的基本生物学（包括人类衰老）方面已证明了实用性。在这个项目中，我们建议利用减少pol I活性的果蝇模型的强度，以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合成是否介导了几种关键衰老途径的效果，并将rRNA转录作为中央衰老过程。其次，我们将阐明衰老中核糖体蛋白的rRNA合成与提供之间的关系。第三，我们将发现从降低的rRNA合成中寿命的分子机制。具体而言，我们将确定寿命是否是由于细胞蛋白质质量控​​制的一般改善和 /或是否是由于特定mRNA的翻译改变而导致的。该项目的结果将使我们更好地了解核糖体的作用及其在动物衰老中的生物发生，而RNA聚合酶在成人物理学和质量培养机构中的作用，从而促进了较旧的机制。反过来，这些知识将为旨在确保在整个生活过程中确保人类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