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

RNA聚合酶III在健康衰老中的作用：巩固从蠕虫和苍蝇到小鼠​​的长寿机制

• 批准号: BB/S014357/1
• 负责人: Nazif Alic
• 金额: $ 58.33万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS014357%2F1
• 关键词: RNA; Polymerase; III; healthy; ageing

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.

在我们的社会中，老年人的比例正在稳步上升。由于年龄是一些使人衰弱的慢性疾病和合并症的主要风险因素，这种人口变化导致人类和社会经济成本不断增加。了解衰老的生物学是一个关键的研究重点，因为它有可能为我们提供保持健康到老年的方法。老年医学的研究已经明确表明，通过确定一套能够延长寿命和改善老年人健康的营养、遗传和药理干预措施，动物衰老是可以改变的。这些干预措施的有益效果在动物物种之间高度保守。营养传感信号通路的下调，例如通过遗传或药理学手段由雷帕霉素激酶复合物1（TORC 1）的靶标控制的那些，是一个很好的例子：它的健康和生存益处可以在从蠕虫到小鼠的物种中观察到。然而，我们仍然没有完全了解驱动衰老的过程，如果我们要设计能够改善人类晚年健康和福祉的治疗方法，这些知识是必要的。我们最近表明，部分抑制进化保守的酶，RNA聚合酶III（Pol III），可以延长酵母，蠕虫和苍蝇的寿命。重要的是，Pol III抑制可以概括全身性TORC 1抑制对寿命的影响，揭示Pol III是驱动TORC 1下游衰老的关键机制。Pol III是在真核细胞核中起作用的三种RNA聚合酶之一。历史上对蛋白质编码基因的关注，仅由Pol II转录，使得Pol III的作用相对未被探索，尽管其具有基本的细胞功能。在这里，我们建议继续努力了解这种未充分研究的酶在衰老生物学中的作用。这一建议的力量来自于它使用三种不同模式生物的协调方法。我们将研究Pol III在蠕虫、苍蝇和小鼠中的活性和作用。我们将利用每种动物模型的优点。所有这三个将被用来探讨全基因组表达的Pol III转录的基因和能力的Pol III抑制，以改善与年龄相关的健康，通过比较控制和长寿的动物。蠕虫和苍蝇中强大的遗传工具将被用来通过识别相关的下游基因和过程来获得对Pol III抑制所实现的长寿的机械见解，而小鼠将被用来建立Pol III在调节哺乳动物衰老中的作用。三个实验室之间的密切合作将促进实验结果的持续整合，并在机器学习方法的帮助下，将全面了解Pol III在衰老中的作用。TORC 1通路和Pol III本身都容易受到药理学抑制。因此，从长远来看，对Pol III保守功能的综合了解有可能为我们提供确保人类一生健康和福祉的手段。

项目成果

In silico identification of Drosophila melanogaster genes encoding RNA polymerase subunits.

• DOI: 10.17912/micropub.biology.000320
• 发表时间: 2020-10-20
• 期刊: microPublication biology
• 作者: Marygold SJ;Alic N;Gilmour DS;Grewal SS
• 通讯作者: Grewal SS

Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.

• DOI: 10.1101/gr.275636.121
• 发表时间: 2022-03
• 期刊: Genome research
• 影响因子: 7
• 作者: Javidnia S;Cranwell S;Mueller SH;Selman C;Tullet JMA;Kuchenbaecker K;Alic N
• 通讯作者: Alic N

RNA Polymerase III, Ageing and Longevity.

• DOI: 10.3389/fgene.2021.705122
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Kulaberoglu Y;Malik Y;Borland G;Selman C;Alic N;Tullet JMA
• 通讯作者: Tullet JMA

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