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

在我们的社会中，老年人的比例正在稳步上升。由于年龄是一些衰弱、慢性病和合并症的主要风险因素，这种人口结构变化正在导致不断增加的人类和社会经济成本。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到老年时保持健康的手段。生物老年学的研究坚定地表明，通过确定一套能够延长老年人寿命和改善老年人健康的营养、遗传和药物干预措施，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具有很强的保守性。营养感应信号通路的下调，例如那些由雷帕霉素激酶复合体1靶标(TORC1)通过遗传或药物手段控制的通路，就是一个很好的例子：从蠕虫到老鼠的各种物种都可以观察到它对健康和生存的好处。然而，我们仍然没有完全了解导致衰老的过程，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，部分抑制进化上保守的酶-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抑制可以概括系统性TORC1抑制对寿命的影响，揭示Pol III是推动TORC1下游衰老的关键机制。POL III是真核细胞中的三种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，尽管POL III具有基本的细胞功能，但其作用相对未知。在这里，我们建议继续我们的努力，以了解这种未被研究的酶在衰老生物学中的作用。这一提议的力量来自于它使用三种不同的模式生物的协调方法。我们将研究POL III在蠕虫、苍蝇和老鼠中的活性和作用。我们将利用每种动物模型的优势。所有这三项都将被用来通过比较对照组和长寿动物来探索POLIII转录基因的全基因组表达以及POLIII抑制改善与年龄相关的健康的能力。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抑制实现的长寿的机械性洞察，而小鼠将被用来确定Pol III在调节哺乳动物衰老中的作用。这三个实验室之间的密切合作将促进实验结果的持续整合，并将在机器学习方法的帮助下，实现对POL III在衰老中的作用的全面了解。TORC1途径和POL III本身都容易受到药物抑制。因此，从长远来看，巩固对POLIII的保守功能的了解，有可能为我们提供手段，确保人类在整个生命过程中的健康和福祉。

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.