Mechanisms mediating the anti-ageing effects of trametinib.

曲美替尼抗衰老作用的介导机制。

• 批准号: BB/V006541/1
• 负责人: Linda Partridge
• 金额: $ 67.92万
• 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%2FV006541%2F1
• 关键词: Mechanisms; mediating; anti; ageing; effects

People are living a lot longer than they used to. From about the 1850s human survival increased steadily in the UK, as a result of improvements in living conditions and better medical care. It is a sign of civilisation that we have succeeded in increasing the length of our lives, but it is coming with a downside. The healthy period of life 'the healthspan' has not kept up with the increase in survival, and there is a growing period of disability and illness at the end of life, particularly in women. Older people are also less resilient to physical and medical challenges, as has become painfully obvious with their increased death rate with Covid-19. There is therefore a growing need to find ways of keeping people in better health later in their lives.Increased exercise and improved diet can often increase health and function in people of any age, and can help to protect against old-age decline. However, there are limits to what can be achieved, and scientific research is being directed to understanding exactly what goes wrong during ageing, with a view to targeting the ageing process itself with drugs. We have learned a lot about the underlying processes of ageing in recent years, and they turn out to be remarkably malleable. In laboratory animals, ageing can be slowed down by drugs, which can keep the animal healthy as it gets older, and protect it against the diseases that come with advancing age. The ageing process is similar in animals and humans. Furthermore, many of the processes at work during ageing are already targets of drugs. This is important, because it is a lot more practical to divert an existing drug to new uses than it is to develop a new drug from scratch, because a lot of the huge expense of drug development has already been met.One of the systems that goes wrong during ageing is devoted to making sure that the cells in the body only do what they can afford, given their current nutritional and general stress level. This system is very ancient, and it seems to be too active during ageing, so that tamping down its activity with drugs can improve health. Several drugs target this system, because it is important in causing some of the diseases that occur in older people. We have found that a particular part of the system, called the Ras pathway, for which there are many drugs because it is important in cancer, plays a key role in ageing, and if we suppress it with a drug called trametinib then we can extend the healthspan of fruitflies and mice. The aim of the research in this project is therefore to understand how trametinib protects against ageing. We will do this using fruitflies, because their relatively short lifespan and excellent experimental toolkit mean we can make faster progress than in mice, yet they share many features with mammals, including the way that they age. They have been extensively used for research into ageing, and have led to many of the key discoveries about the ageing process. During ageing there is a marked deterioration in the structure and function of the intestine, and work that we have done already suggests that trametinib can prevent this age-related decline. We will identify the biological molecules in the intestine that are affected by the drug, and find out how they keep the gut healthy during ageing. We will also identify any health improvements in other tissues from trametinib treatment, including neuromuscular function, activity, circadian rhythm, sleep, molecular markers of muscle and brain ageing, immune function and mitochondrial activity in fat body, and the role of the gut in inducing them. What we learn will inform future work targeting the key processes, first in mice, and ultimately, we hope, in humans. To make sure that we have the capability to advance this research in the most effective way, we are combining the efforts of two research laboratories with complementary expertise and experience, who will collaborate closely to drive forward the project.

人们比过去活得长多了。大约从19世纪50年代起，由于生活条件的改善和更好的医疗保健，英国的人类生存率稳步上升。我们成功地延长了寿命，这是文明的标志，但它也带来了负面影响。生命的健康期“健康寿命”没有跟上生存期的增长，在生命结束时，残疾和疾病的时间越来越长，特别是在妇女中。老年人对身体和医疗挑战的适应力也较低，这一点随着新冠肺炎死亡率的上升而变得显而易见。因此，人们越来越需要找到使人们在晚年保持更好健康的方法。增加锻炼和改善饮食通常可以增强任何年龄段的人的健康和功能，并有助于防止老年衰退。然而，所能取得的成就是有限的，科学研究的方向是了解衰老过程中究竟出了什么问题，以便针对衰老过程本身使用药物。近年来，我们对衰老的潜在过程有了很多了解，而且这些过程具有很大的可塑性。在实验室动物中，衰老可以通过药物来减缓，这可以在动物变老时保持健康，并保护它免受年龄增长带来的疾病。衰老过程在动物和人类中是相似的。此外，衰老过程中的许多过程已经成为药物的目标。这一点很重要，因为将现有药物用于新的用途比从头开始开发新药要实际得多，因为药物开发的大量巨额费用已经得到了满足。衰老过程中出现问题的系统之一是确保身体中的细胞只做它们目前营养和总体压力水平所能承受的事情。这个系统非常古老，在衰老过程中似乎过于活跃，因此用药物降低其活性可以改善健康。有几种药物针对这个系统，因为它在导致老年人发生的一些疾病方面很重要。我们发现，该系统的一个特定部分，称为Ras途径，有许多药物，因为它在癌症中很重要，在衰老中起着关键作用，如果我们用一种名为trametinib的药物抑制它，那么我们可以延长果蝇和小鼠的健康寿命。因此，该项目的研究目的是了解曲美替尼如何防止衰老。我们将使用果蝇来做这件事，因为它们相对较短的寿命和出色的实验工具包意味着我们可以比小鼠更快地取得进展，但它们与哺乳动物有许多共同的特征，包括它们的衰老方式。它们被广泛用于衰老研究，并导致了许多关于衰老过程的关键发现。在衰老过程中，肠道的结构和功能明显恶化，我们已经做的工作表明，曲美替尼可以预防这种与年龄相关的衰退。我们将确定肠道中受药物影响的生物分子，并找出它们如何在衰老过程中保持肠道健康。我们还将确定曲美替尼治疗对其他组织的任何健康改善，包括神经肌肉功能，活动，昼夜节律，睡眠，肌肉和大脑衰老的分子标志物，脂肪体中的免疫功能和线粒体活性，以及肠道在诱导它们中的作用。我们所了解的将为未来针对关键过程的工作提供信息，首先是在小鼠中，我们希望最终是在人类中。为了确保我们有能力以最有效的方式推进这项研究，我们将两个具有互补专业知识和经验的研究实验室的努力结合起来，他们将密切合作，推动该项目的发展。

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