Mechanisms mediating the anti-ageing effects of trametinib.

人们的寿命比过去长了很多。从大约19世纪50年代开始，由于生活条件的改善和更好的医疗保健，英国的人类存活率稳步上升。我们成功地延长了寿命，这是文明的标志，但它也伴随着不利的一面。生命的健康时期‘健康寿命’没有跟上存活率的增加，在生命末期有越来越多的残疾和疾病时期，特别是在妇女中。老年人对身体和医疗挑战的适应能力也较差，服用新冠肺炎后死亡率的上升已经明显地证明了这一点。因此，人们越来越需要找到让人们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加任何年龄的人的健康和机能，并有助于防止老年衰退。然而，可以取得的成果是有限的，科学研究的目的是确切地了解老龄化过程中出现的问题，以期通过药物来瞄准老龄化过程本身。近年来，我们对衰老的潜在过程学到了很多，事实证明，这些过程具有显著的可塑性。在实验室动物中，衰老可以通过药物来减缓，药物可以在动物变老时保持健康，并保护它免受随着年龄增长而来的疾病。动物和人类的衰老过程相似。此外，衰老过程中的许多过程已经是药物的靶标。这一点很重要，因为将现有药物转移到新用途比从零开始开发新药物要实际得多，因为药物开发的大量巨额费用已经到位。在衰老过程中出现问题的系统之一是致力于确保体内细胞只做它们能承受的事情，考虑到它们目前的营养和一般压力水平。这一系统非常古老，在衰老过程中似乎过于活跃，因此用药物抑制其活动可以改善健康。有几种药物针对这一系统，因为它在导致一些发生在老年人身上的疾病方面很重要。我们已经发现，系统的一个特殊部分，称为RAS途径，有许多药物，因为它在癌症中很重要，在衰老过程中发挥着关键作用，如果我们用一种名为曲美替尼的药物抑制它，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预防衰老。我们将使用果蝇来实现这一点，因为它们相对较短的寿命和优秀的实验工具包意味着我们可以比在老鼠身上取得更快的进展，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，肠道的结构和功能会明显恶化，我们所做的工作已经表明，曲美替尼可以防止这种与年龄相关的下降。我们将识别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、肌肉和大脑老化的分子标记物、脂肪体中的免疫功能和线粒体活动，以及肠道在诱导它们方面的作用。我们所学到的将为未来针对关键过程的研究提供信息，首先是在老鼠身上，最终，我们希望是在人类身上。为了确保我们有能力以最有效的方式推进这项研究，我们正在结合两个拥有互补专业知识和经验的研究实验室的努力，他们将密切合作，推动该项目。

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.