Role of autophagy in the accumulation of defective mitochondria during ageing

英国人口逐渐老龄化是我们的社会在21世纪将面临的最严重的问题之一。患有年龄相关疾病的人数的增加给NHS带来了沉重的负担，并有可能使世界上最好的医疗保健系统之一崩溃。解决“老龄化问题”的最简单和最具成本效益的办法是想办法延缓老龄化的速度，延长健康寿命，延缓与年龄有关的疾病的发生，从而延长个人完全独立的时间。为了延缓衰老，我们必须充分了解推动衰老的复杂机制以及它们之间的联系。线粒体是细胞的动力源，产生大部分ATP，这是维持细胞运转所需的细胞货币。就像在任何其他工厂一样，线粒体会产生有害的废物，需要不时地进行维护。自噬是细胞实现这一目标的主要方式。它负责移除和回收受损的成分，以保持细胞，包括线粒体，处于最佳工作条件。随着年龄的增长，自噬完成这一任务的能力会下降。与此同时，受损的线粒体也会积累，导致ATP的枯竭，从而导致细胞死亡和神经退化，并与帕金森氏症或阿尔茨海默病等疾病有关。我们发现了一种新的机制，将与年龄相关的自噬效率降低与缺陷线粒体的积累联系起来。重要的是，这种机制可以针对已经在临床使用的药物。当自噬被中断时，无论是遗传上的还是在衰老过程中，呼吸复合体I(CI)-线粒体产生能量所需的呼吸复合体I(CI)-停止正常工作，并开始以自由基的形式产生异常高的有害废物，可导致细胞死亡和加速衰老。我们发现，绕过CI或恢复其功能可以防止细胞死亡并延长寿命。我们将开发一项研究计划，利用体外和体内模型相结合的方式，建立自噬和线粒体在衰老过程中的联系。首先，我们将研究如何在自噬缺陷细胞中诱导细胞死亡，恢复CI功能和挽救细胞死亡。其次，我们将利用果蝇强大的遗传学来找出自噬的丧失如何导致受损线粒体的积累，并测量它对衰老过程的影响。最后，我们将提高自噬和/或线粒体功能，以询问老年人绕过CI是否足以延缓衰老。到这个项目结束时，我们将确定推动衰老的关键机制，并可以针对已经获得临床批准的治疗方法。

The progressive ageing of the UK population is one of the most serious problems our society will face during the 21st century. The increase in the number of people suffering from age-related diseases is a heavy burden on the NHS and threatens to collapse one of the best health care systems in the world. The simplest and most cost effective solution to the "ageing problem" is to find ways to delay the rate of ageing, extending healthy lifespan, delaying the onset of age-related diseases and therefore extending the time an individual can remain fully independent. To delay ageing, we must fully understand the complex mechanisms that drive it and how they are connected. Mitochondria are the powerhouses of the cell, generating the majority of ATP, the cellular currency required to keep cells going. As in any other factory, mitochondria generate harmful waste and require maintenance from time to time. Autophagy is the main way that the cell achieves this. It is responsible for removal and recycling of damaged components to keep the cell, including mitochondria, in optimal working condition. With age, the capacity of autophagy to do this declines. At the same time damaged mitochondria also accumulate, causing depletion of ATP, which leads to cell death and neurodegeneration and is associated with diseases such as Parkinson's or Alzheimer's disease.We have found a new mechanism that connects the age associated reduction in autophagy efficiency and the accumulation of defective mitochondria. Importantly this mechanism can be targeted with drugs that are already in use in the clinic. When autophagy is interrupted, either genetically or during aging, respiratory complex I (CI) which mitochondria need to produce energy, stops working properly and starts to generate an abnormally high amount of harmful waste in the form of free radicals which can cause cell death and accelerate ageing. We have discovered that by-passing CI or restoring its function prevents cell death and extends lifespan. We will develop a research program that will use a combination of in vitro and in vivo models to establish the connection between autophagy and mitochondria in ageing. Firstly, we will investigate how cell death is induced in autophagy-deficient cells, restoring CI function and rescuing cell death. Secondly, we will use the powerful genetics of the fruit fly to find out how loss of autophagy causes the accumulation of damaged mitochondria and measure it effect on the ageing process. Finally, we will boost autophagy and/or mitochondrial function to ask if by-passing CI in old individuals is enough to delay ageing. By the end of this project, we will have identified key mechanisms that drive ageing and can be targeted with therapies which are already clinically approved.