Role of autophagy in the accumulation of defective mitochondria during ageing

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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.