Role of autophagy in the accumulation of defective mitochondria during ageing

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.

Ageing is one of the most important biomedical challenges of the 21st century. Understanding the underlying mechanisms that drive ageing will provide us with the tools to solve the "ageing problem". Two hallmarks of ageing are diminished autopaghic capacity and accumulation of defective mitochondria.

Autophagy is instrumental for recycling damaged cellular components including mitochondria. Accordingly mutations in genes encoding the autophagy machinery cause severe neurodegeneration. Similarly, mitochondria are essential to produce cellular energy, and mutations in mitochondrial genes cause devastating diseases. Unfortunately, how autophagy dysfunction contributes to the accumulation of respiratory-deficient mitochondria in ageing remains to be established.

We have uncovered a new mechanism where genetic or age-related disruption of autophagy causes accumulation of dysfunctional mitochondria. These mitochondria generate less ATP and more Reactive Oxygen Species (ROS). Interestingly respiratory complex I (CI) is selectively affected in both autophagy-deficient cells and old individuals. CI is the largest respiratory enzyme and main generator of ROS, triggering cell death via apoptosis during dysfunction.

Our research program will determine how decreased autophagic capacity contributes to the accumulation of respiratory-deficient mitochondria and the role of CI in ageing. Firstly, we will investigate how CI triggers apoptosis. Secondly, we will determine how disrupted autophagy leads to the accumulation of CI-deficient mitochondria and how this affects ageing. Finally, we will implement genetic, pharmacological and dietary interventions to boost autophagy and restore CI function, extending healthy lifespan. Our project will provide us with specific targets that can be manipulated with clinically approved drugs, allowing a swift translation of our findings.

Bioscience for health is one of the BBSRC strategic areas and within this area, extending population health span and increasing the independence of senior citizens is at the top of the list of priorities. The present consensus is that fundamental research directed at understanding the proximal causes of ageing is the most promising strategy to extend healthy lifespan. Our research program will operate under this paradigm determining the role autophagy and mitochondria play in ageing.

In the short term our research will have impact on ACADEMIC RESEARCHERS providing them with new knowledge about basic mechanisms of ageing. Our work will provide new tools and targets for drugs to CLINICIANS and HEALTH PROFESSIONALS working on ageing and degenerative diseases. A non-exclusive list includes: cancer, diabetes, immune diseases, Parkinson's disease and mitochondrial disease. In the long term, we aspire to develop treatments or interventions to prevent, delay or reverse ageing and extend healthy lifespan. Since both autophagy and mitochondria have been extensively studied, there are a number of clinically approved drugs (e.g. metformin, rapamycin or the bromodomain inhibitor I-BET 525762A).

Delaying ageing and age-related diseases will have an enormous IMPACT ON SOCIETY. One of the main problems the United Kingdom faces is the rising number of elderly people requiring more and more help to preserve their independence for longer. Alzheimer's disease, diabetes type II, sarcopenia, cancer or age-related cataracts are just a few examples of diseases and conditions that increase frailty and reduce the quality of life of the aged population. Finding a way to boost cellular energy levels in elderly citizens will contribute to this strategy by reducing frailty, extending their independence and dramatically reducing health care costs.

INDUSTRY will benefit from the possibility to perform drug screens in the in vivo and ex vivo models we will generate. Identifying novel or repurposing existing drugs that can prevent, delay or reverse the accumulation of dysfunctional mitochondria will open new markets, significantly increasing the revenue of the pharmaceutical industry. Ageing and age-related diseases will be a highly profitable market for pharmaceutical industry in the future. Our work will generate a list of drugs to be tested in higher model organisms or in humans. We will consider opportunities for commercialization in collaboration with the Newcastle University business development office who will evaluate the potential translational impact and industrial interaction of our research.

To boost the impact of our work, we will publish open access articles in high quality, broad readership journals and communicating our research via oral and poster presentations at scientific meetings before publication. We will take advantage of the websites of Newcastle University (including our own institute and laboratories), as well as social media (Twitter, Facebook) to actively promote our findings. The Newcastle University Press Office will be involved to ensure our findings are disseminated to the wider public as much as possible. Furthermore, we will generate opportunities throughout the project to disseminate and discuss our work with the general public, for whom the topic of healthy ageing is both accessible and interesting.

One of the most immediate impacts will be the CAREER DEVELOPMENT of the PDRA, RT and students who will learn and develop laboratory, analytical and writing skills, all of which are required for a successful career in science and to tackle age-related problems. Our cutting-edge research involving a number of latest TECHNOLOGIES will also train new SKILLED RESEARCHERS in UK.