Studies of cellular processes involved in the control of nutrient signalling and their relevance to ageing

The dramatic increase of human life expectancy and the evidence from laboratory animal models suggest that the lifespan might not have a defined limit. Currently, the best-known means to slow down ageing and to extend the life of laboratory models are dietary restriction or treatments that mimic starvation. The opposite is also true and an excessive calorie intake, characteristic of the contemporary diet in the developed world, contributes to life shortening by promoting age-related diseases including diabetes, cancer and brain dysfunction.

While cellular response to nutrients is infinitely complex and involves a myriad of proteins and pathways, the master coordinator of the response is a signalling pathway called mTOR. This is evident from the fact that inhibition of this pathway by drugs is sufficient to induce a starvation-like response in the presence of nutrients. mTOR acts by promoting cellular synthetic processes, such as metabolism, protein synthesis and cell growth, with reducing degradative capacity of the cellular "self-eating" pathway called autophagy. Many of these processes have been shown to be relevant to ageing and inhibition of mTOR dramatically extends lifespan of every laboratory model from yeast to mice. Therefore, increasing our knowledge of how mTOR is regulated will provide us with better chances to fight age-related diseases and potentially to extend human lifespan in the future.

The proposed project will investigate cellular processes leading to mTOR activation in response to nutrients and will potentially discover the means to control these processes independently of nutrient availability. We will employ a range of molecular techniques, both in vitro and in the fruit fly, which is a powerful laboratory model best equipped for the proposed work. This integrative approach will allow identification of relevant players on the molecular level and will simultaneously test their role in physiological responses at the organismal level.

The outcomes of the research will make a major contribution to our understanding of the fundamental mechanisms underlying cellular nutrient response and will be of wide interest to researchers in the fields of cell signalling, protein degradation, metabolism and ageing. The findings will also potentially inform more applied research aimed towards developing new strategies to combat age-related diseases and to extend lifespan, which would have important implications for medicine.

mTOR and the degradative process autophagy, which it regulates, are the key cellular nutrient response mechanisms. They are vital for cellular physiology and are promising targets to extend healthy lifespan. Despite being in the spotlight of research in the last decade, the molecular details of the mechanisms regulating mTOR and autophagy in response to nutrients are still incomplete.

We will build on our recently published observations showing that mTOR and autophagy are sensitive to nutrient-driven changes of intracellular pH (pHi). The project will aim to identify membrane transporters affecting mTOR activity and processes downstream of mTOR in response to nutrients. We will identify transporters that are required for the observed by us changes in pHi. We will also test the hypothesis that changing pHi alone is sufficient to control mTOR activation independently of nutrient status. The role of identified in cell culture membrane transporters in the nutrient signalling regulation will be assessed on the organismal level using Drosophila as a model organism. The changes in Drosophila TOR (dTOR) activity will be correlated with pHi changes and with the consequences for cellular physiology and lifespan. As one of the targets of this project, we hope to be able to identify (a) long-living mutant(s) in which dTOR activity is uncoupled from the upstream nutrient signalling and is controlled by changes in pHi alone.

This integrative approach will not only expand our knowledge of the molecular mechanisms controlling TOR signalling and downstream processes but will also test the role of thus identified processes for organismal physiology. In addition to providing fundamental knowledge about nutrient-sensing mechanisms, our results may inform studies directed towards identification of new ways to correct perturbations of nutrient response control.

Subjects like mTOR and autophagy are not only populating the pages of the highest impact scientific journals but are also making headlines in the mass media as potential magic bullets that one day will delay ageing and the associated age-related diseases. While the potential is undeniable, we are still a long way away from the realisation of this goal as the molecular events regulating cellular nutrient responses are only starting to be uncovered. This project will provide more detail to the fragmented picture that we have at the moment and, as such, will generate an important body of scientific data. In our opinion, this area of research is underrepresented in the UK and our work will contribute to the country's continuous leadership in biomedical sciences.

The impact will also be generated at the level of local scientific infrastructure contributing to the development of Newcastle into a Science city. Newcastle is a centre of a relatively underdeveloped post-industrial region and its future prosperity relies on the transition to a science and technology-based economy. As a part of this process, the University's Campus for Ageing and Vitality was conceived with the idea to create a world-leading research centre in the field of ageing. The central part of this establishment is the Institute for Ageing and Health with its unique, multidisciplinary environment for research, training, engagement with public and business. The key element that would secure the success of this enterprise is excellence in basic research that would be expected to attract high technology companies and further local investment in healthcare.

Our project will contribute to this process by the following means. 1) It will enhance the infrastructure of the Institute by the establishment of a small research facility for Drosophila husbandry that will provide access to a short-lived genetically tractable model of ageing. 2) We will be working on scientific problems that are of common interest for many research groups in the Institute and this is likely to enhance interactions between the groups, to stimulate collaborations and to generate ideas. 3) It will produce world-class basic research helping to boost the reputation of Newcastle. 4) The results of our research have a potential to be applied to human health and therefore may become an intellectual property and to attract venture capital.

One of the more immediate outcomes of the project will be the professional training of the postdoc employed for the role of RA. He or she will have an opportunity to learn and improve a wide range of techniques in bioinformatics, molecular and cell biology as well as in vivo techniques. This will equip them well for a career as a scientist in academia or in a private sector. Similarly, the technical post will offer the person an opportunity to learn routine laboratory procedures and to develop organisational skills thus enhancing their future employability.

The project will also provide scope for public engagement having impact on better understanding and appreciation of basic science among the local community, the area in which the Institute's proactive approach has been recognised on different occasions. For example, we has been recently presented with a runner-up award for 'Greatest Delivery of Impact' in the BBSRC Excellence with Impact awards, in recognition of the influence at both a national and local level. A range of activities in public relations within the Changing Age initiative, the first of three Grand Challenges adopted by the University to affect wider socioeconomic change in areas in which it has research excellence, has been established in the past (for example, a Debating Matters competition on the topic of ageing) and we will actively participate in such future events.