Amino acid sensing by mTOR: molecular mechanisms and their deregulation in ageing

This project sets out to ask and understand some fundamental questions about how nutrients are recognised by our cells. We will be studying mTORC1, the key signalling pathway allowing the cell to detect available nutrients, most importantly amino acids, building blocks for all the proteins in our bodies. Functional mTORC1 is essential to drive growth of our cells and tissues , however it can have negative impact in older age and interventions such as calorie restriction which suppress this pathway have been shown to extend lifespan and prevent age-related diseases. We are aiming to understand how amino acids are sensed by the mTORC1 machinery and how this process becomes disrupted with age.

To investigate molecular processes leading to the activation of mTORC1 by amino acids we will identify components of the mTORC1 machinery which can recognise amino acids and activate the pathway. Our preliminary data allowed us to narrow the search for the molecular sensor of one of the main activators of mTORC1, the amino acid arginine. These and other candidates will be interrogated during the project. These studies will also help us to better understand how mTORC1 is able to detect the presence of all other essential amino acids inside the cell.

As we age many cells in our bodies become old too, and exist in a state of so-called cellular senescence. These cells can influence neighbouring tissue and promote its ageing process. We have now found that in cellular senescence mTORC1 is no longer tightly regulated by amino acids and does not turn off during starvation. We speculate that this defect in mTORC1 contributes to cellular senescence and overall tissue ageing and we aim to determine the causes and consequences of this age-associated defect in-depth. We will investigate how mTORC1 becomes deregulated and how it may promote senescence of cells and tissues.

This project will take us one step closer to being able to manipulate mTORC1 and its deregulation in ageing. Our hope is that the project will inform further applied research and will have important implications for medicine.

Mammalian (or mechanistic) Target of Rapamycin (mTOR) signalling pathway is the key mediator of cellular responses to nutrients. mTOR complex 1 (mTORC1) is activated by amino acids and growth factors and in turn stimulates cell growth and proliferation. In this project we aim to identify molecular mechanisms governing the sensing of amino acids by mTORC1 and determine the contribution of their deregulation to cellular and organismal senescence and ageing.

Our preliminary data indicate a novel mechanism by which the amino acid arginine, a potent inducer of mTORC1, acts as a permissive factor for the growth factor-dependent input into the pathway. However it remains unclear how arginine, or indeed other amino acids, are sensed by the mTORC1 machinery. This proposal aims to identify the molecular sensor of arginine which, in turn, will be extrapolated to search for the mechanisms allowing mTORC1 to sense the entire complement of essential amino acids. Importantly, we have also found that amino acid-dependent regulation of mTORC1 is lost when cells become senescent and we hypothesise that this has important implications for cellular and organismal senescence. We will investigate both the causes and consequences of deregulated mTORC1 signalling using established in vitro and in vivo models.

While inhibition of mTORC1 by drugs or starvation has been shown to slow ageing and reduce the burden of age-related diseases in laboratory models, more targeted interventions are required in order to exploit this pathway for health benefit in humans. In addition to providing fundamental knowledge about nutrient-sensing mechanisms, data derived from this proposed programme of work will illuminate novel approaches to correct senescence-associated perturbations in mTORC1 signalling.

The project described here will have impact in three main areas: 1) ageing individuals, their carers and dedicated health professionals. 2) Scientists studying ageing process or nutrient response pathways implicated in ageing, 3) Academics and clinicians studying age-related diseases. To facilitate impact of our work we will publish our findings as open access articles in high impact broad readership journals. The data generated during the project will also be publicized in scientific meetings by oral and poster presentations.
Impact will also be generated at the level of local scientific infrastructure by contributing to the development of Newcastle as a strategic centre of the North East region. The new Newcastle University Institute for Ageing (until recently Institute for Ageing and Health) with its unique, multidisciplinary environment for research, training, plus engagement with public and business is a central cog in both the city and University's plans for transformation. The key element that would secure the success of this enterprise is excellence in basic research that attracts high technology companies and promotes further local investment in biosciences and healthcare and this grant will help to maintain the position of the Institute as a leader in the field. Our project will contribute to this process by several means. 1) 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. 2) It will produce world-class basic research helping to boost the reputation of Newcastle. 3) The results of our research have a potential to be applied to human health and therefore may become intellectual property and attract venture capital. Although the project is conceived as a fundamental study and commercialization is not our current priority, will continually review our data and its implications for potential translational impact and industrial interaction.
The project will also provide scope for public engagement having impact on better understanding and appreciation of basic science among the local community. This is an area in which the Institute's proactive approach has been recognised on different occasions including a runner-up of the 'Greatest Delivery of Impact' in the BBSRC Excellence with Impact awards, in recognition of the influence at both 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 ageing). The Institute is also actively engaging with school children by allowing access to the research infrastructure for educational purposes. Thus labs of the applicants have been involved in the past, and will continue to participate, in the University's Leading Edge programme (offering groups from local schools invaluable experience in laboratory projects), local and national Science festivals etc. Access to the Institute's scientific equipment is always the highlight of such projects and leaves an important impact on children's development and choice of future career. The University, Institute and laboratories websites as well as social media will also be actively used to highlight our findings and the University press office is well set up to disseminate the most exciting findings to the national media.
One of the more immediate outcomes will be the professional training of the staff and students involved in the described project. They 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.