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

Lead Research Organisation: Newcastle University
Department Name: Inst for Cell and Molecular Biosciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.
 
Description We have identified a mechanism leading to deregulated nutrient sensing and autophagy in cell senescence. This is important as it identifies potential ways to selectively eliminate senescent cells. We also found evidence for this mechanisms in vivo in mouse models of ageing. Several papers have been published where we described our findings.
Exploitation Route Our findings will be of interest to the academic community as well as will potentially pave the path to new interventions in age-related diseases - it has been demonstrated by others that selective removal of senescent cells improves tissue homeostasis and delays age-related decline. Our data can inform new interventions to achieve the goal of healthspan extension.
Sectors Healthcare

 
Description We have published a paper in Nature Communications (2018) which was covered by press release and featured in several internet news agencies and blogs. It was been used to argue for lifestyle changes required to lead long healthy life. Our publications on new mechanisms underlying senescence in vitro and in vivo (J Cell Biol 2017, Aging Cell 2018 and Biogerontology 2019) have attracted interest from industry and led to a new collaboration with Procter & Gamble (currently supported by BBSRC CASE PhD studentship) where we are investigating novel approaches to prevent skin senescence.
First Year Of Impact 2018
Sector Healthcare
Impact Types Societal

 
Description BBSRC Project Grant
Amount £323,785 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description CASE PhD studentship with P&G
Amount £170,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2020
 
Description Identification of Parkinson disease-specific mitochondrial pathogenesis for disease-modifying therapy
Amount £93,243 (GBP)
Organisation Japan Society for the Promotion of Science (JSPS) 
Sector Public
Country Japan
Start 02/2019 
End 01/2022
 
Description Identification of active ingredients targets to prevent skin ageing
Amount £98,212 (GBP)
Funding ID BB/R506345/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description MRC PhD studentship
Amount £90,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2015 
End 09/2019
 
Description Role of apoptosis in persistent PCV2 infection and replication promoted by oxidative stress-induced autophagy
Amount £12,000 (GBP)
Funding ID IEC\NSFC\170125 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 04/2020
 
Description Understanding the role of autophagy in the pathogenesis of AMD using a patient specific iPSC model
Amount £169,845 (GBP)
Organisation Macular Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 04/2020
 
Description Dr Joao Passos 
Organisation Newcastle University
Department Newcastle University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We work on several joint projects, including the role of autophagy in DNA damage repair and the mechanisms of cell senescence
Collaborator Contribution Dr Passos and his lab provide expertise in cell senescence
Impact To date we have co-authored 5 research articles and continue working together while co-supersiving one PhD student.
Start Year 2011
 
Description Prof Penny Lovat 
Organisation Newcastle University
Department Newcastle University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We started investigating the role of mTOR signalling and its deregulation in melanoma
Collaborator Contribution Dr Lovat and her team provide expertise and resources including clinical samples
Impact Published a paper in J Cell Biol in 2017. Two joint grant applications, one to Newcastle Hospital Trust (JRES programme) and one to British Skin Foundation, both successful. A new investigator award from British Skin Foundation to my postdoc Bernadette Carroll has been successful, Dr Lovat and I are mentors on the grant. Bernadette has now obtained an independent fellowship at Bristol University and continues collaborating with Dr Lovat and me.
Start Year 2012
 
Description 1st Meeting on Vesicular Biology, Coimbra, Portugal 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I gave a Keynote Lecture at this meeting organised by the European COST Action Proteostasis
Year(s) Of Engagement Activity 2017
 
Description 8th Annual Alliance for Healthy Aging Conference, Groningen, the Netherlands 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk at the international conference
Year(s) Of Engagement Activity 2017
 
Description An invited talk - DKFZ, Heidelberg, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk to staff and students, scientific discussions and development of future collaborations
Year(s) Of Engagement Activity 2018
 
Description Cell Detectives event at the Newcastle Centre for Life 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The PI and members of the laboratory were involved in a research exhibition at the Newcastle Centre for Life with approximately 500 children and parents attending the event
Year(s) Of Engagement Activity 2019
 
Description Center for Healthy Aging, University of Copenhagen, Denmark 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I have been invited for a day of meetings and gave a seminar with a view to establish new collaborations
Year(s) Of Engagement Activity 2017
 
Description Invited talk, Beatson Institute, Glasgow, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I gave an invited talk entitled Mechanisms of amino acid sensing by mTOR and their deregulation in senescence followed by group discussions and individual meetings and engaged in networking with groups of students with an interested in ageing and senescence.
Year(s) Of Engagement Activity 2016
 
Description Invited talk, Cardiff University, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I was invited to give a talk on Amino acids and regulation of mTOR, which was well received and followed by discussions and led to new collaborations with groups outside my immediate are of research.
Year(s) Of Engagement Activity 2016
 
Description Invited talk, Institute for Metabolic Science, Cambridge University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I gave a talk entitled Mechanisms of amino acid sensing by mTOR to the scientists, clinicians and students followed by general questions and small group discussions.
Year(s) Of Engagement Activity 2016
 
Description MRC Festival of Medical Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Members of the laboratory were involved in the organisation and running the MRC Festival of Medical Science in collaboration with the Newcastle Falcons Community Foundation where approx 130 local school pupils attended and learned about our scientific activities
Year(s) Of Engagement Activity 2017
 
Description Max Plank Institute on Aging, Cologne, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Invited talk entitled "Mechanistic insights into mTORC1 and autophagy during ageing"
Year(s) Of Engagement Activity 2017
 
Description Nanjing University, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I have been invited to visit Nanjing University in China for a week where I had a number of meetings with local academics and students and gave a seminar
Year(s) Of Engagement Activity 2017
 
Description Press release on our recent publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Our press release was covered by several news agencies.
Year(s) Of Engagement Activity 2018
URL https://www.ncl.ac.uk/press/articles/archive/2018/01/howdidweevolvetolivelonger/
 
Description Public Session on ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As part of the research conference on Redox Biology and Ageing the PI co-organised a Public Session where a lay audience (approx. 100) with an interest in the Biology of Ageing was provided with the opportunity to ask questions from the leaders in the field.
Year(s) Of Engagement Activity 2019
URL https://www.eventsforce.net/biochemsoc/frontend/reg/thome.csp?pageID=20523&eventID=48&traceRedir=2
 
Description The Final COST Action Proteostasis Meeting, Athens, Greece 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact An invited talk entitled "Evolution of selective autophagy as a mechanism of oxidative stress response".
Year(s) Of Engagement Activity 2017