Investigating the mechanisms by which amino acid balance and reduced TOR signalling improve healthy lifespan
Lead Research Organisation:
University College London
Department Name: Genetics Evolution and Environment
Abstract
It is well known that the UK, and many other developed countries, have an ageing population. While increasing life expectancy is a major triumph of medical science, it also poses challenges at a social and economic level. In particular, older individuals are now living long enough to experience the crippling effects of age-related diseases, such as Alzheimer's disease, osteoporosis and cancer. As well as the obvious burden on the individual sufferer, these problems place strain on families, care-givers and the healthcare system. There is thus a strong incentive to investigate new ways to improve the health of ageing individuals. Within the last decade of research into ageing, there have been exciting new findings about the genes involved in aged health. Remarkably, it has been discovered that mutating some genes can extend the lifespan of an organism. Importantly, this extended life is accompanied by improved health. This shows that ageing can be genetically manipulated, and that by studying the action of these genes, we can find ways to improve health into old age. Furthermore, these genes are evolutionarily conserved, which means that laboratory animals can be used to make discoveries about the process of ageing in humans. Interestingly, the functions of these genes that affect lifespan are normally associated with how organisms respond to changes in their nutritional environment, indicating that nutrition is an important focal point for healthy ageing research. 75 years ago, an intervention known as dietary restriction (DR), or calorie restriction, was discovered to extend the lifespan of rats. DR involves moderately restricting food availability to an animal compared with what it would eat by choice. The beneficial effect of DR on lifespan has since been observed in numerous organisms from yeast through to primates, indicating it too is evolutionarily conserved. Importantly, it also appears to improve healthspan, indicating it works via delaying ageing itself. In this proposal, I intend to examine the overlapping effects of both DR and gene mutations that extend life. There is very little work to date on combining these interventions, which has mainly been due to their complexity. However, new discoveries from my work on the effect of specific nutrients on longevity, in combination with new findings about the genes involved in nutrient sensing, offers a new opportunity to study their interaction in a well defined manner. This knowledge and the resources available to me at the Institute of Healthy Ageing at University College London, offer an exciting opportunity to significantly advance our knowledge about the molecular causes of ageing. Furthermore, by studying further how nutrients affect physiology, this project offers information relevant to many levels of our understanding about diets and health: from appetite control to the effects of dietary balance on immune function.
Technical Summary
Both moderate dietary restriction (DR) and nutrient signaling pathway mutations extend lifespan in a range of organisms. We have recently found that nutrient amino acid balance is critical for the beneficial effects of DR in Drosophila which is consistent with findings in mice. In other recent research, a new component of TOR signaling in response to amino acids has been discovered: the Rag GTPases. We thus have a new combination of tools to study the molecular events from nutritional balance to enhanced longevity via the amino acid specific signaling activity of TOR. I propose to study the phenotypic and molecular responses to combining alterations in dietary amino acid balance with changes in Rag protein activity. In particular, I propose to characterize the tissue-specific, whole-transcriptome effects of combining these interventions. By combining these molecular data with the observed phenotypes under the same conditions, we will seek candidate molecular mediators of the responses for further testing. One group of evolutionarily conserved proteins that may be involved is the GATA family of transcription factors. In yeast and mosquitoes these mediate a transcriptional output of TOR and in worms they have been shown to alter lifespan. The connection from dietary amino acids to TOR to GATA transcriptional output has to date remained unexplored. I propose that this constitutes at least part of the important molecular changes required for enhanced healthy lifespan.
Planned Impact
The outcomes from this work will be of relevance for both scientists and the general public. The focus in communicating these outcomes will be on clarification and accuracy and will be aimed at reaching as many people as possible. Not only for the sake of informing people better about ageing research in general, but also to attract the interest of young people into science. This is currently of particular importance as innovation is likely to be key in determining Britain's future sustainable economic success. Scientific and media communications The field of ageing and nutrition has recently received a great deal of interest and attention in the scientific arena and popular press, meaning we have the realistic opportunity to publish this work in the highest impact journals (eg our recent articles in Nature and Cell Metabolism) and communicate our findings to the public through mainstream media outlets (eg our recent coverage in New Scientist and the BBC news). These media activities will be undertaken in conjunction with UCL media relations that maintain a database of experts and offer advice and help for preparing and distributing press releases. They also provide regular opportunities to speak with the press through a variety of media formats that to date have involved the applicant in radio, podcast and television interviews. Web-based communication Since most people turn to the web for information, we will take an active role in correcting and creating appropriate Wikipedia pages on the effects of nutrition on ageing. At the time of writing, the Wikipedia entry for Calorie Restriction contains more than 12 factual errors, some of which could lead readers to unjustifiably alter their dietary practices. We will also create a plain English web page front for the laboratory website that explains our important findings and their context, at the point of publication. This will be overseen by an expert writer who specializes in popularizing science discoveries using accessible English. International collaboration This work will benefit from international collaborations already held by the PI with Prof Linda Partridge (Max Planck, Cologne) and Prof Steve Simpson (Sydney University). The findings of the work in this proposal will complement the work in these collaborations and in the UCL Institute of Healthy Ageing in general. Thus, the participation of these collaborators in my research will raise the international profile of the work as they are often sought for their scientific opinions by the media. Long term benefits It is envisaged that society generally will benefit from research on the mechanisms of ageing, both in terms of lessening individual suffering, but also in alleviating the associated social and financial burdens of caring for the elderly. Other outcomes affecting our knowledge of nutrition on adult physiology are also likely to inform better policy making. This is especially true in the face of the current obesity crisis and various unfounded claims in the media about 'superfoods'. The data are likely also to contribute knowledge on the molecular basis of appetite control that will be invaluable in developing rational dietary management strategies. Moreover, since dietary interventions do not face the challenging time scales, cost and testing constraints involved in drug development, it is reasonable to expect that the discoveries from our work can be rapidly transferred to testing in higher model organisms and then to humans. Where possible, we will seek to exploit this possibility through our current collaborators as well as potential partnerships with industry. Our most likely partners for this work will be Nestle and the Dutch Sugar Manufacturers (DSM), each of which have an active research interest in diet and health.
People |
ORCID iD |
Matthew Piper (Principal Investigator) |
Publications
Afschar S
(2016)
Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila.
in Proceedings of the National Academy of Sciences of the United States of America
Alic N
(2012)
Detrimental effects of RNAi: a cautionary note on its use in Drosophila ageing studies.
in PloS one
Camus MF
(2019)
Sex-specific transcriptomic responses to changes in the nutritional environment.
in eLife
Dobson AJ
(2018)
Tissue-specific transcriptome profiling of Drosophila reveals roles for GATA transcription factors in longevity by dietary restriction.
in NPJ aging and mechanisms of disease
Dobson AJ
(2017)
Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets.
in Cell reports
Leitão-Gonçalves R
(2017)
Commensal bacteria and essential amino acids control food choice behavior and reproduction.
in PLoS biology
Piper M
(2013)
Preparation of a holidic medium for Drosophila melanogaster
in Protocol Exchange
Piper MD
(2014)
A holidic medium for Drosophila melanogaster.
in Nature methods
Description | We have been studying the link between nutritional balance and lifespan, using the fruit fly as a model organism. We previously found that the proportion of protein in the diet is a powerful modulator of lifespan. On the technical side, we developed a new tool for research on diet and ageing: a fully defined synthetic diet for flies and software to automate the laborious task of counting egg laying of female flies. This enables us to have fine-scale control over all aspects of the fly diets and increase the throughput of conditions tested for effects of nutrition on adult fly health. On the biology side, we recently discovered that a drug called rapamycin, which is known to block how the body senses protein, can protect flies against the lifespan shortening effects of a high protein diet. With more detailed studies we find an evolutionarily conserved family of genes involved in controlling gene expression are key players. We think these findings will be widely applicable since both high protein and rapamycin are known to affect lifespan in a variety of organisms, pointing to an evolutionarily conserved mechanism. |
Exploitation Route | We are now examining the molecular mechanisms by which rapamycin interacts with high dietary protein to confer longer life. With these details we aim to find more specific interventions that promote healthy longevity and understand in greater depth how protein interacts with long-term physiology. |
Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
Description | The impacts of this research are hard to quantify. There is no directly measurable effect on policy or public activities that I am aware of. All impacts will be indirect effects of public lectures, exhibitions and debates I have been involved in (reported in engagement activities). |
First Year Of Impact | 2012 |
Sector | Education |
Impact Types | Cultural |
Description | ARC Future Fellowship |
Amount | $850,000 (AUD) |
Funding ID | FT150100237 |
Organisation | Australian Research Council |
Sector | Public |
Country | Australia |
Start | 03/2016 |
End | 04/2020 |
Description | Royal Society Research Fellow grant |
Amount | £138,100 (GBP) |
Funding ID | RG110303 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2012 |
End | 03/2015 |
Description | Royal Society University Research Fellowship |
Amount | £726,751 (GBP) |
Funding ID | UF100158 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2016 |
Description | UCL Crucible Centre PhD studentship |
Amount | £20,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Department | Lifelong Health and Wellbeing (LLHW) |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2011 |
End | 01/2015 |
Description | Wellcome Trust Peoples award |
Amount | £8,000 (GBP) |
Funding ID | 098831/Z/12/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2012 |
End | 07/2012 |
Title | Holidic medium for Drosophila melanogaster |
Description | the first fully defined chemical synthetic diet for fruit flies that supports lifespan and fecundity to the same extent as the flies' natural yeast-based food. |
Type Of Material | Technology assay or reagent |
Year Produced | 2008 |
Provided To Others? | Yes |
Impact | For the first time, people are able to dissect the nutritional components in the diet responsible for influencing any behaviour or phenotype. We published this method in Nature Methods: Piper et al, 2014 |
URL | http://www.nature.com/protocolexchange/protocols/2829 |
Title | tissue-specific RNAseq of DR v rapa |
Description | RNAseq data for multiple tissues of female flies kept on one of three diets (DR, DR+ess AA, DR+ess AA+rapamycin). These represent extension of lifespan either by diet manipulation (reomval of AAs) or by drug (rapamycin). Both are anticipated to work via the same mechanisms and so the overlap of gene expression caused by these interventions is of interest. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | academic referencing and use (one citation on google scholar and another I know if in preparation). Both have accessed the data set and used for comparison. |
URL | https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6584/ |
Description | Nutrient control of circadian rhythms |
Organisation | University of Michigan |
Country | United States |
Sector | Academic/University |
PI Contribution | providing a nutritionally explicit platform in which to assess how diet modifies circadian rhythms |
Collaborator Contribution | assessing fly activity/behaviour and working at the underlying molecular mechanisms |
Impact | Publication: Piper et al, 2014, Nature Methods |
Start Year | 2010 |
Description | Nutrient control of feeding behaviour in Drosophila |
Organisation | Champalimaud Foundation |
Department | Champalimaud Centre for the Unknown |
Country | Portugal |
Sector | Academic/University |
PI Contribution | We have generated an experimental platform within which precise nutritional manipulations can be made for assessing the impact on Drosophila satiety |
Collaborator Contribution | The collaborators are behavioural neuroscientists. They assess the neuronal circuitry underlying aspects of nutrient-specific satiety |
Impact | Publication: Nature Methods, 2014, Piper et al. |
Start Year | 2010 |
Description | Nutrient control of lifespan |
Organisation | Sichuan Agricultural University |
Country | China |
Sector | Academic/University |
PI Contribution | intellectual input |
Collaborator Contribution | design and undertaking experiments |
Impact | Publication: Wu et al, Sexual dimorphism in the nutritional requirement for adult lifespan in Drosophila melanogaster, Aging Cell, https://doi.org/10.1111/acel.13120 |
Start Year | 2012 |
Title | QuantiFly |
Description | An image analysis tool, based on a machine learning algorithm, that can be trained to automatically count fly eggs in a picture. |
Type Of Technology | Software |
Year Produced | 2015 |
Open Source License? | Yes |
Impact | To be determined. It is the subject of an article to be published in PLoS One (accepted April 2015) |
URL | https://github.com/dwaithe/quantifly |
Title | VideoTagger - open source software for visualising and labelling video footage |
Description | Open source software for visualising, scanning and labelling long term video footage of any format. The applications are limited by what footage you can get into it. It allows collaborative labelling so that efficiency in expert time is gained. It also facilitates machine learning plugins for automated action detection. |
Type Of Technology | Software |
Year Produced | 2018 |
Open Source License? | Yes |
Impact | too recent to assess |
URL | https://www.biorxiv.org/node/83724.full |
Description | British Science Association cafe scientifique |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | A pub night for the general public to listen and engage with scientists about their research. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2012 |
Description | Healthy Ageing exhibit at the Royal Society Summer science exhibition, 2012 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | I led a team to present our research to understand the mechanisms of ageing to the general public at the Royal Society Summer science Exhibition. During the week of the exhibition, the exhibit was seen by thousands of secondary school children and various other members of the general public. We generated communication material in the form of posters and interactive age-simulation games no actual impacts realised to date |
Year(s) Of Engagement Activity | 2012 |
Description | Insect Nutrition workshop, Bonn |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Invited speaker at the second international insect nutrition workshop, Bonn, Germany. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2013 |
Description | Royal Society Cafe Scientifique |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | A chance for members of the public to come and discuss areas of research with a scientist over a drink no actual impacts realised to date |
Year(s) Of Engagement Activity | 2013 |
URL | https://royalsociety.org/events/2013/ageing-cafe/ |
Description | Talk/discussion panel at World Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | gave a talk and part of a discussion panel at the World Science Festival in Brisbane, Australia. The focus of the discussion was the effects of nutrition on ageing. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.worldsciencefestival.com.au/program/events/chasing-longevity-quest-longer-life/ |
Description | UCL Lunch hour lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | UCL hosts a series of research talks open to the general public. vodcast - available through the UCL Lunch hour lecture youtube channel no actual impacts realised to date |
Year(s) Of Engagement Activity | 2013 |
Description | Wellcome Trust packed lunch |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The Wellcome Collection host a series of lunchtime interview / talks for the general public to discuss research and what the daily life of a scientist is like. These are open to the general public and podcasted. There were more than 100 people in the audience and the podcast is available through iTunes. further public outreach opportunities |
Year(s) Of Engagement Activity | 2012 |
URL | http://www.wellcomecollection.org/whats-on/events/packed-lunch-podcast/diet-and-ageing.aspx |
Description | XXIV International Congress of Entomology |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research or patient groups |
Results and Impact | Invited speaker at the International Congress of Entomology, South Korea no actual impacts realised to date |
Year(s) Of Engagement Activity | 2012 |
Description | public lecture (Brighton Science Festival) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk sparked discussion and debate. Resulted in a putative collaboration between my lab and one working on breast cancer and nutrition. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.brightonscience.com/events/big-science-sunday/ |