Investigating the mechanisms by which amino acid balance and reduced TOR signalling improve healthy lifespan

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.

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.

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.