Mechanisms mediating the anti-ageing effects of trametinib.

Lead Research Organisation: University College London
Department Name: Genetics Evolution and Environment

Abstract

People are living a lot longer than they used to. From about the 1850s human survival increased steadily in the UK, as a result of improvements in living conditions and better medical care. It is a sign of civilisation that we have succeeded in increasing the length of our lives, but it is coming with a downside. The healthy period of life 'the healthspan' has not kept up with the increase in survival, and there is a growing period of disability and illness at the end of life, particularly in women. Older people are also less resilient to physical and medical challenges, as has become painfully obvious with their increased death rate with Covid-19. There is therefore a growing need to find ways of keeping people in better health later in their lives.

Increased exercise and improved diet can often increase health and function in people of any age, and can help to protect against old-age decline. However, there are limits to what can be achieved, and scientific research is being directed to understanding exactly what goes wrong during ageing, with a view to targeting the ageing process itself with drugs. We have learned a lot about the underlying processes of ageing in recent years, and they turn out to be remarkably malleable. In laboratory animals, ageing can be slowed down by drugs, which can keep the animal healthy as it gets older, and protect it against the diseases that come with advancing age. The ageing process is similar in animals and humans. Furthermore, many of the processes at work during ageing are already targets of drugs. This is important, because it is a lot more practical to divert an existing drug to new uses than it is to develop a new drug from scratch, because a lot of the huge expense of drug development has already been met.

One of the systems that goes wrong during ageing is devoted to making sure that the cells in the body only do what they can afford, given their current nutritional and general stress level. This system is very ancient, and it seems to be too active during ageing, so that tamping down its activity with drugs can improve health. Several drugs target this system, because it is important in causing some of the diseases that occur in older people. We have found that a particular part of the system, called the Ras pathway, for which there are many drugs because it is important in cancer, plays a key role in ageing, and if we suppress it with a drug called trametinib then we can extend the healthspan of fruitflies and mice.

The aim of the research in this project is therefore to understand how trametinib protects against ageing. We will do this using fruitflies, because their relatively short lifespan and excellent experimental toolkit mean we can make faster progress than in mice, yet they share many features with mammals, including the way that they age. They have been extensively used for research into ageing, and have led to many of the key discoveries about the ageing process. During ageing there is a marked deterioration in the structure and function of the intestine, and work that we have done already suggests that trametinib can prevent this age-related decline. We will identify the biological molecules in the intestine that are affected by the drug, and find out how they keep the gut healthy during ageing. We will also identify any health improvements in other tissues from trametinib treatment, including neuromuscular function, activity, circadian rhythm, sleep, molecular markers of muscle and brain ageing, immune function and mitochondrial activity in fat body, and the role of the gut in inducing them. What we learn will inform future work targeting the key processes, first in mice, and ultimately, we hope, in humans. To make sure that we have the capability to advance this research in the most effective way, we are combining the efforts of two research laboratories with complementary expertise and experience, who will collaborate closely to drive forward the project.

Technical Summary

Increasing late-life function and health is a major challenge to societies worldwide. Recent research has shown that ageing has conserved mechanisms, or hallmarks, and that it is a remarkably malleable process in laboratory model organisms. A key hallmark is dysregulated activity of the nutrient-sensing insulin/Igf/TOR (IIT) signalling network. IIT functions well in youth but is overactive at older ages now reached by humans and laboratory animals. Reducing IIT activity genetically or pharmacologically can thus increase healthy lifespan in yeast, worms, the fruitfly Drosophila and mice. Furthermore, variants in genes encoding network components are associated with human longevity. We have recently found that the Ras pathway downstream of the insulin/Igf receptor, important in human cancers, also plays a key role in ageing. Genetic inhibition of different points in the pathway can increase healthspan in flies. Furthermore, we have recently shown that the licensed drug trametinib, an inhibitor of MEK in the Ras pathway, can increase lifespan in both flies and mice. Trametinib has a different mode of action from that of rapamycin, a more established anti-ageing drug, because combinatorial treatment with the two drugs induces an additive increase in the maximal lifespan extension that can be achieved by either drug alone. We therefore propose to investigate the mechanisms underlying the anti-ageing effects of trametinib in flies, where we can make much more rapid progress than in mice. Our preliminary data implicate the gut as an important site of action of trametinib. We shall investigate the molecular mechanisms at work in the intestinal enterocytes and stem cells and their effects on gut structure and function. We shall also examine the effects of trametinib on health and function during ageing, assessing neuromuscular and behavioural traits, molecular markers of muscle and brain ageing, immune and metabolic function in fat body, and role of the gut in inducing them.

Publications

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UreƱa E (2024) Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells. in Proceedings of the National Academy of Sciences of the United States of America

 
Description The drug trametinib has an anti-ageing effect in laboratory animals. We have found that it does so in the fruitfly Drosophila, by preventing the deterioration of the gut that happens during ageing. We have discovered the molecular mechanisms by which it does this, opening the way to discovering if it can maintain gut health during ageing in mammals, including humans.
Exploitation Route Search for parallel mechanisms in humans. Test trametinib as a geroprotector in mice.
Sectors Healthcare

 
Description CMO
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
Impact Contribution to the 2023 CMO report on an ageing society
 
Description Max Planck 
Organisation Max Planck Society
Department Max Planck Institute for the Biology of Ageing
Country Germany 
Sector Academic/University 
PI Contribution Collaboration for the effects of trametinib in mice
Collaborator Contribution Information on our findings with Drosophila to formulate hypotheses for mice
Impact 2 papers in preparation, submission of application to the NIA Intervention Testing Program in the US
Start Year 2022
 
Description BBC Radio 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Appearance on the Infinite Monkey Cage on Radio 4
Year(s) Of Engagement Activity 2022
 
Description Nobel Week Dialogue (Sweden) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Nobel Week Dialogue (Sweden) broadcast globally via live podcast
Year(s) Of Engagement Activity 2014
 
Description Regular participation in television, radio, podcast and print-media interviews 
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 Regular participation in television, radio, podcast and print-media interviews including interviews for BBC1/2 9 O'Clock News and Newsnight programmes, BBC Radio 4 News, the To-Day Programme, Science Now, the World Service, Radio 3 (Private Passions), Radio 4 (Melvyn Bragg's 'In Our Times', The Life Scientific, The Forum, Am I Normal?) and Radio 5 Live, podcasts including Up Close (Australia), ABC Local (Australia), Oxford University (UK), The Naked Scientists (UK), The Science Network (USA), and the Nobel Week Dialogue (Sweden). Interviews for The Financial Times, The Sunday Telegraph, The Sunday Times, Good Housekeeping Magazine, Manager Magazin and De Volkskrant and the Economist. Speaker at The Cheltenham, Edinburgh and Genoa Science Festivals.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2021,2022
 
Description Science Museum lates (ARUK/UCL event): Lost in thought 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Several members of the Partridge lab participated in this event to demonstrate how their work on Drosophila can help us to understand the genetic mechanisms involved in Alzheimer's Disease. The demonstration was provided informally whereby event participants could interact with several working stations displaying fly-based memory tests, behavioural measures of nerve cell dysfunction and had the opportunity to see a whole fly brain under the microscope!

This interactive event was aimed at a wide-ranging lay audience, with an interest in popular science, and included bench-to-bedside demonstrations by dementia researchers from across UCL. The most significant impact of this activity was to highlight the impact of dementia on society and the importance of research to find new treatments to slow-down disease development. For our laboratory, the opportunity to bring lab life, and the role that model organisms can play in understanding the genetic mechanisms of human diseases, was a fun and invaluable experience.
Year(s) Of Engagement Activity 2016
 
Description Science and Cocktails 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Lecture to general public in Copenhagen
Year(s) Of Engagement Activity 2023