Mechanisms mediating the anti-ageing effects of trametinib.

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.

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.