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They say, “you are what you eat”. But what happens when you eat too much, too often? The answer is often ill-health and disease.
“For most of history, humans have lived with very limited access to food,” says Alejo Efeyan, who leads the Metabolism and Cell Signalling Group at the Spanish National Cancer Research Centre. “As a result, our bodies have become very good at efficiently using, consuming, storing and recycling nutrients.”
However, the astronomical increase in nutrient intake and sedentarism seen over the last half century is putting this built-in survival mechanism to the test. “Our cells now face the unprecedented scenario where the very mechanisms developed to keep us alive are triggering harmful responses that drive potentially deadly diseases,” Efeyan explains.
Through the EU-funded NutrientSensingVivo project, supported by the European Research Council, Efeyan and his team set out to better understand how our metabolism, the chemical reactions that transform food into energy that is either burned or stored for later use, changes in accordance with the availability of food. To do this, they turned their attention to the mTOR pathway, a critical nutrient sensing pathway that plays an important role in virtually any aspect of metabolism.
Of mice and metabolism
According to Efeyan, understanding how the mTOR pathway works is important, as it is responsible for much of how a cell consumes energy and nutrients during metabolism. However, when mTOR activity isn’t properly regulated, it can drive the development of such diseases as diabetes and cancer and accelerate ageing.
“Despite mTOR’s nutrient sensing being such a fundamental biological trait, 15 years ago we really had no idea how it worked,” explains Efeyan. “Although we have now largely solved mTOR’s molecular puzzle, we still don’t understand how this pathway operates within our organs.”
Enter the mice.
Using genetically engineered mice, researchers discovered that being able to turn the mTOR pathway off is the key to getting our metabolism to go into its natural ‘fasting state’. “The question now is whether we can trick our cells into thinking they are fasting and thus trigger the benefits that such a response offers,” says Efeyan. “This is something we intend to explore further.”
A sneak peek at what’s ahead
The project also successfully demonstrated that by halting the cellular signal that is sent when there is an abundance of nutrients, one can control the B lymphocyte activity that is responsible for a range of autoimmune diseases and some lymphomas. “This finding opens the door to a future where we can use drugs to specifically target nutrient signalling,” adds Efeyan. “But getting to that point is a long journey that will take many years.”
In support of that journey, researchers created genetically engineered mouse models, some of which had their nutrient signalling switched on and others with the signalling muted – all regardless of actual food intake. “These experiments serve as a sort of preview of what we might be able to do with nutrient signalling inhibitors, while also testing their safety and potentially unwanted side effects,” notes Efeyan.
For example, these tests have indicated the potential of using inhibitors to mimic caloric restriction – a process that not only protects against cancer, but also dramatically improves metabolic health and even extends life expectancy. “Although still a long way off, our work serves as a stepping stone towards developing the drugs and treatments that could treat cancer, control obesity and redefine how we can therapeutically intervene on cellular metabolism,” concludes Efeyan.