The role of lipid metabolism in mitochondrial function and interlinked T cell ageing - across scales

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The world is facing a health crisis caused by an ageing population with poor health. In 2025, about 1.2 billion people will be over the age of 60, and this will increase to 2 billion by 2050. While an increase in lifespan may be desirable, this does not coincide with an increase in healthspan (the length of time an individual is able to maintain good health), and the elderly often suffer from frailty and poor health.Lipids or 'fats' in the blood change as we age, and some lipids are associated with poor health. Changes in the diet, such as caloric restriction, reduce lipids associated with poor health and are associated with longevity in model organisms such as mice. This proposal aims to understand how lipid-changes during ageing affect our immune systems, which deteriorate as we age and promotes poor health.Ageing particularly affects a type of immune cell, called a T cell, whose primary function is to kill virally-infected or malignant cells. This leaves older individuals susceptible to infections by viruses such as Influenza (that causes flu) and SARS CoV2 (that causes COVID-19). As demonstrated by the SARS CoV2 pandemic, elderly individuals had much higher morbidity and mortality than the younger population. In addition to chronological age, biological age also affects immune deterioration, and as such many other factors contribute to severe illness associated with COVID-19, including having cancer, having a chronic infection, being overweight or obese, having diabetes, or being immunocompromised.Understanding the biology of healthy ageing is of paramount importance as we strive to find ways to expand the healthspan in an ageing population.Mitochondria are organelles that generate an important fuel for biochemical reactions called adenosine triphosphate (ATP). Mitochondria are very efficient at generating ATP, and are considered "the powerhouses of the cell". Mitochondrial dysfunction is a primary hallmark of ageing. Mitochondrial dysfunction in T cells impairs their normal function and accelerates ageing, but the cause of mitochondrial dysfunction during ageing is not understood. Lipids are key regulators of mitochondrial function. Lipids in the mitochondria are important as membrane components, as signalling mediators, and for energy production. This proposal aims to understand how lipids regulate T cell ageing and interlinked mitochondrial function. The outcome of this proposal will be new insight into the mechanisms underlying T cell ageing in the healthy UK population.