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

世界正面临着由健康状况不佳的老龄化人口造成的健康危机。到2025年，大约有12亿人将超过60岁，到2050年这一数字将增加到20亿。虽然寿命的延长可能是可取的，但这与健康寿命的延长（一个人能够保持良好健康的时间长度）并不一致，老年人往往身体虚弱，健康状况不佳。随着年龄的增长，血液中的脂质或“脂肪”会发生变化，而一些脂质与健康状况不佳有关。饮食的改变，如热量限制，降低了与健康状况不佳有关的脂质，并与小鼠等模式生物的寿命有关。这项提议旨在了解衰老过程中脂质变化如何影响我们的免疫系统，免疫系统随着年龄的增长而恶化，并导致健康状况不佳。衰老尤其会影响一种叫做T细胞的免疫细胞，它的主要功能是杀死病毒感染的细胞或恶性细胞。这使得老年人容易受到流感（导致流感）和SARS CoV2（导致COVID-19）等病毒的感染。正如SARS CoV2大流行所证明的那样，老年人的发病率和死亡率远高于年轻人。除了实足年龄外，生物年龄也会影响免疫功能退化，因此，许多其他因素也会导致与COVID-19相关的严重疾病，包括癌症、慢性感染、超重或肥胖、糖尿病或免疫功能低下。在我们努力寻找扩大老龄化人口健康寿命的方法时，了解健康老龄化的生物学至关重要。线粒体是产生三磷酸腺苷（ATP）这一生化反应重要燃料的细胞器。线粒体在产生ATP方面效率很高，被认为是“细胞的发电站”。线粒体功能障碍是衰老的主要标志。线粒体功能障碍损害T细胞的正常功能并加速衰老，但衰老过程中线粒体功能障碍的原因尚不清楚。脂质是线粒体功能的关键调节因子。线粒体中的脂质是重要的膜成分，作为信号介质和能量生产。这项提议旨在了解脂质如何调节T细胞老化和相互关联的线粒体功能。这项提议的结果将是对健康英国人群中T细胞衰老机制的新见解。

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.