Investigating the relationship between mitochondrial activity, programmed repression of the heat shock response, protein homeostasis and ageing

衰老是生物学的一个基本特征，但衰老的根本原因仍然是个谜。我在伦敦大学学院的健康老龄化研究所工作，利用小蠕虫秀丽隐杆线虫来了解推动衰老的过程，希望有一天能设计出促进人类长期健康的干预措施。人们普遍认为，衰老是细胞损伤逐渐积累的结果，主要是由于保护我们免受环境和生理压力的途径失效。这种衰老模型直观地符合我们对周围世界的体验，其中“磨损”与我们周围物品的年龄密切相关。然而，最近的证据表明，衰老的基本原理比这复杂得多。在蠕虫、苍蝇、小鼠和人类中观察到的许多与年龄相关的变化中，受损和无功能蛋白质数量的增加是老年的一个基本特征。蛋白质是所有细胞的重要组成部分，必须正常运作才能使细胞保持健康；因此，这种“蛋白质稳态的丧失”可能是衰老的基础。为了支持这一理论，维持蛋白质稳态的策略与延长寿命有关，而加速蛋白质稳态丧失的治疗导致早期衰老和与年龄相关的疾病。因此，通过理解为什么蛋白质平衡会随着年龄的增长而下降，以及这是如何影响寿命的，有可能确定可以靶向维持蛋白质平衡和促进健康衰老的基因和途径。尽管简单且寿命短（2-3周），秀丽隐杆线虫具有多种组织类型（肌肉、肠道、神经），并表现出伴随人类衰老的许多变化，包括蛋白质稳态的丧失。由于蛋白质稳态是生命的基础，维持人类蛋白质稳态所需的基因也在秀丽隐杆线虫中发现，因此，蠕虫代表了一个很好的模型系统，可以利用遗传学来理解蛋白质稳态变化与衰老之间的关系。我的工作揭示了许多保护性通路在成年早期下降，包括热休克反应，这是防止细胞中受损和功能失调蛋白质积累的必要途径。这使得动物在成年后容易受到环境压力和蛋白质错误折叠的影响。令人惊讶的是，我的数据表明，热休克反应不会随着年龄的增长而逐渐下降，而是在动物繁殖成熟时被积极抑制。我发现这种现象是由与生殖（生殖系干细胞）和生长（线粒体活动）相关的两种不同途径控制的。我之前已经确定了生殖系维持热休克反应和蛋白质平衡的机制，然而，尚不清楚在生命早期损害线粒体（每个细胞的能量工厂）的活性如何阻止热休克反应的抑制，维持蛋白质平衡，并促进长期健康。在我的研究期间，我将利用秀丽隐杆线虫遗传学的力量和传感器来解决这些问题，这些传感器允许在整个成年期在活体动物的不同组织中监测蛋白质稳态，这只有在秀丽隐杆线虫中才有可能。我的工作将回答关于生命早期的途径如何随着年龄的增长控制蛋白质停滞的关键问题。特别是，我将在线粒体活动和成年期热休克反应的程序性抑制之间建立一个之前未被发现的联系。这将导致确定促进长期健康的新目标，并对管理老龄化的原则提供重要见解。

Ageing is a fundamental feature of biology yet the root causes of ageing remain a mystery. My work within the institute of healthy ageing at University College London uses the small worm C. elegans to understand the processes that drive ageing in the hope of one day designing interventions that can promote long-term health in humans. It is widely thought that ageing is the consequence of a gradual accumulation of damage to cells, primarily due to the failure of pathways that protect us from environmental and physiological stresses. This model of ageing fits intuitively with our experiences of the world around us in which "wear and tear" is closely associated with the age of the items that surround us. However, recent evidence suggests that the fundamentals of ageing are much more complex than this. Among the many age-associated changes observed in worms, flies, mice, and humans, an increase in the quantity of damaged and non-functional proteins is a fundamental feature of old age. Proteins are an important component of all cells and must function properly for cells to remain healthy; therefore, it is possible that this "loss of protein homeostasis" underlies ageing. In support of this theory, strategies that maintain protein homeostasis are associated with increased lifespan whereas treatments that accelerate the loss of protein homeostasis result in early ageing and age-related disease. Therefore, by understanding why proteostasis declines with age and how this impacts longevity, it may be possible to identify genes and pathways that can be targeted to maintain proteostasis and promote healthy ageing. Despite their simplicity and short lifespan (2-3 weeks), C. elegans have multiple tissue types (muscle, intestine, nerves) and exhibit many of the changes that accompany ageing in humans, including a loss of protein homeostasis. Because protein homeostasis is fundamental for life, the genes necessary to maintain protein homeostasis in humans are also found in C. elegans, therefore, worms represent an excellent model system with which to use genetics to understand the relationship between changes in protein homeostasis and ageing. My work has revealed that many protective pathways decline early in adulthood, including the heat shock response, a pathway that is essential to prevent the accumulation of damaged and malfunctioning proteins in cells. This leaves animals vulnerable to environmental stress and protein misfolding later in adulthood. Surprisingly, my data suggest that the heat shock response does not decline gradually with age but is instead actively repressed as animals become reproductively mature. I have found that this phenomenon is controlled by two distinct pathways linked to reproduction (germ line stem cells) and growth (mitochondrial activity). I have previously identified the mechanism by which the germ line can maintain the heat shock response and proteostasis, however, it is unknown how impairing the activity of mitochondria (the energy factories of each cell) early in life prevents repression of the heat shock response, maintains proteostasis, and promotes long-term health. During my Fellowship period I will address these questions using the power of C. elegans genetics coupled with sensors that allow protein homeostasis to be monitored in different tissues throughout adulthood in living animals, something only possible in C. elegans. My work will answer critical questions regarding how pathways early in life control proteostasis with age. In particular, I will establish a previously unidentified link between mitochondrial activity and the programmed repression of the heat shock response during adulthood. This will lead to the identification of new targets for the promotion of long-term health and provide important insight into the principles that govern ageing.