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

研究线粒体活性、热休克反应的程序性抑制、蛋白质稳态和衰老之间的关系

• 批准号: BB/P005535/1
• 负责人: Johnathan Labbadia
• 金额: $ 101.66万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP005535%2F1
• 关键词: Investigating; relationship; between; mitochondrial; activity

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.

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。我在伦敦大学学院健康老龄化研究所的工作是利用小蠕虫线虫来了解推动衰老的过程，希望有一天能设计出能够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影响的途径失败所致。这种老化模型直观地符合我们对周围世界的经验，在这个世界里，“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，老龄化的基本面比这复杂得多。在蠕虫、苍蝇、老鼠和人类身上观察到的许多与年龄相关的变化中，受损和非功能性蛋白质的数量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“蛋白质动态平衡的丧失”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会导致过早衰老和与年龄相关的疾病。因此，通过了解蛋白质稳定性为什么会随着年龄的增长而下降，以及这是如何影响寿命的，就有可能确定可以有针对性地维持蛋白质稳定性和促进健康衰老的基因和途径。尽管线虫很简单，寿命很短(2-3周)，但它们有多种组织类型(肌肉、肠道、神经)，并表现出许多伴随人类衰老的变化，包括蛋白质动态平衡的丧失。由于蛋白质稳态是生命的基础，在线虫中也发现了维持人类蛋白质稳态所必需的基因，因此，蠕虫是一个很好的模型系统，可以利用遗传学来理解蛋白质稳态的变化与衰老之间的关系。我的工作表明，许多保护性途径在成年早期就会衰退，包括热休克反应，这是防止受损和功能失调的蛋白质在细胞中积累的关键途径。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，热休克反应并没有随着年龄的增长而逐渐下降，而是随着动物的生殖成熟而受到积极的抑制。我发现，这种现象由两条不同的途径控制，一条是生殖(生殖系干细胞)，另一条是生长(线粒体活动)。我之前已经确定了胚系维持热休克反应和蛋白稳定的机制，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)的活动如何防止抑制热休克反应，维持蛋白稳定，并促进长期健康。在我的团契期间，我将使用线虫遗传学的力量结合传感器来解决这些问题，这些传感器允许在活着的动物成年后监测不同组织中的蛋白质稳态，这是只有线虫才可能做到的。我的工作将回答有关生命早期的通路如何控制蛋白质随年龄变化的关键问题。特别是，我将在线粒体活动和成年期间对热休克反应的程序性抑制之间建立一种以前未被发现的联系。这将导致确定促进长期健康的新目标，并为管理老龄化的原则提供重要的见解。

项目成果

A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse.

• DOI: 10.1016/j.devcel.2020.06.038
• 发表时间: 2020-07
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Rhianna Williams;Mihails Laskovs;Rebecca Williams;Ananya Mahadevan;Johnathan Labbadia

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging.

• DOI: 10.1016/j.celrep.2017.10.038
• 发表时间: 2017-11-07
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Labbadia J;Brielmann RM;Neto MF;Lin YF;Haynes CM;Morimoto RI
• 通讯作者: Morimoto RI

Two human metabolites rescue a C. elegans model of Alzheimer's disease via a cytosolic unfolded protein response.

• DOI: 10.1038/s42003-021-02218-7
• 发表时间: 2021-07-07
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Joshi P;Perni M;Limbocker R;Mannini B;Casford S;Chia S;Habchi J;Labbadia J;Dobson CM;Vendruscolo M
• 通讯作者: Vendruscolo M

Autophagy in healthy aging and disease.

健康衰老和疾病中的自噬。

• DOI: 10.1038/s43587-021-00098-4
• 发表时间: 2021-08
• 期刊: Nature aging
• 作者: Aman Y;Schmauck-Medina T;Hansen M;Morimoto RI;Simon AK;Bjedov I;Palikaras K;Simonsen A;Johansen T;Tavernarakis N;Rubinsztein DC;Partridge L;Kroemer G;Labbadia J;Fang EF
• 通讯作者: Fang EF

Using the drug-protein interactome to identify anti-ageing compounds for humans

使用药物-蛋白质相互作用组来识别人类抗衰老化合物

• DOI: 10.1101/438234
• 发表时间: 2018
• 作者: Fuentealba Valenzuela M