Role of Mitochondrial Reactive Oxygen Species in Stress Adaptation during Ageing

如今，衰老是现代生物学需要回答的主要问题之一。我们需要了解我们是如何衰老的，尤其是为什么我们会变老，才能完全理解进化的过程。此外，不断增长的老龄化人口是英国的主要问题之一。减轻与年龄相关的退行性疾病(如阿尔茨海默氏症、帕金森氏症、癌症或糖尿病)造成的痛苦的唯一方法是充分了解推动衰老的潜在进化力量，并设计延缓衰老进程的战略。线粒体是细胞的动力源，产生生存所需的大部分能量。这些小型电池工厂在老化过程中会恶化，无法提供细胞维护所需的能量。线粒体失效的原因目前尚不清楚，但可能与它们产生能量的方式有关。线粒体使用氧气作为最终的电子受体来进行操作。正常情况下，这种氧气是由线粒体安全地管理的，线粒体被完全还原为具有四个电子和两个质子的水。然而，在极少数情况下，氧被不完全还原(少于四个电子)产生所谓的活性氧物种(ROS)，它可以破坏所有细胞成分。线粒体自由基衰老理论(MFRTA)是上个世纪流行的解释衰老的理论。MFRTA提出，作为呼吸副产品产生的ROS会导致氧化损伤，积累并导致衰老。MFRTA主要由相关数据支持。氧化损伤随着年龄的增长而积累，在与衰老相关的退行性疾病中，mtROS水平会发生变化。然而，直接的实验证据不能支持MFRTA。增加mtROS不会缩短寿命，补充抗氧化剂对健康影响不大。已有研究表明，mtROS对细胞分化、免疫反应和应激适应具有重要作用。总而言之，mtROS对衰老的贡献尚不清楚。由于ROS在病理和非病理情况下的重要性，我们必须了解它们在活体中所起的生理作用。在本提案中，我们旨在详细了解ROS在正常生理和压力适应中所起的作用，特别是在衰老过程中。根据我们的初步结果，我们假设存在两种不同类型的ROS种群。一个种群是好的，它的产生与清理细胞的机制的激活有关。当这些ROS被抑制时，质量控制机制就不能正常工作，细胞动态平衡就会丧失。这将解释与补充或过度表达抗氧化剂相关的负面后果。另一个种群是有害的，只有当线粒体质量控制机制失效时才会产生这种种群。这些ROS的特征是由高水平的游离铁和羟基自由基导致的非常激进的化学作用。利用果蝇遗传学的力量，我们将产生新的转基因模型，使我们能够在体内精确操纵这两个ROS种群。我们将使用这项新技术来表征ROS激活的下游生理反应。我们的目标是找到特定药物或基因干预可能针对的确切途径和基因。这些干预措施应有助于延长健康寿命。由于必要的代谢途径在进化过程中高度保守，预计类似的策略可能会在人类身上实施，以延缓衰老并防止与年龄相关的疾病的发生。

Nowadays, ageing is one of the main questions that modern biology needs to answer. We need to understand how and especially why we age to fully understand the process of evolution. In addition, a growing ageing population is one of the main problems in United Kingdom. The only way to alleviate the suffering caused by age-related degenerative disease (e.g. Alzheimer, Parkinson, cancer or diabetes) is to fully understand the underlying evolutionary forces, which drive ageing and design strategies to delay the ageing process. Mitochondria are the powerhouses of the cell generating most of the energy required for survival. These small cell factories deteriorate during ageing, failing to deliver the energy required for cellular maintenance. The reason why mitochondria fail is currently unknown, but it could be related with the way they produce energy. To operate, mitochondria use oxygen as final electron acceptor. Normally, this oxygen is safely managed by mitochondria being completely reduced to water with four electrons and two protons. However, in a minimal number of occasions oxygen is incompletely reduced (with less than four electrons) producing the so-called Reactive Oxygen Species (ROS) that can damage all cellular components.The Mitochondrial Free Radical Theory of Ageing (MFRTA) was a popular theory to explain ageing in the past century. MFRTA proposes that ROS, produced as by-products of respiration, cause oxidative damage that accumulates and causes ageing. MFRTA is mainly supported by correlative data. Oxidative damage accumulates with age, and mtROS levels are altered in degenerative disease associated with ageing. However, direct experimental evidence fails to support MFRTA. Increasing mtROS does not shorten lifespan, and antioxidant supplementation has poor effects on health. It has been shown that mtROS are instrumental for cell differentiation, the immune response and stress adaptation. In conclusion, the contribution of mtROS to ageing is unclear. Because of the importance ROS have in pathological and non-pathological situations it is imperative to understand the physiological role they play in vivo.In this proposal, we aim to understand in detail the role ROS play in normal physiology and in stress adaptation, particularly during ageing. Based on our preliminary results, we hypothesize that there are two different types of ROS populations. One population is good, and its generation is associated with the activation of mechanisms that clean up the cells. When these ROS are suppressed quality control mechanisms do not work properly and cellular homeostasis is lost. This would explain the negative consequences associated with supplementation or overexpression of antioxidants. The other population is deleterious, and it is produced only when mechanisms of mitochondrial quality control fail. These ROS are characterized by a very aggressive chemistry led by high levels of free iron and hydroxyl radicals. Using the power of fruit fly genetics we will generate new transgenic models that will allow a precise manipulation of these two ROS populations in vivo. We will use this new technology to characterize the downstream physiological responses activated by ROS. We aim to find the exact pathways and genes that may be targeted by specific drugs or genetic interventions. These interventions should help to extend healthy lifespan. Since essential metabolic pathways are highly conserved during evolution, it is expected that similar strategies may be implemented in humans to delay ageing and prevent the onset of age-related diseases.