The role of mitochondrial oxidative damage in ageing: a chemical intervention approach

随着年龄的增长，人类的身体变得越来越不能做它曾经可以做的事情。原因是损伤累积到组成细胞的分子和整个组织。一种常见的损伤形式来自氧气，氧气对呼吸和呼吸至关重要，但对生物分子也是一种危险。在细胞中，能量储存分子ATP是在线粒体中产生的，通过使用氧气燃烧食物供应，如糖和脂肪。当对能量的需求很高时，例如在运动期间，线粒体不是一个大问题。但是当它们因为能量没有被消耗而无事可做时，它们变得更有可能与氧气相互作用，产生危险的活性分子。这些可以继续破坏重要的生物分子，如DNA和蛋白质以及生物膜中的脂质，这种损害可能是衰老过程的重要组成部分。这种损害特别可能发生在线粒体本身。因此，线粒体可能是衰老过程中的关键角色，既是产生破坏性分子的场所，又是它们造成的损害的主要目标。在这个项目中，我们计划开发和使用针对线粒体的化学物质来测试这些想法，并尝试干预损伤过程。线粒体表面有一个电荷。我们将使用带电的化学“拖船”将生物活性分子拖进线粒体。这些分子中的一些充当报告者，例如线粒体产生危险反应分子的速率，它们造成的损伤量以及线粒体表面电荷的大小。另一些则通过解毒来防止危险的活性分子。我们将测试这些分子的效力在一个短命的物种，果蝇果蝇，通过添加到食物中。果蝇在这方面的优势之一是我们可以通过限制果蝇的饮食或基因突变来制造长寿的品系。因此，我们可以评估线粒体损伤在减缓这些长寿菌株衰老过程中的作用。最终，这项工作的目标是随着年龄的增长改善人们的健康和生活质量，该项目的目的是为生产可以实现这一目标的药物铺平道路。

During ageing the human body becomes less able to do what it once could. The reason is that damage accumulates to the molecules of which cells are made up and to whole tissues. One common form of damage comes from oxygen, which is essential for breathing and respiration, but is also a danger to biological molecules. In cells, the energy-storage molecule ATP is produced in the mitochondria, by using oxygen to burn food supplies such as sugar and fats. When demand for energy is high, as for example during exercise, the mitochondria are not much of a problem. But when they have nothing to do because energy is not being consumed, they become much more likely to interact with oxygen to produce dangerous reactive molecules. These can go on to damage important biological molecules such as DNA and protein and the lipids in biological membranes, and this damage may be an important part of the ageing process. The damage is particularly likely to happen in the mitochondria themselves. So mitochondria may be key players in the ageing process, both as the site at which damaging molecules are produced and then as the main target of the damage that they cause. In this project we plan to develop and use chemicals that are targeted to the mitochondria to test these ideas and to try and intervene in the damage process. There is a charge across the surface of the mitochondria. We shall use a charged chemical 'tug' to drag biologically active molecules into the mitochondria. Some of these molecules act as reporters, for instance of the rate at which the mitochondria are generating the dangerous reactive molecules, the amount of damage that they are causing and the size of the charge across the surface of the mitochondria. Others protect against dangerous reactive molecules by detoxifying them. We shall test the efficacy of these molecules in a short-lived species, the fruit fly Drosophila, by adding them to the food. One of the advantages of Drosophila for this kind of work is that we can make long-lived strains, by feeding the flies on a restricted diet or making mutations in genes. We can therefore assess the role of mitochondrial damage in slowing down the ageing process in these long-lived strains. Ultimately, the goal of this work is to improve the health and quality of life of people as they age, and the aim of this project is to pave the way to the production of drugs that could achieve this goal.