Why do mitochondria produce more ROS when we age?

不断增长的老龄化人口是本世纪我们将面临的最严峻的挑战。老龄化是一个健康和社会经济问题，将决定未来的政治决定。社会正在将越来越多的公共和私人资源用于照顾老年人。在民意调查中发现，失去拥有积极和独立生活的能力是老年人主要担心的问题。由于没有一项全球战略将老龄化作为一种单一疾病而不是作为与年龄相关的无关疾病来处理，这一问题变得更加严重。为了取得进展，我们需要了解导致老龄化的根本原因，并确定和实施针对这些原因的战略。我们必须准确定位并调查衰老的根本原因，建立适当的动物模型来严格检验假设，并将这些发现转化为人类的临床研究。这项提议将产生关于我们如何以及为什么衰老的直接知识，以及延长动物寿命的干预措施。在过去，我们和其他人已经证明，有缺陷的线粒体的积累是衰老的一个标志，这种标志在进化过程中是保守的。线粒体是细胞能量代谢的中心。当它们功能失调时，能量产生就会中断，细胞动态平衡就会丧失。因此，衰老的特征是细胞能量的丧失。在过去的十年里，我们已经了解了大量关于携带功能失调的线粒体的负面后果。例如，作为有毒代谢副产品产生的自由基会导致细胞损伤，并与许多与年龄有关的疾病有关，如阿尔茨海默氏症和帕金森氏症。然而，我们仍然不知道为什么随着我们年龄的增长，线粒体会产生更少的能量和更多的毒素。这个项目将通过确定功能失调的线粒体在衰老过程中积累的原因和方式来填补我们知识中的这一空白。我们将利用果蝇的短寿命和强大的遗传学来研究衰老的线粒体是如何产生破坏细胞的自由基的。我们将首先调查在正常情况下和在压力下，在哪里以及在什么水平上产生自由基。接下来，我们将调查有缺陷的线粒体积累的原因。我们将使用最先进的技术来操纵表观基因组。表观基因组是读取储存在基因组中的信息的“操作手册”。在衰老过程中，这种“手册”被破坏，细胞失去了正确解释遗传密码的能力。最后，我们将利用这一新知识开发创新策略，以防止、延迟或逆转有缺陷的线粒体的积累，询问这是否足以延长苍蝇的寿命。主要目标是了解预防、延缓和逆转人类衰老所需的条件。

An ever-increasing ageing population is the most critical challenge that we will face in this century. Ageing is a health and a socio-economic problem that will determine future political decisions. Societies are dedicating a growing number of public and private resources to the care of the elderly. Losing the ability to have an active and independent life is found to be a main concern amongst the elderly in opinion polls. This problem is aggravated by the absence of a global strategy to address ageing as a single ailment rather than as unconnected individual age-associated diseases. In order to make progress, we need to understand the fundamental causes that drive ageing and identify and implement strategies that target these causes. We must pinpoint and investigate the root causes of ageing, generate appropriate animal models to test hypotheses rigorously and translate these findings into clinical studies in humans. This proposal will generate direct knowledge about how and why we age and interventions that extend animal lifespan. In the past, we and others have shown that the accumulation of defective mitochondria is a hallmark of ageing that is conserved across evolution. Mitochondria are central to cellular energy metabolism. When they are dysfunctional, energy production is interrupted, and cell homeostasis is lost. Accordingly, ageing is characterised by a loss in cellular power. Over the last ten years, we have learned a significant amount about the negative consequences of carrying dysfunctional mitochondria. For example, free radicals produced as toxic metabolic by-products cause cellular damage and are associated with many age-related diseases such as Alzheimer's and Parkinson's diseases. However, it is still unknown why, as we age, mitochondria produce less energy and more toxins. This project will fill this gap in our knowledge by determining why and how dysfunctional mitochondria accumulate during ageing. We will take advantage of the fruit fly's short lifespan and powerful genetics to study how old mitochondria produce free radicals that damage the cell. We will begin by investigating where and at what level free radicals are produced in normal conditions and under stress. Next, we will investigate why defective mitochondria accumulate. We will employ state-of-the-art technology to manipulate the epigenome. The epigenome is the "instruction manual" that reads the information stored in the genome. During ageing, this "manual" is damaged, and cells lose their ability to interpret the genetic code correctly. Finally, we will use this new knowledge to develop innovative strategies to prevent, delay or reverse the accumulation of defective mitochondria, asking whether this is sufficient to extend fly lifespan. The primary goal is to understand what is required for the prevention, delay and reversal of ageing in humans.