Why do mitochondria produce more ROS when we age?

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci


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.

Technical Summary

A universal hallmark of ageing is the accumulation of defective mitochondria that produce high levels of mitochondrial Reactive Oxygen Species (mtROS). We and others have characterised the consequences of this build-up of dysfunctional mitochondria in detail, e.g. oxidative stress that triggers inflammation and cellular senescence. In contrast, we do not yet know how and why mitochondria produce more mtROS during ageing. This is a significant barrier since we cannot restore redox balance in old individuals without a deep understanding of the mechanisms underlying this.

We will dissect how and why damaged mitochondria accumulate during ageing. We will start by characterising the mechanism by which old mitochondria produce mtROS. We will study whether the sources of mtROS are the same in young and old mitochondria and determine which kind of ROS (e.g., hydrogen peroxide or hydroxyl radicals) is most abundant. We will then investigate why dysfunctional mitochondria are the dominant population in aged individuals, testing two hypotheses. One is that epigenetic drift results in the assembly of "faulty mitochondria". We anticipate that increasing epigenetic alterations will result in the population of dysfunctional mitochondria in young individuals. The other hypothesis states that ROS produced extra-mitochondrially results in an increase in mtROS levels. This could be a compensatory mechanism where mitochondria increase the intensity of mtROS signals to get above the "noise" of ROS produced at other sites. We predict that by reducing extra-mitochondrial ROS production, mitochondrial signalling will be restored. Finally, we will develop interventions that restore redox signalling in old individuals, extending lifespan and stress resistance. This will be achieved by combining genetic and pharmacological approaches to attenuate epigenetic drift and silence ROS generators that do not participate in redox signalling.


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