Abstract

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.