The pro- and anti-ageing roles of macrophage subpopulations in vivo

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Immunosenescence increases susceptibility to infection and through decreased immune surveillance promotes ageing more generally. The ageing immune system also becomes overactive or dysregulated, causing inflammation, an important ageing mechanism. These aspects of the ageing immune system were highlighted by COVID-19, with the elderly and immunocompromised at high risk, and, seemingly in contradiction, patients with overly strong immune reactions at high risk of mortality. To combat ageing, it is crucial to understand which immune components require potentiation and which require suppression during ageing. Progress in understanding the ageing immune system has been hindered by the absence of tools allowing precise manipulation of immune cell subpopulations.The white blood cells known as macrophages play key roles in development, homeostasis and immunity. Macrophages are highly heterogeneous and this diversity is critical to their ability to perform a wide range of functions in healthy individuals but also relates to their pleiotropic dysfunction in many diseases. We recently identified pro-inflammatory macrophage subpopulations in fruit flies (Drosophila) that change in their abundance during ageing, importantly developing tools to manipulate them precisely. Only when we understand the fundamental biology of ageing immune systems can we develop rejuvenation therapies - we aim to make key progress in this area by combining ageing research with immune biology, key areas of expertise in the Simons and Evans labs, respectively.Objectives and experimental approachWe hypothesise that, depending on macrophage subpopulation, either decreasing or increasing the numbers of these cells will rejuvenate immunity and deter ageing. Molecular characterisation of subpopulations during ageing will identify candidate mechanisms underlying how immune cells prevent and/or drive ageing. Our model uniquely allows large-scale, in vivo testing of the importance of macrophage subpopulations during ageing. Firstly, we will characterise where these cells localise and how their abundance changes during ageing. Secondly, we will increase and decrease subpopulations to directly test their function during ageing; assays on functional performance (lifespan/fecundity/injury responses/infection) will identify which aspects of physiology are impacted. Thirdly, we will compare transcriptomes of macrophages in young and aged flies to identify candidate mechanisms and test for causality using functional genetics. Importantly, we have already generated the cutting-edge tools to manipulate and visualise subpopulations during ageing.