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

免疫衰老增加了对感染的易感性，并通过减少免疫监视促进更普遍的衰老。衰老的免疫系统也变得过度活跃或失调，引起炎症，这是一种重要的衰老机制。新型冠状病毒疫情凸显了免疫系统老化的这些方面，老年人和免疫功能低下者面临高风险，而免疫反应过强的患者面临高死亡风险，这似乎是矛盾的。为了对抗衰老，关键是要了解哪些免疫成分需要增强，哪些需要在衰老过程中抑制。由于缺乏精确操纵免疫细胞亚群的工具，对衰老免疫系统的理解进展受阻。被称为巨噬细胞的白色血细胞在发育、稳态和免疫中起着关键作用。巨噬细胞是高度异质性的，这种多样性对它们在健康个体中执行广泛功能的能力至关重要，但也与它们在许多疾病中的多效性功能障碍有关。我们最近在果蝇（果蝇）中发现了促炎性巨噬细胞亚群，它们在衰老过程中的丰度会发生变化，重要的是开发了精确操纵它们的工具。只有当我们了解衰老免疫系统的基本生物学时，我们才能开发出复壮疗法-我们的目标是通过将衰老研究与免疫生物学相结合，分别在西蒙斯和埃文斯实验室的关键专业领域，在这一领域取得关键进展。目标和实验方法我们假设，根据巨噬细胞亚群，减少或增加这些细胞的数量将恢复免疫力并阻止衰老。衰老过程中亚群的分子表征将确定免疫细胞如何预防和/或驱动衰老的潜在机制。我们的模型独特地允许大规模的，在体内测试的重要性，巨噬细胞亚群在老化过程中。首先，我们将研究这些细胞的位置以及它们在衰老过程中的丰度如何变化。其次，我们将增加和减少亚群，以直接测试它们在衰老过程中的功能;功能性能（寿命/繁殖力/损伤反应/感染）的测定将确定生理学的哪些方面受到影响。第三，我们将比较年轻和老年果蝇中巨噬细胞的转录组，以确定候选机制，并使用功能遗传学测试因果关系。重要的是，我们已经开发出尖端工具来操纵和可视化衰老过程中的亚群。

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.