Sex differences in immune senescence and responses to geroprotective drug treatments

老龄化是发达国家最大杀手的最大风险因素，而与年龄有关的疾病的影响是社会面临的最大挑战之一。免疫缺陷是衰老的原因和结果。例如，炎症是对创伤和感染的基本反应，但当炎症被误导或慢性时，组织损伤加剧，与年龄相关的疾病的发展加速。抵抗感染的能力也随着年龄的增长而下降，最近的大流行病就证明了这一点。抗衰老或“老年保护”治疗正在开发中，其中许多针对免疫系统。免疫力的性别差异，与年龄相关的免疫功能下降和寿命在人群中和不同分类群中可见（1）。支持这些性别差异的机制尚未得到很好的理解，但将对针对这些过程的治疗产生深远的影响。我们已经证明了对靶向营养感应途径以维持肠道健康的治疗的反应存在保守的性别差异（2，3）。我们的下一个目标是了解先天免疫系统老化的性别差异以及对靶向免疫组织的老年保护药物的反应。我们想了解男性和女性在维持免疫功能方面的不同投资，在分子，细胞和组织规模上失败的是什么，以及可以挽救的是什么。我们使用果蝇模型（4）来解决性别，先天免疫和衰老相互作用的复杂和关键问题。为此，我们使用了几种方法，包括：感染和寿命研究，体内显微镜，人口统计学分析，遗传学和转录组学。研究的细节可以根据申请人的需要量身定制。将提供全面的培训，并将有足够的机会获得任何（或所有）的技能：感染生物学，病理生理学，果蝇功能遗传学，转录组学（包括单细胞测序），显微镜，生物信息学和建模方法（与合作者）。

Ageing is the largest risk factor for the developed world's biggest killers, and the impact of age-related disease is one of society's foremost challenges. Defective immunity is implicated as both cause and effect of ageing. For example, inflammation is an essential response to wounding and infection, but when inflammation is misdirected, or chronic, tissues damage ensues and development of age-related disease is accelerated. The ability to resist infection also decreases with age, as has been demonstrated during the recent pandemic. Anti-ageing or 'geroprotective' treatments are under development, and many of these target the immune system.Sex differences in immunity, age-related decreases in immune function, and lifespan are seen in human populations and across taxa (1). The mechanisms underpinning these sex differences are not well-understood, yet will have a profound impact on treatments that target those processes. We have demonstrated conserved sex differences in responses to treatments that target nutrient sensing pathways to maintain intestinal health (2,3). Our next goal is to understand sex differences in ageing of the innate immune system and responses to geroprotective drugs that target immune tissues. We want to understand the different investments males and females make in maintaining immune function, what fails on a molecular, cellular and tissue scale, and what can be rescued. We use a Drosophila model (4) to tackle the complex and key issues of the reciprocal interactions of sex, innate immunity and ageing. To do this we use several methodological approaches, including; infection and lifespan studies, in vivo microscopy, demographic analyses, genetics and transcriptomics. The details of the study can be tailored to suit the applicant. Full training will be provided, and there will be ample opportunity to gain skills in any (or all) of: infection biology, pathophysiology, Drosophila functional genetics, transcriptomics (including single cell sequencing), microscopy, bioinformatics, and modelling approaches (with collaborators).