Aging of tissue-specific clocks in the immune system of Drosophila

描述（由申请人提供）：免疫系统功能的老化或免疫衰老，目前尚不清楚，但被认为是老年人感染易感性增加的基础。免疫衰老的一个主要标志是巨噬细胞（一种免疫血细胞）的功能障碍。老年人的巨噬细胞数量和吞噬活性（微生物的摄入）减少，以及异常的炎症反应，这会影响衰老的炎症病理学。巨噬细胞衰老的原因仍然未知。从苍蝇到人类，动物衰老的另一个经典标志是昼夜节律调节的丧失。该提案验证了一个假设，即衰老导致位于免疫血细胞中的生物钟缺陷，这反过来又导致其细胞功能缺陷，并导致对感染的易感性增加。我们开发了一个模型系统来研究果蝇中原始巨噬细胞的昼夜节律调节，使用其他系统中不可用的遗传和免疫工具。我们发现抵抗感染的免疫力是受昼夜节律调节的。具体地，巨噬细胞（或吞噬细胞）的吞噬作用是昼夜节律调节的，并且这种昼夜节律调节对感染的存活具有显著影响。我们目前的数据表明，果蝇的衰老导致了对感染的显著易感性，特别是老年果蝇失去了吞噬作用的昼夜调节。因为我们和其他人发现吞噬细胞中的时钟调节它们的功能，这些数据提出了一个模型：衰老导致吞噬细胞的昼夜节律失调，这导致吞噬功能缺陷和感染易感性增加。为了测试这个模型，我们将：1。验证吞噬细胞中的生物钟经历衰老相关衰老的假设，并确定潜在的分子机制。2.确定老化吞噬细胞时钟对基因表达和细胞功能的影响。3.调查昼夜健康周期、免疫衰老和寿命之间的因果关系。因此，拟议的实验将分析分子，细胞和有机体水平上的免疫系统功能的昼夜节律调节的老化。吞噬作用是包括人类在内的所有动物先天免疫系统的一个古老而重要的组成部分。由于先天免疫和昼夜节律生物学的高度进化保守性，在果蝇中定义这些分子机制将为改善或预防人类先天免疫系统功能老化的方法提供深入见解。

DESCRIPTION (provided by applicant): Aging of immune system function, or immunosenescence, is poorly understood but is thought to underlie increased susceptibility to infection of the elderly. A major hallmark of immunosenescence is dysfunction of macrophages, a type of immune blood cell. Macrophages in elderly people exhibit decreased number and phagocytic activity (the ingestion of microbes), as well as abnormal inflammatory responses, which impact inflammatory pathologies of aging. The cause(s) of macrophage senescence remains unknown. Another classic sign of aging in animals from flies to humans is loss of circadian regulation. This proposal tests the hypothesis that aging causes defects in the circadian clock located in immune blood cells, which in turn causes defects in their cellular function and contributes to increased susceptibility to infection. We developed a model system to study circadian regulation of primitive macrophages in Drosophila, using genetic and immunological tools unavailable in other systems. We found that immunity against infection is circadian- regulated. Specifically, phagocytosis by macrophages (or phagocytes) is circadian-regulated and this circadian regulation has significant effects on survival of infection. Our current data show that aging of Drosophila causes dramatic susceptibility to infection-specifically, old flies lose circadian regulation of phagocytosis. Because we and others find that the clock in phagocytes regulates their function, these data suggest a model: aging causes circadian dysregulation in phagocytes, which causes defects in phagocytosis and increased susceptibility to infection. To test this model, we will: 1. Test the hypothesis that the clock in phagocytes undergoes aging-related senescence and identify the underlying molecular mechanism. 2. Determine the effect of the aging phagocyte clock on gene expression and cellular function. 3. Investigate the causal relationships between circadian healthspan, immunosenescence, and lifespan. Thus the proposed experiments will analyze the aging of circadian regulation of immune system function on molecular, cellular, and organismal levels. Phagocytosis is an ancient and crucial part of every animal's innate immune system, including humans. Because of the high evolutionary conservation of both innate immunity and circadian biology, defining these molecular mechanisms in Drosophila will provide insight into ways to ameliorate or prevent aging of human innate immune system function.