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，人们对此知之甚少，但被认为是老年人感染易感性增加的原因。免疫衰老的一个主要标志是巨噬细胞功能障碍，巨噬细胞是一种免疫血细胞。老年人的巨噬细胞数量和吞噬活性降低(微生物的摄取)，以及异常的炎症反应，这影响了衰老的炎症病理。巨噬细胞衰老的原因(S)尚不清楚。从苍蝇到人类的动物衰老的另一个典型迹象是昼夜节律的丧失。这一建议检验了一种假设，即衰老会导致免疫血细胞中生物钟的缺陷，而免疫血细胞又会导致细胞功能缺陷，从而增加感染的易感性。我们开发了一个模型系统来研究果蝇原始巨噬细胞的昼夜节律调节，使用了其他系统中没有的遗传和免疫学工具。我们发现对感染的免疫力是受昼夜节律调节的。具体地说，巨噬细胞(或吞噬细胞)的吞噬作用受昼夜节律的调节，这种昼夜节律对感染的存活率有重大影响。我们目前的数据表明，果蝇的衰老导致了对感染的极大易感性--具体地说，老年果蝇失去了吞噬功能的昼夜调节。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，从而导致吞噬功能障碍，增加感染的易感性。为了检验这个模型，我们将：1.检验吞噬细胞中的时钟经历与衰老相关的衰老的假说，并确定其潜在的分子机制。2.确定衰老吞噬细胞时钟对基因表达和细胞功能的影响。3.研究昼夜健康寿命、免疫衰老和寿命之间的因果关系。因此，拟议的实验将在分子、细胞和生物水平上分析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中一个古老而关键的部分。由于先天免疫和昼夜节律生物学的高度进化保守性，在果蝇中阐明这些分子机制将为改善或防止人类先天免疫系统功能老化的方法提供洞察力。

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.