NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration.
NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration.
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DOI：
10.1016/j.celrep.2017.04.007
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发表时间：
2017-04-25
期刊：
影响因子：
8.8
通讯作者：
Ligoxygakis P
中科院分区：
文献类型：
--
作者：
Kounatidis I;Chtarbanova S;Cao Y;Hayne M;Jayanth D;Ganetzky B;Ligoxygakis P
在衰老过程中，先天免疫发展到一个长期活跃的状态。然而，是什么将那些“年龄很好”的人与那些发展与年龄相关的神经系统疾病的人区分开来尚不清楚。我们用果蝇来探索衰老大脑中免疫力的代价。我们发现，IMD/NF-κB通路的细胞内负调节因子的突变使果蝇易受抗菌肽毒性水平的影响，导致早期运动缺陷、广泛的神经退行性变和寿命缩短。这些表型被拯救时，免疫抑制神经胶质细胞。在健康的果蝇中，抑制神经胶质细胞中的免疫力导致脂肪动力学激素信号增加，在以后的生活中具有高营养水平，并延长了活跃的寿命。因此，当IMD/NF-κB水平偏离正常时，有两种机制在起作用：较低水平的IMD/NF-κB降低免疫-内分泌轴，从而动员营养物质，导致寿命延长，而较高水平的IMD/NF-κ B增加抗菌肽，导致神经退行性变。因此，苍蝇大脑中的免疫力是决定寿命的关键因素。组成性免疫使寿命缩短并伴有严重的神经退行性变阻断神经胶质中的组成性免疫可拯救易感的果蝇抑制健康果蝇神经胶质中的免疫可触发脂肪动力学信号传导这一免疫-内分泌轴可动员营养物质并延长活跃的寿命在人类中，健康衰老和年龄依赖性神经退行性变都伴随着先天免疫的上调。原因是什么，后果是什么，目前还不清楚。Kounatidis等人表明，在果蝇中，NF-κB免疫信号控制健康果蝇的寿命，以及那些易患早期神经变性的果蝇。
During aging, innate immunity progresses to a chronically active state. However, what distinguishes those that “age well” from those developing age-related neurological conditions is unclear. We used Drosophila to explore the cost of immunity in the aging brain. We show that mutations in intracellular negative regulators of the IMD/NF-κB pathway predisposed flies to toxic levels of antimicrobial peptides, resulting in early locomotor defects, extensive neurodegeneration, and reduced lifespan. These phenotypes were rescued when immunity was suppressed in glia. In healthy flies, suppressing immunity in glial cells resulted in increased adipokinetic hormonal signaling with high nutrient levels in later life and an extension of active lifespan. Thus, when levels of IMD/NF-κB deviate from normal, two mechanisms are at play: lower levels derepress an immune-endocrine axis, which mobilizes nutrients, leading to lifespan extension, whereas higher levels increase antimicrobial peptides, causing neurodegeneration. Immunity in the fly brain is therefore a key lifespan determinant. Constitutive immunity predisposes to short lifespan with severe neurodegeneration Blocking constitutive immunity in glia rescues predisposed flies Suppression of immunity in glia of healthy flies triggers adipokinetic signaling This immune-endocrine axis mobilizes nutrients and extends active lifespan In humans, both healthy aging and age-dependent neurodegeneration are accompanied by an upregulation of innate immunity. What is the cause and what is the consequence remain unclear. Kounatidis et al. show that, in flies, NF-κB immune signaling controls lifespan in healthy flies, as well as in those predisposed to early neurodegeneration.