Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
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DOI：
10.1016/j.cmet.2018.12.008
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发表时间：
2019-05-07
期刊：
影响因子：
29
通讯作者：
Jurk, Diana
中科院分区：
文献类型：
--
作者：
Ogrodnik, Mikolaj;Zhu, Yi;Jurk, Diana
细胞衰老需要稳定的细胞周期停滞和促炎分泌表型，这有助于衰老和年龄相关疾病。肥胖与衰老细胞负担增加和神经精神疾病（包括焦虑和抑郁）有关。为了研究衰老在肥胖相关神经精神功能障碍中的作用，我们使用INK-ATTAC小鼠模型，从中可以消除表达p16（Ink4a）的衰老细胞，并使用抗衰老药物达沙替尼和槲皮素。我们发现肥胖导致衰老神经胶质细胞在侧脑室附近积聚，而侧脑室是成人神经发生的区域。此外，衰老的神经胶质细胞表现出过多的脂肪沉积，我们将这种表型称为“衰老时脂质积累”。清除高脂肪喂养或瘦素受体缺乏的肥胖小鼠的衰老细胞可恢复神经发生并减轻焦虑相关行为。我们的研究提供了概念验证的证据，衰老细胞是肥胖引起焦虑的主要因素，衰老药物是治疗神经精神疾病的潜在新治疗途径。
Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16(Ink4a)-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed "accumulation of lipids in senescence." Clearing senescent cells from high fat-fed or leptin receptor deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.