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Restoring metabolism of myeloid cells reverses cognitive decline in ageing

机译：恢复骨髓细胞的新陈代谢逆转老龄化的认知下降

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摘要

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty~(1-3). The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease~(4-6). Systemically, circulating pro-inflammatory factors can promote cognitive decline~(7,8), and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration~(9,10). However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E_(2)(PGE_(2)), a major modulator of inflammation~(11). In ageing macrophages and microglia, PGE_(2)signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
机译：老化的特征在于持续的促炎反应的发展，这些反应有助于动脉粥样硬化，代谢综合征，癌症和脆弱〜（1-3）。老龄化脑也容易受到炎症，正如年龄相关的认知下降和阿尔茨海默病的高患病率所证明〜（4-6）。系统性地，循环促炎因子可以促进认知下降〜（7,8），并且在大脑中，小胶鸡失去了清除与神经变性相关的错误折叠〜（9,10）的蛋白质的能力。然而，与老化的发起和维持不良炎症的潜在机制并不明确。在这里，我们表明，在衰老小鼠中，粘蛋白细胞生物共生学响应于脂质通信前列腺素e_（2）（PGE_（2）），炎症的主要调节剂〜（11）。在衰老巨噬细胞和微胶质细胞中，通过其EP2受体的PGE_（2）信号传导促进葡萄糖将葡萄糖的螯合成糖原，降低葡萄糖助焊剂和线粒体呼吸。这种能量缺陷的状态驱动不良促炎反应，进一步增强了老年髓细胞作为主要燃料源的葡萄糖的依赖性。在老年的小鼠中，抑制骨髓EP2信号传导恢复细胞生物能源，全身性和脑炎症状态，海马突触塑性和空间记忆。此外，封闭的外周骨髓EP2信号传导足以恢复老年小鼠中的认知。我们的研究表明，认知老龄化不是静态或不可撤销的病症，但可以通过重编程骨髓葡萄糖代谢来恢复恢复青春免疫功能。

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  • 来源
    《Nature》 |2021年第7844期|122-128|共7页
  • 作者

    Paras S Minhas; Amira Latif-Hernandez; Melanie R McReynolds; Aarooran S Durairaj; Qian Wang; Amanda Rubin; Amit U Joshi; Joy Q He; Esha Gauba; Ling Liu; Congcong Wang; Miles Linde; Yuki Sugiura; Peter K Moon; Ravi Majeti; Makoto Suematsu; Daria Mochly-Rosen; Irving L Weissman; Frank M Longo; Joshua D Rabinowitz; Katrin I Andreasson;

  • 作者单位

    Department of Neurology and Neurological Sciences Stanford University School of Medicine|Neurosciences Graduate Program Stanford University|Medical Scientist Training Program Stanford University;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Chemistry Princeton University|Lewis-Sigler Institute for Integrative Genomics Princeton University;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine|Neurosciences Graduate Program Stanford University;

    Department of Chemical and Systems Biology Stanford University;

    Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Chemistry Princeton University|Lewis-Sigler Institute for Integrative Genomics Princeton University;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Hematology Stanford University School of Medicine;

    Department of Biochemistry Keio University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Hematology Stanford University School of Medicine;

    Department of Biochemistry Keio University School of Medicine;

    Department of Chemical and Systems Biology Stanford University;

    Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine;

    Department of Chemistry Princeton University|Lewis-Sigler Institute for Integrative Genomics Princeton University;

    Department of Neurology and Neurological Sciences Stanford University School of Medicine|Wu Tsai Neurosciences Institute Stanford University|Stanford Immunology Program Stanford University;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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