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恢复髓样细胞的代谢可逆转老年时期的认知下降
作者:小柯机器人 发布时间:2021/1/21 12:38:40

美国斯坦福大学医学院Katrin I. Andreasson研究团队发现,恢复髓样细胞的代谢可以逆转老年时期的认知能力下降。相关论文于2021年1月20日在线发表在《自然》杂志上。

研究人员表示,衰老的特征在于持续的促炎反应形成,进而导致动脉粥样硬化、代谢综合征、癌症和体弱。衰老的大脑也很容易发炎,并且会出现与年龄相关的认知能力下降以及阿尔茨海默氏病患病率的升高。在系统上,循环的促炎因子可以导致认知能力的下降;而在大脑中,小胶质细胞也会失去清除与神经变性相关错误折叠蛋白的能力。但是,引发和维持衰老的潜在机制尚不明确。

先前的研究表明,细胞能量代谢在调节免疫系统的激活状态和功能中起着重要的作用。为了维持体内平衡,免疫细胞需要强大的糖酵解和线粒体代谢来满足对能量和生物合成前体的需求。与此相符的是,最近的研究表明,衰老的巨噬细胞显示出引起免疫功能异常的糖酵解和线粒体氧化磷酸化水平的显著降低。

研究人员发现,在衰老的小鼠中,髓细胞生物能量代谢被脂质信使前列腺素E2(PGE2,一种主要的炎症调节剂)响应增加的信号传导所抑制。在衰老的巨噬细胞和小胶质细胞中,通过其EP2受体发出的PGE2信号促进了葡萄糖向葡萄糖原的螯合,并减少了葡萄糖通量和线粒体呼吸。衰老的髓样细胞对葡萄糖作为主要燃料来源的依赖性进一步加剧了这种能量不足状态,该状态驱动了适应不良的促炎性反应。在老年小鼠中,对髓样EP2信号的抑制可以恢复细胞生物能、全身和脑部炎症状态、海马突触可塑性和空间记忆。此外,对外周血髓样EP2信号的阻断足以恢复老年小鼠的认知。

因此,这项研究表明,认知衰老不是一个静态或不可挽回的状况,但可以通过重新编程髓样细胞中的葡萄糖代谢来恢复年轻的免疫功能。因此,抑制依赖于EP2的髓样细胞代谢变化可能是一种应对衰老的新方法。

附:英文原文

Title: Restoring metabolism of myeloid cells reverses cognitive decline in ageing

Author: 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

Issue&Volume: 2021-01-20

Abstract: Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1,2,3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease4,5,6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. 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 E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 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.

DOI: 10.1038/s41586-020-03160-0

Source: https://www.nature.com/articles/s41586-020-03160-0

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html