Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty^1,2,3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease^4,5,6. 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 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.

衰老的特点是持续促炎反应的发展，这些反应会导致动脉粥样硬化、代谢综合征、癌症和虚弱^1,2,3。衰老的大脑也容易受到炎症的影响，与年龄相关的认知能力下降和阿尔茨海默氏病的高患病率就证明了这一点^4,5,6。系统地，循环促炎因子可促进认知能力下降^7,8，而在大脑中，小胶质细胞失去清除与神经变性相关的错误折叠蛋白质的能力^9,10. 然而，随着衰老引发和维持适应不良炎症的潜在机制尚不清楚。在这里，我们表明在衰老小鼠中，髓样细胞生物能量学受到抑制，以响应脂质信使前列腺素 E ₂ (PGE ₂ )（炎症的主要调节剂¹¹ ）增加的信号传导。在老化的巨噬细胞和小胶质细胞中，PGE ₂通过其 EP2 受体的信号促进葡萄糖螯合成糖原，减少葡萄糖通量和线粒体呼吸。这种能量不足的状态会导致适应不良的促炎反应，而衰老的骨髓细胞对葡萄糖作为主要燃料来源的依赖会进一步加剧这种状态。在老年小鼠中，抑制骨髓 EP2 信号转导可使细胞生物能量学、全身和大脑炎症状态、海马体突触可塑性和空间记忆恢复活力。此外，外周髓细胞 EP2 信号通路的阻断足以恢复老年小鼠的认知能力。我们的研究表明，认知老化不是静态或不可逆转的情况，而是可以通过重新编程骨髓葡萄糖代谢来恢复年轻的免疫功能来逆转。