Inflammaging is associated with aging-associated cognitive loss and neurodegeneration. Chronic nonsteroidal anti-inflammatory drug (NSAID) use has been reported to reduce the incidence of Alzheimer's disease (AD), presumably by inhibiting inflammation, although NSAIDs appear to not be good candidates for anti-AD therapeutics given disappointing clinical trial results. Prostaglandin E2 (PGE2) acts downstream of NSAID target COX-2, a cyclooxygenase, to activate several G-protein coupled receptors (GPCRs) including EP2, which is now reported to reduce glycolysis and oxidative phosphorylation during aging by increasing glycogen synthesis and polarizing myeloid cells toward the M1 proinflammatory phenotype. Inhibiting EP2 using small molecule drugs polarizes macrophages toward the anti-inflammatory phenotype, restores youthful metabolism and mitochondrial morphology as well as youthful hippocampus-based memory capability. EP2 may be a better target than COXs for the development of drugs that improve age-associated mild cognitive impairment and possibly even for the development of drugs to treat dementias.

中文翻译：

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代谢重编程使衰老的髓样细胞恢复活力，恢复认知

炎症与衰老相关的认知丧失和神经变性有关。据报道，慢性非甾体抗炎药 (NSAID) 的使用可降低阿尔茨海默病 (AD) 的发病率，这可能是通过抑制炎症来实现的，尽管鉴于令人失望的临床试验结果，NSAIDs 似乎不是抗 AD 疗法的良好候选药物。前列腺素 E2 (PGE2) 在 NSAID 靶标 COX-2（一种环氧合酶）的下游起作用，以激活包括 EP2 在内的几种 G 蛋白偶联受体 (GPCR)，据报道，EP2 可通过增加糖原合成和极化骨髓来减少衰老过程中的糖酵解和氧化磷酸化细胞趋向 M1 促炎表型。使用小分子药物抑制 EP2 使巨噬细胞向抗炎表型极化，恢复年轻的新陈代谢和线粒体形态以及年轻的海马记忆能力。对于开发改善与年龄相关的轻度认知障碍的药物，甚至可能开发治疗痴呆症的药物，EP2 可能是比 COX 更好的靶点。