The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

大脑需要以 ATP 形式持续供应能量，其中大部分是通过线粒体中的氧化磷酸化从葡萄糖产生的，并辅以细胞质中的有氧糖酵解。当葡萄糖水平有限时，肝脏中产生的酮体和骨骼肌运动产生的乳酸也可以成为大脑的重要能量底物。在衰老引起的神经退行性疾病中，大脑葡萄糖代谢以进行性、区域特异性和疾病特异性的方式恶化——这一问题在阿尔茨海默病中最为明显，它始于症状发生前。本综述讨论了通过改善、保存或挽救大脑能量来对抗衰老神经退行性疾病的治疗策略的现状和前景。所描述的方法包括恢复氧化磷酸化和糖酵解、增加胰岛素敏感性、纠正线粒体功能障碍、基于酮的干预措施、通过调节大脑能量的激素、RNA疗法和补充性多模式生活方式改变发挥作用。