The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
Ageing Res Rev. 2015 May;21:30-42. doi: 10.1016/j.arr.2015.02.001. Epub 2015 Feb 12.
To develop successful therapies that prevent or treat neurodegenerative diseases requires an understanding of the upstream events. Ageing is by far the greatest risk factor for most of these diseases, and to clarify their causes will require an understanding of the process of ageing itself. Starting with the question Why do we age as individual organisms, but the line of pluripotent embryonic stem cells and germ cells carried by individuals and transmitted to descendants is immortal? this review discusses how the process of cellular differentiation leads to the accumulation of biological imperfections with ageing, and how these imperfections may be the cause of chronic inflammatory responses to stress that undermine cellular function. Both differentiation and inflammation involve drastic metabolic changes associated with alterations in mitochondrial dynamics that shift the balance between aerobic glycolysis and oxidative phosphorylation. With ageing, mitochondrial dysfunction can be both the cause and consequence of inflammatory processes and elicit metabolic adaptations that might be either protective or become progressively detrimental. It is argued here that an understanding of the relationship between metabolism, differentiation and inflammation is essential to understand the pathological mechanisms governing brain health and disease during ageing.
要开发成功的治疗方法来预防或治疗神经退行性疾病，需要了解上游事件。衰老迄今为止是大多数这些疾病的最大风险因素，要阐明其原因，就需要了解衰老本身的过程。从个体生物为什么会衰老这一问题开始，但个体携带并传递给后代的多能胚胎干细胞和生殖细胞的寿命却是无限的，本综述讨论了细胞分化过程如何导致生物缺陷随着衰老而积累，以及这些缺陷如何可能成为对压力的慢性炎症反应的原因，这种反应会破坏细胞功能。分化和炎症都涉及与线粒体动态变化相关的剧烈代谢变化，这种变化改变了有氧糖酵解和氧化磷酸化之间的平衡。随着衰老，线粒体功能障碍既可以是炎症过程的原因，也可以是后果，并引发可能具有保护作用或逐渐产生有害作用的代谢适应。这里认为，理解代谢、分化和炎症之间的关系对于理解衰老过程中大脑健康和疾病的病理机制至关重要。
