Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, H4A 3J1, Canada; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
Mech Ageing Dev. 2020 Sep;190:111297. doi: 10.1016/j.mad.2020.111297. Epub 2020 Jun 28.
While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of these diseases, the disease-causing mutation is present from birth but symptoms appear decades later. This indicates that these mutations are well tolerated in younger individuals but not in older adults. Based on this observation, we hypothesized that changes taking place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in the treatment of neurodegenerative disease. In this review, we examine the effects of five compounds that have been shown to extend longevity (metformin, rapamycin, resveratrol, N-acetyl-l-cysteine, curcumin) in four of the most common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis). While not all investigations observe a beneficial effect of these compounds, there are multiple studies that show a protective effect of each of these lifespan-extending compounds in animal models of neurodegenerative disease. Combined with genetic studies, this suggests the possibility that targeting the aging process may be an effective strategy to treat neurodegenerative disease.
虽然衰老时导致神经退行性疾病发生的最大风险因素，但衰老在这些疾病中的作用仍知之甚少。在这些疾病的遗传性形式中，致病突变从出生时就存在，但症状要几十年后才出现。这表明这些突变在年轻个体中可以很好地耐受，但在老年个体中则不能。基于这一观察结果，我们假设在正常衰老过程中发生的变化使大脑（和其他地方）中的细胞容易受到致病突变的影响。如果是这样，那么延迟其中一些与年龄相关的变化可能有益于神经退行性疾病的治疗。在这篇综述中，我们检查了已经显示能延长寿命的五种化合物（二甲双胍、雷帕霉素、白藜芦醇、N-乙酰-L-半胱氨酸、姜黄素）在四种最常见的神经退行性疾病（阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症）中的作用。虽然并非所有研究都观察到这些化合物的有益效果，但有多项研究表明，这些延长寿命的化合物中的每一种在神经退行性疾病的动物模型中都具有保护作用。结合遗传研究，这表明靶向衰老过程可能是治疗神经退行性疾病的有效策略。
