Cohen Ehud
Biochemistry and Molecular Biology, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
Rambam Maimonides Med J. 2012 Oct 31;3(4):e0021. doi: 10.5041/RMMJ.10088. Print 2012 Oct.
Late onset is a key unifying feature of human neurodegenerative maladies such as Alzheimer's and Parkinson's diseases and prion disorders. While sporadic cases typically emerge during the patient's seventh decade of life or later, mutation-linked, familial cases manifest during the fifth or sixth decade. This common temporal emergence pattern raises the prospect that slowing aging may prevent the accumulation of toxic protein aggregates that lead to the development of these disorders, postpone the onset of these maladies, and alleviate their symptoms once emerged. Invertebrate-based studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway, protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway-protected Alzheimer's model mice from the behavioral and biochemical impairments associated with the disease. Here I review the recent advances in the field, describe the known mechanistic links between toxic protein aggregation and the aging process, and delineate the future therapeutic potential of IIS reduction as a treatment for various neurodegenerative disorders.
发病较晚是人类神经退行性疾病（如阿尔茨海默病、帕金森病和朊病毒病）的一个关键统一特征。散发性病例通常在患者七十岁或更晚时出现，而与突变相关的家族性病例则在五十或六十岁时出现。这种常见的发病时间模式引发了一种可能性，即延缓衰老可能会阻止导致这些疾病发生的有毒蛋白质聚集体的积累，推迟这些疾病的发病，并在发病后减轻其症状。基于无脊椎动物的研究表明，降低胰岛素/胰岛素样生长因子信号传导（IIS）（一种重要的衰老调节途径）的活性，可以防止与神经退行性变相关的有毒蛋白质聚集。这种方法的有效性已在哺乳动物中得到测试和证实，因为降低IGF-1信号通路的活性可保护阿尔茨海默病模型小鼠免受与该疾病相关的行为和生化损伤。在此，我将回顾该领域的最新进展，描述有毒蛋白质聚集与衰老过程之间已知的机制联系，并阐述降低IIS作为治疗各种神经退行性疾病的未来治疗潜力。
