Reduced levels of neural activity are associated with a longer life span in the nematode Caenorhabditis elegans and in mice. Augmented neural activity is associated with a shorter life span. Recent studies show that levels of repressor element 1-silencing transcription factor (REST) increase with normal aging in mice and humans, and reduce neuronal excitation. In C. elegans, increased expression of spr-4, a functional REST homologue, increased the worm life span and is required for classical life span increase mediated by reduced DAF-2/insulin-IGF-1 and increased DAF-16. Preliminary evidence shows that REST and FOXO1, a DAF-16, homologue increase during mammalian aging, and that REST activity is needed for the age-related FOXO1 increase. On the contrary, REST is activated in epilepsy and plays a role in the pathogenesis of Huntington's disease. A simple unifying hypothesis suggests that REST is a "goldilocks-effect factor": too little REST promotes excitotoxic activity, which in turn leads to neurodegenerative diseases such as Alzheimer's. Appropriate increased levels of REST maintain the excitation/inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of REST beyond this are toxic as neurons become dysfunctional due to loss of a neuronal phenotype.

中文翻译：

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增加REST以优化寿命？

神经活动水平的降低与线虫秀丽隐杆线虫和小鼠的寿命更长有关。增强的神经活动与较短的寿命有关。最近的研究表明，抑制因子1沉默转录因子（REST）的水平随着小鼠和人类正常衰老而增加，并减少神经元兴奋。在秀丽隐杆线虫中，功能性REST同源物spr-4的表达增加，延长了蠕虫的寿命，这是减少DAF-2 /胰岛素-IGF-1和增加DAF-16介导的经典寿命的必要条件。初步证据表明，在哺乳动物衰老过程中，REST和FOXO1（一种DAF-16）的同系物增加，并且与年龄相关的FOXO1增长需要REST活性。相反，REST在癫痫病中被激活，并在亨廷顿舞蹈病的发病机理中起作用。一个简单的统一假设表明REST是一个“金雀花效应因子”：REST太少会促进兴奋性毒性活动，进而导致神经退行性疾病，例如阿尔茨海默氏病。适当增加的REST水平可通过减少潜在的兴奋性毒性活性来维持兴奋/抑制（EI）平衡。由于神经元表型的丧失，神经元功能失调，因此增加的REST含量是有毒的。