美国哈佛大学医学院Bruce A. Yankner研究团队发现神经兴奋和转录因子REST参与调控寿命。2019年10月16日，《自然》在线发表了这一成果。

研究人员发现人类的长寿与大脑皮层中独特的转录组特征相关，其特征是与神经兴奋和突触功能相关的基因的下调。在秀丽隐杆线虫中，神经兴奋随着年龄的增长而增加，并且在全局范围内、或者在谷氨酸能或胆碱能神经元中抑制兴奋能够增加寿命。

此外，寿命是由神经回路的兴奋抑制性平衡动态调节的。转录因子REST在长寿人类中被上调，并抑制与兴奋有关的基因。

值得注意的是，REST缺陷小鼠在衰老过程中表现出更高的皮质活性和神经元兴奋性。同样，秀丽隐杆线虫REST直系同源基因spr-3和spr-4的功能丧失突变会增强神经兴奋，并降低长寿突变体daf-2的寿命。在野生型线虫中，spr-4的过度表达会抑制兴奋并延长其寿命。REST、SPR-3、SPR-4以及兴奋的减少分别激活哺乳动物和线虫中与寿命相关的转录因子FOXO1和DAF-16。这些发现揭示了由神经回路活动介导并受REST调节的保守衰老机制。

研究人员介绍，目前为止，关于人类寿命延长的机制了解甚少。

附：英文原文

Title: Regulation of lifespan by neural excitation and REST

Author: Joseph M. Zullo, Derek Drake, Liviu Aron, Patrick OHern, Sameer C. Dhamne, Noah Davidsohn, Chai-An Mao, William H. Klein, Alexander Rotenberg, David A. Bennett, George M. Church, Monica P. Colaicovo, Bruce A. Yankner

Issue&Volume: 2019-10-16

Abstract: 

The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory–inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST.

DOI: 10.1038/s41586-019-1647-8

Source:https://www.nature.com/articles/s41586-019-1647-8