Zimmerman Stephanie M, Kim Stuart K
Department of Genetics, Stanford University Medical Center, Stanford, CA, 94305, USA.
Aging Cell. 2014 Apr;13(2):329-39. doi: 10.1111/acel.12179. Epub 2013 Dec 6.
Aging is associated with a large number of both phenotypic and molecular changes, but for most of these, it is not known whether these changes are detrimental, neutral, or protective. We have identified a conserved Caenorhabditis elegans GATA transcription factor/MTA-1 homolog egr-1 (lin-40) that extends lifespan and promotes resistance to heat and UV stress when overexpressed. Expression of egr-1 increases with age, suggesting that it may promote survival during normal aging. This increase in expression is dependent on the presence of the germline, raising the possibility that egr-1 expression is regulated by signals from the germline. In addition, loss of egr-1 suppresses the long lifespan of insulin receptor daf-2 mutants. The DAF-16 FOXO transcription factor is required for the increased stress resistance of egr-1 overexpression mutants, and egr-1 is necessary for the proper regulation of sod-3 (a reporter for DAF-16 activity). These results indicate that egr-1 acts within the insulin signaling pathway. egr-1 can also activate the expression of its paralog egl-27, another factor known to extend lifespan and increase stress resistance, suggesting that the two genes act in a common program to promote survival. These results identify egr-1 as part of a longevity-promoting circuit that changes with age in a manner that is beneficial for the lifespan of the organism.
衰老与大量表型和分子变化相关,但对于其中大多数变化,尚不清楚这些变化是有害的、中性的还是具有保护作用的。我们鉴定出一种保守的秀丽隐杆线虫GATA转录因子/MTA-1同源物egr-1(lin-40),其过表达时可延长寿命并增强对热和紫外线应激的抵抗力。egr-1的表达随年龄增长而增加,这表明它可能在正常衰老过程中促进生存。这种表达增加依赖于生殖系的存在,这增加了egr-1表达受来自生殖系信号调控的可能性。此外,egr-1的缺失抑制了胰岛素受体daf-2突变体的长寿命。DAF-16 FOXO转录因子是egr-1过表达突变体增强应激抵抗力所必需的,而egr-1对于sod-3(DAF-16活性的报告基因)的正常调控是必需的。这些结果表明egr-1在胰岛素信号通路中起作用。egr-1还可以激活其旁系同源物egl-27的表达,egl-27是另一个已知可延长寿命并增加应激抵抗力的因子,这表明这两个基因在促进生存的共同程序中发挥作用。这些结果确定egr-1是促进长寿回路的一部分,该回路随年龄变化,其方式对生物体的寿命有益。