Qian Hong, Xu Xiangru, Niklason Laura E
Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Biomedical Engineering, Yale University, New Haven,CT 06520, USA.
Aging (Albany NY). 2015 Jan;7(1):1-13. doi: 10.18632/aging.100713.
Components or downstream targets of many signaling pathways such as Insulin/IGF-1 and TOR, as well as genes involved in cellular metabolism and bioenergetics can extend worm lifespan 20% or more. The C. elegans gene pch-2 and its homologs, including TRIP13 in humans, have been studied for their functions in cell mitosis and meiosis, but have never been implicated in lifespan regulation. Here we show that over-expression of TRIP13 in human fibroblasts confers resistance to environmental stressors such as UV radiation and oxidative stress. Furthermore, pch-2 overexpression in C. elegans extends worm lifespan, and enhances worm survival in response to various stressors. Conversely, reducing pch-2 expression with RNAi shortens worm lifespan. Additional genetic epistasis analysis indicates that the molecular mechanism of pch-2 in worm longevity is tied to functions of the sirtuin family, implying that pch-2 is another chromatin regulator for worm longevity. These findings suggest a novel function of the pch-2 gene involved in lifespan determination.
许多信号通路的组成部分或下游靶点，如胰岛素/胰岛素样生长因子-1（Insulin/IGF-1）和雷帕霉素靶蛋白（TOR），以及参与细胞代谢和生物能量学的基因，都可以使线虫的寿命延长20%或更多。秀丽隐杆线虫（C. elegans）基因pch-2及其同源物，包括人类中的TRIP13，已对其在细胞有丝分裂和减数分裂中的功能进行了研究，但从未涉及寿命调控。在这里，我们表明在人类成纤维细胞中过表达TRIP13可赋予对紫外线辐射和氧化应激等环境应激源的抗性。此外，在秀丽隐杆线虫中过表达pch-2可延长线虫寿命，并增强线虫对各种应激源的存活能力。相反，用RNA干扰降低pch-2的表达会缩短线虫寿命。额外的遗传上位性分析表明，pch-2在线虫长寿中的分子机制与沉默调节蛋白家族的功能相关，这意味着pch-2是线虫长寿的另一种染色质调节因子。这些发现表明pch-2基因在寿命决定中具有新功能。
