Hou Lei, Wang Dan, Chen Di, Liu Yi, Zhang Yue, Cheng Hao, Xu Chi, Sun Na, McDermott Joseph, Mair William B, Han Jing-Dong J
Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Metab. 2016 Mar 8;23(3):529-40. doi: 10.1016/j.cmet.2016.02.002.
Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.
饮食限制（DR）是延长寿命最有效的自然方法。尽管有几个基因可以介导对不同饮食限制方案的反应，但没有单一的基因干预能够重现饮食限制的全部效果，并且对于不同的饮食限制方案，尚无统一的系统。在这里，我们在秀丽隐杆线虫的卡路里限制和间歇性禁食期间获得了时间分辨转录组，并发现早期和晚期反应分别涉及代谢和细胞周期/DNA损伤。我们通过其靶标特异性揭示了饮食限制调节因子的三个网络模块。通过对代表离散模块的节点进行基因操作，随着多个节点受到干扰，我们诱导出逐渐类似于饮食限制的转录组。同时靶向所有三个节点会产生对饮食限制具有抗性的极长寿动物。这些结果和动态模拟表明，可以利用调节因子之间广泛的反馈控制来驱动调节电路达到更年轻的稳态，从而重现饮食限制的全部效果。
