Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210061, China; Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, Zhejiang 314400, China.
Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210061, China.
J Genet Genomics. 2024 May;51(5):507-516. doi: 10.1016/j.jgg.2023.11.002. Epub 2023 Nov 10.
The highly conserved target of rapamycin (TOR) pathway plays an important role in aging across species. Previous studies have established that inhibition of the TOR complex 1 (TORC1) significantly extends lifespan in Caenorhabditiselegans. However, it has not been clear whether TORC1 perturbation affects aging in a spatiotemporal manner. Here, we apply the auxin-inducible degradation tool to knock down endogenous DAF-15, the C. elegans ortholog of regulatory associated protein of TOR (Raptor), to characterize its roles in aging. Global or tissue-specific inhibition of DAF-15 during development results in various growth defects, whereas neuron-specific knockdown of DAF-15 during adulthood significantly extends lifespan and healthspan. The neuronal DAF-15 deficiency-induced longevity requires the intestinal activities of DAF-16/FOXO and PHA-4/FOXA transcription factors, as well as the AAK-2/AMP-activated protein kinase α catalytic subunit. Transcriptome profiling reveals that the neuronal DAF-15 knockdown promotes the expression of genes involved in protection. These findings define the tissue-specific roles of TORC1 in healthy aging and highlight the importance of neuronal modulation of aging.
雷帕霉素靶蛋白（TOR）途径高度保守，在不同物种的衰老过程中发挥重要作用。先前的研究已经证实，抑制 TOR 复合物 1（TORC1）可以显著延长秀丽隐杆线虫的寿命。然而，TORC1 的干扰是否以时空方式影响衰老还不清楚。在这里，我们应用生长素诱导的降解工具来敲低内源性 DAF-15，即秀丽隐杆线虫 TOR 的调节相关蛋白（Raptor）的同源物，以研究其在衰老过程中的作用。在发育过程中，DAF-15 的全局或组织特异性抑制会导致各种生长缺陷，而成年期神经元特异性敲低 DAF-15 会显著延长寿命和健康寿命。神经元 DAF-15 缺乏诱导的长寿需要肠道中 DAF-16/FOXO 和 PHA-4/FOXA 转录因子的活性，以及 AAK-2/AMP 激活蛋白激酶α催化亚基的活性。转录组谱分析表明，神经元 DAF-15 的敲低促进了参与保护的基因的表达。这些发现定义了 TORC1 在健康衰老中的组织特异性作用，并强调了神经元对衰老的调节的重要性。
