DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan
DDS, 4,4′-diaminodiphenylsulfone, extends organismic lifespan
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DOI：
10.1073/pnas.1005078107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Lee, Junho
中科院分区：
文献类型：
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作者：
Cho, Sung Chun;Park, Moon Cheol;Lee, Junho
DDS，即4，4 '-二氨基二苯砜，是治疗汉森病患者的最常用药物。除了其抗菌活性外，DDS还被报道参与真核细胞中发生的其他细胞过程。由于DDS治疗显着增强人体的抗氧化活性，我们研究了其对寿命延长的影响。在这里，我们表明，DDS延长器官寿命秀丽隐杆线虫作为一个模型系统。DDS治疗导致衰老延迟，并降低了线粒体复合物的水平。耗氧率也明显降低。与这些数据一致，百草枯处理引起DDS处理的蠕虫中活性氧较少，这些蠕虫对百草枯不太敏感。足够有趣的是，DDS治疗引起的所有分子事件在用DDS治疗3个月的小鼠和C2 C12肌肉细胞系中一致地再现。结构预测确定丙酮酸激酶（PK）为DDS的蛋白质靶点。事实上，DDS在体外结合并抑制PK，在体内抑制PK，并且PK突变赋予C的寿命延长。优雅补充丙酮酸对百草枯引起的C2 C12细胞凋亡有保护作用。我们的研究结果确立了DDS在降低活性氧产生和延长寿命方面的意义，这为研究DDS对人类寿命延长的可能影响提供了理论基础。
DDS, 4,4'-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.