Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109, USA.
Geroscience. 2024 Oct;46(5):4689-4706. doi: 10.1007/s11357-024-01207-y. Epub 2024 May 24.
Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.
饮食限制（DR）和低氧（缺氧）通过诱导趋同的下游长寿基因 fmo-2 延长秀丽隐杆线虫的寿命。黄素单加氧酶（FMOs）是高度保守的异生物质代谢酶，在促进线虫的长寿中具有明确的作用，并且在哺乳动物中可能具有类似的作用。这使得它们成为刺激长寿途径的健康促进作用的小分子药物的有吸引力的潜在靶标。在这里，我们利用秀丽隐杆线虫中的 fmo-2 荧光转录报告基因筛选了一组 80 种先前显示可提高小鼠成纤维细胞应激抗性的化合物。我们的数据表明，有 19 种化合物显著诱导了 fmo-2，其中 10 种化合物诱导 fmo-2 的程度超过两倍。有趣的是，这 10 种高 fmo-2 诱导剂中有 9 种也延长了秀丽隐杆线虫的寿命。其中两种药物是线粒体呼吸链复合物抑制剂，它们与低氧途径相互作用诱导 fmo-2，而两种多巴胺受体 2（DRD2）拮抗剂与 DR 途径相互作用诱导 fmo-2，表明多巴胺信号参与 DR 介导的 fmo-2 诱导。总之，我们的数据确定了九种药物，它们都（1）提高了小鼠成纤维细胞的应激抗性，（2）诱导了秀丽隐杆线虫中的 fmo-2，（3）延长了线虫的寿命，其中一些是通过已知的长寿途径。这些结果将 fmo-2 诱导确定为识别和理解潜在长寿化合物机制的可行方法。
