Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity,Aging Cell

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Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity
Aging Cell ( IF 8.0 ) Pub Date : 2021-07-06 , DOI: 10.1111/acel.13381
Rebecca L McIntyre ₁ , Simone W Denis ₁ , Rashmi Kamble ₁ , Marte Molenaars ₁ , Michael Petr ₂ , Bauke V Schomakers _{1,

3} , Mizanur Rahman ₄ , Siddhartha Gupta ₅ , Marton L Toth ₅ , Siva A Vanapalli _{4,

5} , Aldo Jongejan ₆ , Morten Scheibye-Knudsen ₂ , Riekelt H Houtkooper ₁ , Georges E Janssens ₁

Affiliation

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

中文翻译：

阿曲库铵抑制神经肌肉乙酰胆碱受体激活 FOXO/DAF-16 诱导的寿命

基于转录组的药物筛选正在成为一种强大的工具，可以识别老年保护化合物以干预与年龄相关的疾病。我们假设，通过模仿FOXO3（蠕虫中的daf - 16）过表达的高度保守的长寿干预的转录特征，我们可以识别和重新利用具有类似下游效应的化合物以延长寿命。我们的计算机筛选利用遗传和化合物干预的 LINCS 转录组数据库，确定了几种 FDA 批准的化合物，这些化合物可激活哺乳动物细胞中的 FOXO 下游靶标。其中包括神经肌肉阻滞剂阿曲库铵，它还有力地延长了秀丽隐杆线虫。这种长寿取决于daf - 16信号传导和神经肌肉乙酰胆碱受体亚基unc - 38的抑制。我们发现unc - 38 RNAi 可以改善健康寿命、寿命并刺激 DAF-16 核定位，类似于阿曲库铵治疗。最后，使用 RNA-seq 转录组学，我们确定了 DAF-16 下游效应子的阿曲库铵活化。总之，这些数据证明了用药物模拟遗传寿命干预的能力，并在此过程中揭示了神经肌肉乙酰胆碱受体调节高度保守的 FOXO/DAF-16 寿命通路。

更新日期：2021-08-19

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