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阿曲库铵抑制神经肌肉乙酰胆碱受体可激活 FOXO/DAF-16 诱导的长寿。

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

机构信息

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

出版信息

Aging Cell. 2021 Aug;20(8):e13381. doi: 10.1111/acel.13381. Epub 2021 Jul 6.

DOI:10.1111/acel.13381
PMID:34227219
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8373276/
Abstract

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.

摘要

基于转录组的药物筛选作为一种强大的工具，正在被用于鉴定抗衰老化合物以干预与年龄相关的疾病。我们假设，通过模拟高度保守的长寿干预因子 FOXO3（线虫中的 daf-16）过表达的转录特征，我们可以识别和重新利用具有相似下游效应的化合物，以延长寿命。我们的基于 LINCS 转录组数据库的遗传和化合物干预的计算筛选，鉴定出了几种已获得 FDA 批准的化合物，这些化合物可以激活哺乳动物细胞中的 FOXO 下游靶点。其中包括神经肌肉阻滞剂阿曲库铵，它也能显著延长秀丽隐杆线虫的寿命和健康寿命。这种长寿依赖于 daf-16 信号和抑制神经肌肉乙酰胆碱受体亚基 unc-38。我们发现 unc-38 RNAi 可以改善健康寿命、寿命，并刺激 DAF-16 的核定位，类似于阿曲库铵处理。最后，我们使用 RNA-seq 转录组学，鉴定出阿曲库铵对 DAF-16 下游效应物的激活作用。总之，这些数据表明可以用药物模拟遗传寿命干预，并且表明神经肌肉乙酰胆碱受体调节高度保守的 FOXO/DAF-16 长寿途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/209374ef80fd/ACEL-20-e13381-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/ff3ca1911849/ACEL-20-e13381-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/6a3e645d96d6/ACEL-20-e13381-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/369247048a96/ACEL-20-e13381-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/6f4273e358e5/ACEL-20-e13381-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/209374ef80fd/ACEL-20-e13381-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/ff3ca1911849/ACEL-20-e13381-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/6a3e645d96d6/ACEL-20-e13381-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/369247048a96/ACEL-20-e13381-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/6f4273e358e5/ACEL-20-e13381-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/507e/8373276/209374ef80fd/ACEL-20-e13381-g001.jpg

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