Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF‐16‐induced longevity. Issue 8 (6th July 2021)

• Record Type: Journal Article
• Authors: McIntyre, Rebecca L.; Denis, Simone W.; Kamble, Rashmi; Molenaars, Marte; Petr, Michael; Schomakers, Bauke V.; Rahman, Mizanur; Gupta, Siddhartha; Toth, Marton L.; Vanapalli, Siva A.; Jongejan, Aldo; Scheibye‐Knudsen, Morten; Houtkooper, Riekelt H.; Janssens, Georges E.
• Is Part Of: Aging cell. Volume 20:Issue 8(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-06
• Subjects: acetylcholine -- aging -- atracurium -- DAF‐16 -- FOXO -- longevity -- neuromuscular junction; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13381
• Languages: English
• ISSNs: 1474-9718

Abstract

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. Abstract : Transcriptome‐based drug screening is a powerful tool to identify geroprotective compounds. By mimicking the transcriptional signature of FOXO3 ( daf ‐ 16 in worms) overexpression, we identified the neuromuscular blocker atracurium, which extends both lifespan and healthspan in Caenorhabditis elegans . Here we demonstrate the capacity to mimic genetic lifespan interventions with drugs, and reveal that the neuromuscular acetylcholine receptor regulates the highly conserved DAF‐16 longevity pathway.