TY - JOUR
T1 - Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity
AU - McIntyre, Rebecca L.
AU - Denis, Simone W.
AU - Kamble, Rashmi
AU - Molenaars, Marte
AU - Petr, Michael
AU - Schomakers, Bauke V.
AU - Rahman, Mizanur
AU - Gupta, Siddhartha
AU - Toth, Marton L.
AU - Vanapalli, Siva A.
AU - Jongejan, Aldo
AU - Scheibye-Knudsen, Morten
AU - Houtkooper, Riekelt H.
AU - Janssens, Georges E.
N1 - Funding Information: The authors thank the Caenorhabditis Genetics Center at the University of Minnesota for providing C. elegans strains. The CGC is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We thank Perry D. Moerland for assistance in analysis of the RNA sequencing, and Ron A. Hoebe, Daisy I. Picavet and Serhii Chornyi for their assistance in confocal microscopy. Work in the Houtkooper group is financially supported by an ERC Starting grant (no. 638290), a VIDI grant from ZonMw (no. 91715305), and the Velux Stiftung (no. 1063). GEJ is supported by a VENI grant from ZonMw (no. 09150161810014). Funding Information: The authors thank the Genetics Center at the University of Minnesota for providing . strains. The CGC is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We thank Perry D. Moerland for assistance in analysis of the RNA sequencing, and Ron A. Hoebe, Daisy I. Picavet and Serhii Chornyi for their assistance in confocal microscopy. Work in the Houtkooper group is financially supported by an ERC Starting grant (no. 638290), a VIDI grant from ZonMw (no. 91715305), and the Velux Stiftung (no. 1063). GEJ is supported by a VENI grant from ZonMw (no. 09150161810014). Caenorhabditis C elegans Publisher Copyright: © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - DAF-16
KW - FOXO
KW - acetylcholine
KW - aging
KW - atracurium
KW - longevity
KW - neuromuscular junction
UR - http://www.scopus.com/inward/record.url?scp=85109167319&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/acel.13381
DO - https://doi.org/10.1111/acel.13381
M3 - Article
C2 - 34227219
SN - 1474-9718
VL - 20
SP - e13381
JO - Aging cell
JF - Aging cell
IS - 8
M1 - e13381
ER -