Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.
DAF-16
FOXO
acetylcholine
aging
atracurium
longevity
neuromuscular junction
Journal
Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
02
03
2021
received:
23
07
2020
accepted:
26
04
2021
pubmed:
7
7
2021
medline:
1
2
2022
entrez:
6
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34227219
doi: 10.1111/acel.13381
pmc: PMC8373276
doi:
Substances chimiques
Caenorhabditis elegans Proteins
0
Forkhead Transcription Factors
0
Receptors, Cholinergic
0
daf-16 protein, C elegans
0
Atracurium
2GQ1IRY63P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13381Subventions
Organisme : NIH HHS
ID : P40 OD010440
Pays : United States
Informations de copyright
© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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