Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan

Giovanna Grigolon, Elisa Araldi, Reto Erni, Jia Yee Wu, Carolin Thomas, Marco Fortezza, Beate Laube, Doris Pöhlmann, Markus Stoffel, Kim Zarse, Erick M. Carreira, Michael Ristow () and Fabian Fischer
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Giovanna Grigolon: Swiss Federal Institute of Technology (ETH) Zurich
Elisa Araldi: Swiss Federal Institute of Technology (ETH) Zurich
Reto Erni: Swiss Federal Institute of Technology (ETH) Zurich
Jia Yee Wu: Swiss Federal Institute of Technology (ETH) Zurich
Carolin Thomas: Swiss Federal Institute of Technology (ETH) Zurich
Marco Fortezza: Swiss Federal Institute of Technology (ETH) Zurich
Beate Laube: Swiss Federal Institute of Technology (ETH) Zurich
Doris Pöhlmann: Swiss Federal Institute of Technology (ETH) Zurich
Markus Stoffel: Swiss Federal Institute of Technology (ETH) Zurich
Kim Zarse: Swiss Federal Institute of Technology (ETH) Zurich
Erick M. Carreira: Swiss Federal Institute of Technology (ETH) Zurich
Michael Ristow: Swiss Federal Institute of Technology (ETH) Zurich
Fabian Fischer: Swiss Federal Institute of Technology (ETH) Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Aging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.

Date: 2022
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DOI: 10.1038/s41467-021-27732-4

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