2. Academic Validation
  3. Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan

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

  • Nat Commun. 2022 Jan 10;13(1):107. doi: 10.1038/s41467-021-27732-4.
Giovanna Grigolon # 1,  Elisa Araldi 1 2,  Reto Erni 3,  Jia Yee Wu 1,  Carolin Thomas 1,  Marco La Fortezza 4,  Beate Laube 1,  Doris Pöhlmann 1,  Markus Stoffel 2,  Kim Zarse 1,  Erick M Carreira 3,  Michael Ristow 5,  Fabian Fischer # 1
Affiliations

Affiliations

  • 1 Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.
  • 2 Metabolism and Metabolic Disease Laboratory, Institute for Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, CH-8093, Switzerland.
  • 3 Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, CH-8093, Switzerland.
  • 4 Evolutionary Biology Laboratory, Department of Environmental Systems Science, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, CH-8092, Switzerland.
  • 5 Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland. [email protected].
  • # Contributed equally.
PMID: 35013237 DOI: 10.1038/s41467-021-27732-4
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.

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