Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A.

Animals Basic Helix-Loop-Helix Transcription Factors / genetics Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Longevity / genetics Mice Oxidation-Reduction Transcription Factors / genetics Zebrafish / genetics
Aging Arginine kinase Creatine kinase ROS Redox Transcription

Journal

Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639

Informations de publication

Date de publication:
05 2020
Historique:
received: 31 12 2019
accepted: 02 02 2020
pubmed: 24 3 2020
medline: 22 6 2021
entrez: 24 3 2020
Statut: ppublish

Résumé

Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms. Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference (RNAi) screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematodal lifespan in a ROS-dependent manner. We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.

Identifiants

DOI: 10.1016/j.redox.2020.101448 PMID: 32203922 PMC: PMC7096751
pubmed: 32203922
pii: S2213-2317(19)31618-0
doi: 10.1016/j.redox.2020.101448
pmc: PMC7096751
pii:
doi:

Substances chimiques

Basic Helix-Loop-Helix Transcription Factors 0
Caenorhabditis elegans Proteins 0
HLH-2 protein, C elegans 0
Transcription Factors 0

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

101448

Subventions

Organisme : NIA NIH HHS
ID : R01 AG042188
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046949
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057909
Pays : United States
Organisme : NIH HHS
ID : P40 OD010440
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG044829
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG038072
Pays : United States

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest None declared.

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Auteurs

Leonid Rozanov (L)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Meenakshi Ravichandran (M)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Giovanna Grigolon (G)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Maria Clara Zanellati (MC)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Johannes Mansfeld (J)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Kim Zarse (K)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland.

Nir Barzilai (N)

Albert Einstein College of Medicine, Departments of Genetics and of Medicine, Bronx, NY, 10461, USA.

Gil Atzmon (G)

Albert Einstein College of Medicine, Departments of Genetics and of Medicine, Bronx, NY, 10461, USA; University of Haifa, Faculty of Natural Sciences, Haifa, 3498838, Israel.

Fabian Fischer (F)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland. Electronic address: fabian-fischer@ethz.ch.

Michael Ristow (M)

Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland. Electronic address: michael-ristow@ethz.ch.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Redox-mediated regulation of aging and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Redox-mediated regulation of aging and...
questionsmedicales.fr › Eucaryotes › Animaux › Invertébrés › Helminthes › Nematoda › Chromadorea › Rhabditida › Rhabditoidea › Caenorhabditis › Caenorhabditis elegans › Redox-mediated regulation of aging and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines d'helminthes › Protéines de Caenorhabditis elegans › Redox-mediated regulation of aging and...
questionsmedicales.fr › Phénomènes physiologiques › Longévité › Redox-mediated regulation of aging and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Redox-mediated regulation of aging and...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Oxydoréduction › Redox-mediated regulation of aging and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Redox-mediated regulation of aging and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Poissons › Cypriniformes › Cyprinidae › Danio zébré › Redox-mediated regulation of aging and...