Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A
Leonid Rozanov,
Meenakshi Ravichandran,
Giovanna Grigolon,
Maria Clara Zanellati,
Johannes Mansfeld,
Kim Zarse,
Nir Barzilai,
Gil Atzmon,
Fabian Fischer,
Michael Ristow
Affiliations
Leonid Rozanov
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
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
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
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
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
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
Albert Einstein College of Medicine, Departments of Genetics and of Medicine, Bronx, NY, 10461, USA
Gil Atzmon
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
Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland; Corresponding author.
Michael Ristow
Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, CH-8603, Switzerland; Corresponding author.
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.
