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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number101448
JournalRedox Biology
Volume32
DOIs
StatePublished - May 2020

Keywords

  • Aging
  • Arginine kinase
  • Creatine kinase
  • ROS
  • Redox
  • Transcription

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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    Rozanov, L., Ravichandran, M., Grigolon, G., Zanellati, M. C., Mansfeld, J., Zarse, K., Barzilai, N., Atzmon, G., Fischer, F., & Ristow, M. (2020). Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A. Redox Biology, 32, [101448]. https://doi.org/10.1016/j.redox.2020.101448