ArticleRedox biology2020
Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A.
Article in Redox biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 23 citations in OpenAlex.
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- Functional analysis of conserved C. elegans bHLH family members uncovers lifespan control by a peptidergic hub neuron.PLoS biology · 2025Article
- 20(S)-protopanaxadiol prolongs lifespan and enhances stress resistance inFrontiers in pharmacology · 2025Article
- Unzipping the defense: a comprehensive review on bZIP transcription factors inFrontiers in cellular and infection microbiology · 2025Review
- Functional analysis of conservedbioRxiv : the preprint server for biology · 2024Article
- Redox regulation in lifespan determination.The Journal of biological chemistry · 2024Review
- A naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging.Nature communications · 2023Article
- Sanguinarine promotes healthspan and innate immunity through a conserved mechanism of ROS-mediated PMK-1/SKN-1 activation.iScience · 2022Article
- Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan.Nature communications · 2022Article
- Transcriptomic Analysis ofFrontiers in physiology · 2022Article
- Targeting metabolic pathways for extension of lifespan and healthspan across multiple species.Ageing research reviews · 2020Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.