{"doi":"10.1016/j.redox.2020.101448","title":"Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A","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.","journal":"Redox Biology","year":2020,"id":105245,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":243025,"name":"Meenakshi Ravichandran","orcid":"0000-0002-4104-5497","position":1,"is_corresponding":false},{"id":509715,"name":"Giovanna Grigolon","orcid":"0000-0002-0838-8826","position":2,"is_corresponding":false},{"id":509716,"name":"Maria Clara Zanellati","orcid":"0000-0003-0597-4923","position":3,"is_corresponding":false},{"id":510808,"name":"Johannes Mansfeld","orcid":null,"position":4,"is_corresponding":false},{"id":509717,"name":"Kim Zarse","orcid":"0000-0003-2542-6123","position":5,"is_corresponding":false},{"id":90076,"name":"Nir Barzilai","orcid":"0000-0002-7787-6268","position":6,"is_corresponding":false},{"id":1031,"name":"Gil Atzmon","orcid":"0000-0001-6895-3607","position":7,"is_corresponding":false},{"id":509718,"name":"Fabian Fischer","orcid":"0000-0002-4159-3178","position":8,"is_corresponding":false},{"id":509719,"name":"Michael Ristow","orcid":"0000-0003-2109-2453","position":9,"is_corresponding":false},{"id":509714,"name":"Leonid Rozanov","orcid":"0000-0002-2191-9230","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-18T23:12:17.683386Z","pmid":"32203922","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}