{"doi":"10.1126/sciadv.abj8658","title":"Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression","abstract":"The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer’s disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine–activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose–dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant–elongated life span and diminishes daf-16 –induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.","journal":"Science Advances","year":2022,"id":240412,"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":45,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":380550,"name":"Hiroshi Qadota","orcid":"0000-0002-6769-9464","position":1,"is_corresponding":false},{"id":315504,"name":"Zhi-Hao Wang","orcid":"0000-0002-2517-8679","position":2,"is_corresponding":false},{"id":679968,"name":"Pai Liu","orcid":"0000-0003-1029-4973","position":3,"is_corresponding":false},{"id":297920,"name":"Xia Liu","orcid":"0000-0002-0180-2166","position":4,"is_corresponding":false},{"id":315507,"name":"Karen X. Ye","orcid":"0000-0003-1970-2056","position":5,"is_corresponding":false},{"id":826258,"name":"Courtney J. Matheny","orcid":"0000-0001-7707-5180","position":6,"is_corresponding":false},{"id":536274,"name":"Ken Berglund","orcid":"0000-0003-4341-0838","position":7,"is_corresponding":false},{"id":315506,"name":"Shan Ping Yu","orcid":"0000-0003-1335-1398","position":8,"is_corresponding":false},{"id":551075,"name":"Derek Drake","orcid":null,"position":9,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":10,"is_corresponding":false},{"id":315508,"name":"Xiaochuan Wang","orcid":"0000-0001-8207-0042","position":11,"is_corresponding":false},{"id":587112,"name":"Bruce A. Yankner","orcid":"0009-0008-8982-225X","position":12,"is_corresponding":false},{"id":380554,"name":"Guy M. Benian","orcid":"0000-0002-8236-3176","position":13,"is_corresponding":false},{"id":303997,"name":"Keqiang Ye","orcid":"0000-0002-7657-8154","position":14,"is_corresponding":false},{"id":315503,"name":"Yiyuan Xia","orcid":"0000-0001-7833-0497","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:22:46.554789Z","pmid":"35353567","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":[]}