{"doi":"10.1101/2025.10.10.681695","title":"Aged brain multi-omic integration captures immunometabolic and sex variation","abstract":"Resolving the molecular basis for heterogeneous ageing in the human brain requires integrating its diverse molecular layers. Here we applied a tensor-decomposition framework to jointly analyse single-nucleus RNA-seq, DNA methylation, H3K9ac histone acetylation and proteomic data from 276 post-mortem human cortices. The analysis uncovered two dominant, multi-omic themes. First, we identified an immunometabolic axis characterised by microglial activation, suppression of PI3K-Akt-mTOR signalling and epigenetic signatures that suggest repurposing of developmental transcription factors such as BARHL1. Second, we decomposed the effect of sex into a multi-omic program linked to cellular plasticity: although driven by canonical sex-chromosome genes, this axis was epigenetically enriched for pathways regulating stem-cell pluripotency and exhibited a female-biased shift toward precursor-like states in the oligodendrocyte lineage. Together, these findings deliver a high-resolution atlas of glial ageing and demonstrate that broad risk factors manifest as complex, cell-specific vulnerabilities; an insight critical for the development of targeted therapeutic strategies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577733,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8918,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":468003,"name":"Holly C. Hunsberger","orcid":"0000-0002-4797-9311","position":1,"is_corresponding":false},{"id":322308,"name":"David Bennett","orcid":"0000-0001-5354-152X","position":2,"is_corresponding":false},{"id":282469,"name":"Melissa Lamar","orcid":"0000-0001-6130-5543","position":3,"is_corresponding":false},{"id":1096570,"name":"Daniel A. Peterson","orcid":"0000-0001-7275-6403","position":4,"is_corresponding":false},{"id":312027,"name":"Grace E. Stutzmann","orcid":"0000-0003-2841-8532","position":5,"is_corresponding":false},{"id":14205,"name":"Justin P. Whalley","orcid":"0000-0002-0403-3091","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:58:16.148027Z","pmid":"41279712","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":[]}