{"doi":"10.1016/j.celrep.2025.115562","title":"SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19","abstract":"Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD + -dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD + booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.","journal":"Cell Reports","year":2025,"id":513282,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"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":1038708,"name":"Biyun Xue","orcid":null,"position":1,"is_corresponding":false},{"id":817064,"name":"Jian Zheng","orcid":"0000-0003-0616-5570","position":2,"is_corresponding":false},{"id":1214555,"name":"Yifei Wang","orcid":"0000-0002-8873-613X","position":3,"is_corresponding":false},{"id":775242,"name":"Zehan Song","orcid":"0009-0007-0413-3117","position":4,"is_corresponding":false},{"id":228829,"name":"Wei‐Chieh Mu","orcid":"0000-0003-2669-7312","position":5,"is_corresponding":false},{"id":902640,"name":"Chih-Ling Wang","orcid":"0000-0002-0836-5026","position":6,"is_corresponding":false},{"id":1207526,"name":"Jiayue Guo","orcid":"0000-0001-5753-1505","position":7,"is_corresponding":false},{"id":372053,"name":"Fanghan Yang","orcid":"0000-0002-3498-4517","position":8,"is_corresponding":false},{"id":902642,"name":"Yuze Ma","orcid":"0000-0003-4356-9531","position":9,"is_corresponding":false},{"id":494931,"name":"Xuetong Wei","orcid":null,"position":10,"is_corresponding":false},{"id":2361,"name":"Chengjin Ye","orcid":"0000-0002-1934-9494","position":11,"is_corresponding":false},{"id":1374971,"name":"N.A. Sims","orcid":null,"position":12,"is_corresponding":false},{"id":2423,"name":"Luis Martínez‐Sobrido","orcid":"0000-0001-7084-0804","position":13,"is_corresponding":false},{"id":77538,"name":"Stanley Perlman","orcid":"0000-0003-4213-2354","position":14,"is_corresponding":false},{"id":228832,"name":"Danica Chen","orcid":"0000-0001-9169-4973","position":15,"is_corresponding":false},{"id":902641,"name":"Marine Barthez","orcid":"0000-0001-6910-0403","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-19T02:48:17.908238Z","pmid":"40220296","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":[]}