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Adv."],"published-print":{"date-parts":[[2026,6,26]]},"abstract":"<jats:p>\n                    The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer\u2019s disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used\n                    <jats:italic toggle=\"yes\">Nlrp3<\/jats:italic>\n                    knockout mouse models, Nlrp3 haploinsufficient mice\u2014more representative of the effects of pharmacological inhibition\u2014are rarely included and remain poorly characterized. Here, we report the long-term effects of\n                    <jats:italic toggle=\"yes\">Nlrp3<\/jats:italic>\n                    haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age,\n                    <jats:italic toggle=\"yes\">Nlrp3<\/jats:italic>\n                    heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec9499","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:59:33Z","timestamp":1782496773000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7240-8334","authenticated-orcid":true,"given":"In\u00e9s","family":"Muela-Zarzuela","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-431X","authenticated-orcid":true,"given":"Elisabet","family":"Alcocer-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Departamento de Psicolog\u00eda Experimental, Facultad de Psicolog\u00eda, Universidad de Sevilla, 41009 Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6260-7284","authenticated-orcid":true,"given":"Juan M.","family":"Suarez-Rivero","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-5123","authenticated-orcid":true,"given":"Evon","family":"Low","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6344-466X","authenticated-orcid":true,"given":"Abbas","family":"Ishaq","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-3202","authenticated-orcid":true,"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[{"name":"Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), CIBERehd, Derio, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9090-3048","authenticated-orcid":true,"given":"Amparo","family":"Luque-Sierra","sequence":"additional","affiliation":[{"name":"Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University Pablo Olavide-University of Seville-CSIC, Seville, Spain."},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Martin","sequence":"additional","affiliation":[{"name":"Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University Pablo Olavide-University of Seville-CSIC, Seville, Spain."},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-5438","authenticated-orcid":true,"given":"F\u00e9lix","family":"Elortza","sequence":"additional","affiliation":[{"name":"Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), CIBERehd, Derio, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1276-5276","authenticated-orcid":true,"given":"Antonio","family":"Astorga-Gamaza","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Ant\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica F\u00edsica Blas Cabrera (IQF), CSIC, E-28006 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sof\u00eda","family":"Bali","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-4472","authenticated-orcid":true,"given":"Joaquin","family":"Tamargo-Azpilicueta","sequence":"additional","affiliation":[{"name":"Institute for Chemical Research, cicCartuja, University of Seville-CSIC, Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-1678","authenticated-orcid":true,"given":"Alejandra","family":"Guerra-Castellano","sequence":"additional","affiliation":[{"name":"Institute for Chemical Research, cicCartuja, University of Seville-CSIC, Seville, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-7644","authenticated-orcid":true,"given":"Irene","family":"D\u00edaz-Moreno","sequence":"additional","affiliation":[{"name":"Institute for Chemical Research, cicCartuja, University of Seville-CSIC, Seville, 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UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2149-1753","authenticated-orcid":true,"given":"Alberto","family":"Sanz","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0151-3644","authenticated-orcid":true,"given":"Mario D.","family":"Cordero","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, 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Gorbunova cGAS deficient mice display premature aging associated with de-repression of LINE1 elements and inflammation. bioRxiv 2024.10.10.617645 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.10.10.617645.","DOI":"10.1101\/2024.10.10.617645"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811411115"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-021-00948-8"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.915348"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.06.006"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1322"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1511"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1192"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2103"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.168"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu830"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.729513"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.11.032"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv333"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aec9499","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:00:16Z","timestamp":1782496816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aec9499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":36,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2026,6,26]]}},"alternative-id":["10.1126\/sciadv.aec9499"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aec9499","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"assertion":[{"value":"2025-10-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec9499"}}