{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:41:00Z","timestamp":1792176060792,"version":"4.4.0"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2024A4240240"],"award-info":[{"award-number":["2024A4240240"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Guangdong Province, China","award":["2024B9240170"],"award-info":[{"award-number":["2024B9240170"]}]},{"name":"Double First-Class Initiative Foundation","award":["D6240290"],"award-info":[{"award-number":["D6240290"]}]},{"name":"Double First-Class Initiative Foundation","award":["D6251350"],"award-info":[{"award-number":["D6251350"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Aging-related cognitive decline is closely associated with microglial senescence and the resulting chronic neuroinflammation. Emerging evidence identifies the cyclic GMP-AMP synthase\u2013stimulator of interferon genes (cGAS-STING) pathway as a pivotal innate immune signaling pathway linking DNA damage to cellular senescence and the senescence-associated secretory phenotype (SASP), particularly in microglia. Targeting the formation or selective clearance of senescent cells thus emerges as a promising therapeutic approach to ameliorate cognitive dysfunction. Resveratrol has shown promise in modulating immune response and exerting anti-aging effects. However, the therapeutic potential and underlying mechanisms of resveratrol in mitigating age-associated microglial senescence and cognitive decline are not fully understood. Methods: In the present study, we employed a well-established murine model of accelerated aging induced by chronic intraperitoneal injection of D-galactose (D-gal) to elicit pronounced senescence-associated phenotypes and neuroinflammation. Resveratrol was administered via oral gavage daily for three weeks following D-gal injections. Behavioral assays were conducted to assess cognitive performance. Immunohistochemistry, quantitative PCR, and Western blot analyses were used to evaluate markers of cellular senescence, microglial activation and pro-inflammatory cytokine expression. In addition, in vitro assays in cultured microglia coupled with RNA sequencing were used to investigate the downstream signaling events following resveratrol treatment. Results: Chronic D-gal treatment induced significant cognitive impairment, enhanced microglial activation, elevated pro-inflammatory cytokine levels, and increased markers of cellular senescence in the brain. Resveratrol administration remarkably attenuated these effects, as evidenced by improved memory performance, reduced microglial senescence markers, and suppressed expression of Cxcl-10, Il-1\u03b2, and other SASP factors. Mechanistically, unbiased transcriptomic analysis revealed that the cGAS-STING signaling and neuroinflammation pathways were prominently dysregulated with double-stranded DNA-induced cellular senescence, which was effectively normalized by resveratrol in cultured microglia. Interestingly, resveratrol inhibited the translocation of STING from the endoplasmic reticulum to the Golgi apparatus and suppressed phosphorylation of TBK1, thereby blocking downstream STING signaling. Conclusions: These findings demonstrate that resveratrol mitigates microglial senescence and neuroinflammation and preserves cognitive function in D-gal-induced aging mice, at least partly through modulation of the cGAS-STING signaling. Therefore, targeting this pathway may represent a promising therapeutic strategy for age-related neuroinflammatory and cognitive disorders.<\/jats:p>","DOI":"10.3390\/cells15060523","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:13:14Z","timestamp":1773659594000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Resveratrol Mitigates Age-Associated Cognitive Decline via Inhibition of cGAS-STING-Mediated Microglial Senescence"],"prefix":"10.3390","volume":"15","author":[{"given":"Xinxin","family":"Duan","sequence":"first","affiliation":[{"name":"School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7387-4532","authenticated-orcid":false,"given":"Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3587-9425","authenticated-orcid":false,"given":"Zhi","family":"Ruan","sequence":"additional","affiliation":[{"name":"School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eads1560","DOI":"10.1126\/sciadv.ads1560","article-title":"Age and cognitive skills: Use it or lose it","volume":"11","author":"Hanushek","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e336","DOI":"10.1016\/S2666-7568(24)00033-3","article-title":"The time course of motor and cognitive decline in older adults and their associations with brain pathologies: A multicohort study","volume":"5","author":"Oveisgharan","year":"2024","journal-title":"Lancet Healthy Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1016\/j.cell.2025.03.011","article-title":"From geroscience to precision geromedicine: Understanding and managing aging","volume":"188","author":"Kroemer","year":"2025","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/d41586-025-01886-3","article-title":"How your brain controls ageing- and why zombie cells could be key","volume":"642","author":"Kwon","year":"2025","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41586-023-06373-1","article-title":"cGAS-STING drives ageing-related inflammation and neurodegeneration","volume":"620","author":"Gulen","year":"2023","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13024-020-00396-2","article-title":"P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice","volume":"15","author":"Ruan","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eadx0043","DOI":"10.1126\/science.adx0043","article-title":"Neuroinflammation across neurological diseases","volume":"388","author":"Shi","year":"2025","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/d41586-022-04430-9","article-title":"Senescent cells damage the body throughout life","volume":"613","author":"Glass","year":"2023","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-020-2496-1","article-title":"A single-cell transcriptomic atlas characterizes ageing tissues in the mouse","volume":"583","year":"2020","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7314","DOI":"10.1016\/j.cell.2024.09.021","article-title":"Identifying specific functional roles for senescence across cell types","volume":"187","author":"Zhao","year":"2024","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/ncb3586","article-title":"Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence","volume":"19","author":"Gluck","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanisms and cellular functions of cGAS-STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41577-022-00751-y","article-title":"DNA damage and repair in age-related inflammation","volume":"23","author":"Zhao","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4666","DOI":"10.1038\/s44318-025-00482-5","article-title":"cGAS-STING are responsible for premature aging of telomerase-deficient zebrafish","volume":"44","author":"Serifoglu","year":"2025","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e136824","DOI":"10.1172\/JCI136824","article-title":"Brain immune cells undergo cGAS\/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production","volume":"131","author":"Reinert","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115749","DOI":"10.1016\/j.celrep.2025.115749","article-title":"Microglial STING is a central safeguard against neurological decline with age","volume":"44","author":"Sulka","year":"2025","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e81943","DOI":"10.7554\/eLife.81943","article-title":"Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice","volume":"11","author":"Szego","year":"2022","journal-title":"Elife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12974-023-02724-x","article-title":"Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress","volume":"20","author":"Bao","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2118819119","DOI":"10.1073\/pnas.2118819119","article-title":"STING mediates neurodegeneration and neuroinflammation in nigrostriatal alpha-synucleinopathy","volume":"119","author":"Hinkle","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1093\/nar\/gkad1184","article-title":"cGAS-STING signalling regulates microglial chemotaxis in genome instability","volume":"52","author":"Talbot","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109206","DOI":"10.1016\/j.neuropharm.2022.109206","article-title":"Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain","volume":"217","author":"Wu","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1016\/j.neuron.2024.09.006","article-title":"Alzheimer\u2019s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model","volume":"112","author":"Carling","year":"2024","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1016\/j.immuni.2025.05.023","article-title":"The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway","volume":"58","author":"Naguib","year":"2025","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1002\/fsn3.855","article-title":"Resveratrol: A miraculous natural compound for diseases treatment","volume":"6","author":"Koushki","year":"2018","journal-title":"Food Sci. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.bbi.2017.03.003","article-title":"Resveratrol regulates microglia M1\/M2 polarization via PGC-1alpha in conditions of neuroinflammatory injury","volume":"64","author":"Yang","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1742-2094-7-46","article-title":"Resveratrol differentially modulates inflammatory responses of microglia and astrocytes","volume":"7","author":"Lu","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.2337\/db11-1498","article-title":"Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet","volume":"61","author":"Jeon","year":"2012","journal-title":"Diabetes"},{"key":"ref_29","first-page":"441","article-title":"Resveratrol inhibits isoprostane production in young and aged rat brain","volume":"24","author":"Chiavaroli","year":"2010","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Puranik, N., Kumari, M., Tiwari, S., Dhakal, T., and Song, M. (2025). Resveratrol as a Therapeutic Agent in Alzheimer\u2019s Disease: Evidence from Clinical Studies. Nutrients, 17.","DOI":"10.3390\/nu17152557"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101271","DOI":"10.1016\/j.arr.2021.101271","article-title":"The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer\u2019s disease pathology: From antioxidant to epigenetic therapy","volume":"67","author":"Izquierdo","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.7150\/thno.96890","article-title":"Microglial circ-UBE2K exacerbates depression by regulating parental gene UBE2K via targeting HNRNPU","volume":"14","author":"Cai","year":"2024","journal-title":"Theranostics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1038\/s41593-023-01355-y","article-title":"Identification of a protective microglial state mediated by miR-155 and interferon-gamma signaling in a mouse model of Alzheimer\u2019s disease","volume":"26","author":"Yin","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eadk7844","DOI":"10.1126\/science.adk7844","article-title":"Tlr7 drives sex differences in age- and Alzheimer\u2019s disease-related demyelination","volume":"386","author":"Kodama","year":"2024","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101384","DOI":"10.1016\/j.xpro.2022.101384","article-title":"Protocol to induce and assess cGAS-STING pathway activation in vitro","volume":"3","author":"Chamma","year":"2022","journal-title":"STAR Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41401-022-01009-y","article-title":"Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice","volume":"44","author":"Hong","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.exger.2017.10.029","article-title":"Role of D-galactose-induced brain aging and its potential used for therapeutic interventions","volume":"101","author":"Shwe","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/978-1-4939-8994-2_9","article-title":"The Open Field Test for Measuring Locomotor Activity and Anxiety-Like Behavior","volume":"1916","author":"Kraeuter","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.neubiorev.2005.04.017","article-title":"Ethological and temporal analyses of anxiety-like behavior: The elevated plus-maze model 20 years on","volume":"29","author":"Carobrez","year":"2005","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.nlm.2004.01.001","article-title":"Short and long-term motor skill learning in an accelerated rotarod training paradigm","volume":"81","author":"Buitrago","year":"2004","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1034\/j.1601-183X.2003.00028.x","article-title":"Differences among eight inbred strains of mice in motor ability and motor learning on a rotorod","volume":"2","author":"McFadyen","year":"2003","journal-title":"Genes. Brain Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118790","DOI":"10.1016\/j.biopha.2025.118790","article-title":"Cytosolic DNA sensing pathway in senescence and aging: Underlying mechanisms and targeted interventions","volume":"193","author":"Moqadami","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/s41586-019-1000-2","article-title":"Structural basis of STING binding with and phosphorylation by TBK1","volume":"567","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/s12974-025-03563-8","article-title":"cGAS-STING signaling in brain aging and neurodegeneration: Molecular links and therapeutic perspectives","volume":"22","author":"Li","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.tins.2020.10.008","article-title":"Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging","volume":"44","author":"Paul","year":"2021","journal-title":"Trends Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2011226118","DOI":"10.1073\/pnas.2011226118","article-title":"NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer\u2019s disease via cGAS-STING","volume":"118","author":"Hou","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12974-025-03396-5","article-title":"Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism","volume":"22","author":"Lu","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1038\/s41594-025-01602-9","article-title":"Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration","volume":"32","author":"Miao","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"112306","DOI":"10.1016\/j.celrep.2023.112306","article-title":"The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus","volume":"42","author":"Kong","year":"2023","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e70260","DOI":"10.1111\/acel.70260","article-title":"HSPA12B Protects Against Age-Related Endothelial Cell Senescence by Regulating STING Degradation","volume":"24","author":"Li","year":"2025","journal-title":"Aging Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1038\/s41598-017-18943-1","article-title":"Molecular Mechanism of Resveratrol\u2019s Lipid Membrane Protection","volume":"8","author":"Fei","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Revin, V.V., Pinyaev, S.I., Parchaykina, M.V., Revina, E.S., Maksimov, G.V., and Kuzmenko, T.P. (2019). The Effect of Resveratrol on the Composition and State of Lipids and the Activity of Phospholipase A(2) During the Excitation and Regeneration of Somatic Nerves. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00384"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1007\/s12035-018-0924-0","article-title":"Effect of Resveratrol on Oxidative Stress and Mitochondrial Dysfunction in Immature Brain during Epileptogenesis","volume":"55","author":"Folbergrova","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"114544","DOI":"10.1016\/j.ecoenv.2023.114544","article-title":"Resveratrol attenuated oxidative stress and inflammatory and mitochondrial dysfunction induced by acute ammonia exposure in gibel carp (Carassius gibelio)","volume":"251","author":"Wu","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/6\/523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:29:38Z","timestamp":1773660578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/6\/523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":54,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cells15060523"],"URL":"https:\/\/doi.org\/10.3390\/cells15060523","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]}}}