Objective To explore the mechanism by which aerobic exercise improves hippocampal neuroinflammation and learning and memory ability in brain-aged mice via interferon regulatory factor 7 (IRF7).Methods A total of 60 male specific pathogen-free (SPF) C57BL/6J mice were enrolled in the experiment, including 30 young mice (2 months old) and 30 naturally aging mice (12 months old). Young mice and old mice were respectively randomly assigned to four groups: young control group (group C, n=15), young exercise group (group CE, n=15), and aging control group (group A, n=15), aging exercise group (group AE, n=15). Mice in the exercise groups received an 8-week continuous treadmill aerobic exercise intervention, while control mice were kept under routine feeding without exercise intervention. After the intervention, Barnes maze and Y-maze behavioral tests were performed to comprehensively assess the learning and memory abilities of each group of mice. Transmission electron microscopy was used to observe the ultrastructural morphological changes of hippocampal synapses. Western blot assay was utilized to detect the protein expression and phosphorylation levels of Janus kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1), as well as the expression of postsynaptic density protein 95 (PSD95). Immunofluorescence staining was applied to quantify the fluorescence intensity of ionized calcium-binding adapter molecule 1 (IBA1) in hippocampal tissues. The expression levels of inflammatory cytokines including interferon-α (IFN-α), interferon-β (IFN-β), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA expression level of IRF7, and DNA methylation assay was further conducted to analyze the methylation level of the IRF7 gene in mouse hippocampus.Results At the molecular level, compared with group C, the protein expression levels of JAK1, STAT1, p-JAK1, and p-STAT1 in group A were significantly increased (P<0.05), whereas PSD95 expression was decreased (P<0.05). ELISA assays showed that the levels of IFN-α, IFN-β, TNF-α, and IL-1β were significantly elevated in group A (P<0.001). RT-PCR analysis revealed that, compared with group C, the mRNA expression of IRF7 in group A was markedly upregulated (P<0.000 1), while the CpG methylation rate of the IRF7 promoter was significantly reduced (P<0.05). In contrast, all the above parameters in the AE group showed improvements reletive to those in group A. Immunofluorescence staining indicated positive IBA1 expression in the brain tissues of group A mice. Exercise intervention reversed these abnormal changes.Conclusion In aged mice, aerobic exercise induces hypermethylation of the IRF7 promoter region, suppresses IRF7 expression and activation of the downstream IFN-I/JAK1/STAT1 signaling pathway, accompanied by alleviated neuroinflammation, improved learning and memory, and ameliorated brain aging-related phenotypes.