Our previous study demonstrated that the expression of sodium channel voltage-gated beta 2 (SCN2B) increased with aging in senescence-accelerated mouse prone 8 (SAMP8) mice, and was identified to be associated with a decline in learning and memory, while the underlying mechanism is unclear. In the present study, multiple differentially expressed miRNAs, which may be involved in the process of aging by regulating target genes, were identified in the prefrontal cortex and hippocampus of SAMP8 mice though miRNA microarray analysis. Using bioinformatics prediction, SCN2B was identified to be one of the potential target genes of miR-449a, which was downregulated in the hippocampus. Previous studies demonstrated that miR-449a is involved in the occurrence and progression of aging by regulating a variety of target genes. Therefore, it was hypothesized that miR-449a may be involved in the process of brain aging by targeting SCN2B. To verify this hypothesis, the following experiments were conducted: A reverse transcription-quantitative polymerase chain reaction assay revealed that the expression level of miR-449a was significantly decreased in the prefrontal cortex and hippocampus of 12-month old SAMP8 mice; a dual-luciferase reporter assay verified that miR-449a regulated SCN2B expression by binding to the 3 '-UTR 'seed region'; an anti-Ago co-immunoprecipitation combined with Affymetrix micro-array analyses demonstrated that the target mRNA highly enriched with Ago-miRNPs was confirmed to be SCN2B. Finally, overexpression of miR-449a or inhibition of SCN2B promoted the extension of hippocampal neurons in vitro. The results of the present study suggested that miR-449a was downregulated in the prefrontal cortex and hippocampus of SAMP8 mice and may regulate the process of brain aging by targeting SCN2B.