Integrative bibliometric and transcriptomic analyses identify selenium-associated molecular signatures in the aging brain

Background and purpose: The aging brain is particularly sensitive to alterations in selenium status. Selenium deficiency has been associated with impaired neural function, cognitive decline, and increased vulnerability to neurodegeneration. However, the molecular mechanisms that link selenium biology to brain aging remain poorly understood. Methods: We conducted a bibliometric analysis of 1,826 publications and identified brain-aging DEGs from public datasets. After intersecting these with selenium-related gene sets, we used machine-learning feature selection and SHAP/nomogram evaluation to prioritize core genes, validated findings in an independent cohort, performed immune-infiltration and gene-drug enrichment analyses, and confirmed age-related transcriptional and protein changes in mouse brain tissue. Results: Bibliometric analysis showed a steady increase in publications on selenium and aging over the past two decades, with major research hotspots focusing on oxidative stress, selenoproteins, and cognitive function, while the selenium-cognition relationship remains relatively underexplored. Intersection analysis identified seven potential targets linking selenium to brain aging, from which machine-learning feature selection prioritized three core genes (SP1, SEPHS2, and MSRB1) that were significantly differentially expressed in aged samples. SHAP and nomogram analyses indicated that SP1 and SEPHS2 were the main contributors to model discrimination. Animal experiments further confirmed increased SP1 and decreased SEPHS2 expression at both mRNA and protein levels in aged mouse brains, consistent with the bioinformatic findings. Conclusion: This study identifies SP1 and SEPHS2 as key genes linking selenium to brain aging, providing new insights into the role of selenium in brain aging and suggesting that these genes may represent potential biomarkers or therapeutic targets for brain aging and aging-related brain disorders.