Selenium and brain aging: A comprehensive review with a focus on hippocampal neurogenesis

Brain aging is accompanied by progressive cognitive decline and increased risk of neurodegenerative diseases, with adult hippocampal neurogenesis (AHN) playing a pivotal role in maintaining cognitive resilience. Selenium, an essential trace element, exerts significant neuroprotective and neurogenic effects predominantly through its incorporation into selenoproteins, which regulate oxidative stress, neuroinflammation, and synaptic plasticity. This review synthesizes recent advances delineating selenium's metabolism, bioavailability, and its multifaceted roles in brain development, function, and aging, emphasizing mechanisms underpinning hippocampal neurogenesis. Key molecular pathways influenced by selenium include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Wingless/Integrated (Wnt) and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways that promote neural progenitor cell proliferation and differentiation. Selenium transport via selenoprotein P and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) is critical for adequate selenium delivery to the hippocampus to support neurogenesis, with exercise demonstrated to potentiate this axis. Selenium also mitigates ferroptosis, preserves mitochondrial integrity, and modulates neuroimmune interactions by attenuating microglial activation and inflammasome signaling, fostering a neurogenic environment. Emerging evidence highlights selenium's regulatory effects on RNA expression, including microRNAs modifications, further influencing neuronal health. Despite promising preclinical and observational data, clinical translation remains limited by heterogeneous and short-term studies. Future research priorities include multi-omics investigations, longitudinal cohorts, and addressing global selenium intake disparities through policy initiatives and precision nutrition. By consolidating mechanistic insights with clinical perspectives, this review underscores selenium's potential as a modifiable factor to enhance AHN and cognitive health, advocating for integrated translational strategies to combat brain aging and neurodegeneration.