Abstract Body: Introduction: Aging is accompanied by a gradual increase in inflammation, oxidative stress and immune system dysfunction. Our previous work with heterochronic parabiosis, in which the circulatory systems of young and aged mice are shared, provided insights into how systemic factors influence brain aging. Notably, our findings revealed that aged blood induces a reactive oxygen species-induced senescence pathway in the young brain, while young blood activates a selenium network pathway in the aged brain. We hypothesize that selenium deficiency increases oxidative stress and ROS-induced senescence in microglia, thereby contributing to neuroinflammation and cognitive decline.
Methods: We fed aged (16-month) C57BL/6 male mice either a selenium deficient or control diet (n = 9-10/grp) for 3 months. Cognition and motor activity were assessed at 1- and 3-months with the novel object recognition test (NORT) and open field (OF). Brain and spleen were harvested after 3 months for flow cytometric (FC) analysis and immunohistochemistry (IHC). Additionally, we explored the potential therapeutic effects of selenium supplementation on senescence markers in primary microglial cell cultures, which were assessed by qPCR and stained for senescence activity (beta-galactosidase).
Results: After one month, selenium deficient mice had significantly impaired locomotor activity in the OF (p=.0010) and an increase in cognitive impairment in the NORT (p=.0792). Surprisingly, these deficits normalized to levels seen in the control group after 3 months of selenium deficient diet, raising the possibility of an adaptive or compensatory redox signaling mechanism in the aged brain. FC analysis at 3 months revealed only mild alterations in microglia, brain endothelial cells, and splenic neutrophils, consistent with the behavioral outcomes. In vitro experiments demonstrated that treatment with selenomethionine (p=.0134) and selenium nanoparticles (p=.0176) alleviated senescence-associated phenotypes in microglia post-H2O2 stimulation.
Conclusion: We have established an important role for dietary selenium in healthy brain aging and novel evidence for a delayed compensatory redox mechanism to mitigate the detrimental effects of chronic selenium deficiency in aged mice. By elucidating the role of dietary selenium in brain aging, this study aims to identify novel therapeutic targets for preventing or delaying the cognitive decline associated with aging.