Ascorbic acid improves cognitive levels in middle-aged mice and increases CD8 + T cells by binding Myh9 protein and enriches gut microbiota Akkermansia muciniphila

<title>Abstract</title> <bold>Background: </bold>Immunosenescence accelerates systemic aging and influences cognitive function, with antioxidants potentially mitigating these effects. The significance of ascorbic acid (vitamin C) as a crucial antioxidant in anti-aging and cognition, as well as the potential impact of the gut microbiome on this process, has yet to be investigated. <bold>Results: </bold>In this study, we systematically<bold> </bold>assessed the impact of ascorbic acid on immunosenescence and cognitive function in middle-aged and aged mice. The findings demonstrated a notable rise in peripheral blood lymphocytes, a decline in myeloid immune cells, and enhanced cognitive performance. <italic>In vitro</italic> studies indicated that ascorbic acid facilitated the differentiation of mouse hematopoietic stem cells (HSCs) and spleen monocytes into CD8⁺ T cells, with its efficacy primarily mediated by its interaction with the protein Myh9 protein. A positive correlation was observed between CD8⁺ T cells and cognitive function. Furthermore, a distinction exists between the efficacy of oral and intravenous administration of ascorbic acid in enhancing cognitive function, potentially attributable to the modulation of the gut microbiome <italic>Akkermansia muciniphila</italic>. Intravenous delivery notably enhances <italic>A. muciniphila</italic> abundance and significantly enhances cognitive performance in middle-aged and elderly mice, whereas oral ascorbic acid supplementation increases CD8⁺ T cell count and cognitive function in this demographic only when co-administered with <italic>A. muciniphila</italic>. <bold>Conclusion: </bold>This study demonstrated that the administration of ascorbic acid can mitigate immunosenescence and, in conjunction with <italic>A. muciniphila</italic>, improves cognitive function in mice. These findings offer a mechanistic rationale for utilizing nutritional interventions to mitigate immunosenescence and enhance cognitive function, and underscores the importance of selecting the optimal route of administration for achieving the intended effects.