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Background <p>​​ Immune function decline (immunosenescence) accelerates systemic aging and adversely impacts cognitive function. Antioxidants may mitigate these effects; however, the role of ascorbic acid (AA), a key antioxidant, in counteracting immunosenescence and enhancing cognition remains inadequately explored.</p> Results <p>In this study, AA administration (0.1 mg/g, tail vein, every 2 days for 30 days) significantly improved cognitive function in aged (16-month) C57BL/6 mice, without altering anxiety-like behavior (as assessed in the open field test). This was associated with elevated peripheral blood lymphocytes (T cells, B cells) and CD8⁺ T cells, alongside reduced myeloid cells (CD11b⁺). Single-cell RNA sequencing of PBMCs revealed AA reversed immunosenescent signatures—increasing T/B cell populations and decreasing neutrophils/macrophages—mimicking youthful immune profiles. <i>In vitro</i>, AA skewed hematopoietic stem cell (HSC) differentiation toward CD8⁺ T cells (increasing DN2 stage, suppressing myeloid CD11b⁺ cells) and enhanced splenic CD8⁺ T cell generation. Mechanistically, AA bound MYH9, activating cytoskeletal pathways. MYH9 inhibition (blebbistatin) reduced CD8⁺ T cells and increased CD11b⁺ cells—effects rescued by AA. Crucially, CD8⁺ T cell depletion abolished AA’s cognitive benefits, confirming their essential role.</p> Conclusions <p>In summary, AA mitigates immunosenescence and improves cognitive function by targeting MYH9 to regulate CD8⁺ T cell differentiation and function. These findings establish a mechanistic basis for AA as a potential therapeutic agent against age-related immune and cognitive decline.</p> Graphical abstract <p></p>

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Ascorbic acid attenuates immunosenescence and cognitive decline via MYH9-Mediated CD8⁺ T cell differentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月5日

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  • Taotao Mi,
  • Shanshan Yang,
  • Nan Wang,
  • Fengjiao Huo,
  • Meili Zhao,
  • Shuyao Lv,
  • Tingting Su,
  • Shengyu Feng,
  • Hao Wang,
  • Liuling Guo,
  • Jian-Kang Zhu,
  • Hailiang Liu

摘要

Background

​​ Immune function decline (immunosenescence) accelerates systemic aging and adversely impacts cognitive function. Antioxidants may mitigate these effects; however, the role of ascorbic acid (AA), a key antioxidant, in counteracting immunosenescence and enhancing cognition remains inadequately explored.

Results

In this study, AA administration (0.1 mg/g, tail vein, every 2 days for 30 days) significantly improved cognitive function in aged (16-month) C57BL/6 mice, without altering anxiety-like behavior (as assessed in the open field test). This was associated with elevated peripheral blood lymphocytes (T cells, B cells) and CD8⁺ T cells, alongside reduced myeloid cells (CD11b⁺). Single-cell RNA sequencing of PBMCs revealed AA reversed immunosenescent signatures—increasing T/B cell populations and decreasing neutrophils/macrophages—mimicking youthful immune profiles. In vitro, AA skewed hematopoietic stem cell (HSC) differentiation toward CD8⁺ T cells (increasing DN2 stage, suppressing myeloid CD11b⁺ cells) and enhanced splenic CD8⁺ T cell generation. Mechanistically, AA bound MYH9, activating cytoskeletal pathways. MYH9 inhibition (blebbistatin) reduced CD8⁺ T cells and increased CD11b⁺ cells—effects rescued by AA. Crucially, CD8⁺ T cell depletion abolished AA’s cognitive benefits, confirming their essential role.

Conclusions

In summary, AA mitigates immunosenescence and improves cognitive function by targeting MYH9 to regulate CD8⁺ T cell differentiation and function. These findings establish a mechanistic basis for AA as a potential therapeutic agent against age-related immune and cognitive decline.

Graphical abstract