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

  • Immun Ageing. 2025 Nov 5;22(1):51. doi: 10.1186/s12979-025-00538-4.
Taotao Mi  1 ,  Shanshan Yang  1 ,  Nan Wang  1 ,  Fengjiao Huo  1 ,  Meili Zhao  1 ,  Shuyao Lv  1 ,  Tingting Su  2 ,  Shengyu Feng  1 ,  Hao Wang  1 ,  Liuling Guo  1 ,  Jian-Kang Zhu  3 ,  Hailiang Liu  4  5  6
Affiliations
  • 1. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, China.
  • 2. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization of Ministry of Education, College of Life Sciences, Shihezi University, Shihezi, 832003, China.
  • 3. Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 4. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, China. [email protected].
  • 5. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization of Ministry of Education, College of Life Sciences, Shihezi University, Shihezi, 832003, China. [email protected].
  • 6. Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
PMID: 41194177 DOI: 10.1186/s12979-025-00538-4
Abstract

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.

Keywords
Ascorbic acid; CD8+ t cells; Cognitive functions; Immunosenescence.
Products