Aging Impairs Macrophage Phagocytosis Through Mitochondrial ROS-Induced Collagen Production

  • Aging Cell. 2026 Jun;25(6):e70594. doi: 10.1111/acel.70594.
Yuming Wang  1  2 ,  Xin Xu  3  4 ,  Nuanqin Shen  3  4 ,  Ping Han  3  4 ,  Liuyi Wu  3  4 ,  Yi Jin  5 ,  Yiming Sun  3  4 ,  Lanlan Xiao  6 ,  Jinyou Li  1  2 ,  Lan Wang  1  2 ,  Yunmei Yang  1  2 ,  Qin Zhang  1  2 ,  Weiqian Chen  6 ,  Chaohui Yu  3 ,  Bowen Wu  4  6
Affiliations
  • 1. Department of Geriatrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Zhejiang Key Laboratory for Diagnosis and Treatment of Physic-Chemical and Aging-Related Injuries, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
  • 5. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • 6. Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
PMID: 42298889 DOI: 10.1111/acel.70594
Abstract

Macrophages are pivotal immune cells due to their phagocytic capabilities, yet the impact of aging on macrophage phagocytosis remains poorly understood. Using comprehensive in vitro and in vivo phagocytic assays, we demonstrate significantly reduced phagocytic activity in monocyte-derived macrophages from aged humans and mice compared to young counterparts. RNA-seq analysis revealed upregulated expression of extracellular matrix protein genes, particularly collagens, in aged macrophages; manipulation of COL1A1 expression can significantly affect phagocytosis. Protein interaction assay identified binding between Collagen and actin filaments, which inhibits F-actin turnover and consequently impairs phagocytic function. Also, we found that mitochondrial ROS is the driving force of Collagen overproduction and MitoTEMPO rejuvenates macrophage phagocytosis via restoring actin dynamics. In a mouse model, MitoTEMPO significantly boosted the phagocytosis of peritoneal macrophages against bacteria. These findings highlight the fundamental role of mitochondrial redox balance and Collagen production in controlling macrophage phagocytic function, identifying them as targetable mechanisms for promoting healthy immune aging.

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