Abstract

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.