Macrophage Senescence: Friend or Foe?

Abstract

Macrophages are pivotal players in innate immunity, orchestrating host defense, tissue repair, and tissue homeostasis. Accumulating studies suggest that macrophages themselves can undergo cellular senescence in response to aging, metabolic stress, and chronic inflammation, leading to a state of "immunosenescence." Senescent macrophages exhibit a distinct phenotype characterized by pro-inflammatory secretory activity (SASP), impaired phagocytosis, metabolic dysfunction, and altered polarization. These features exert context-dependent dual effects on tissue integrity: while facilitating tissue remodeling and the resolution of acute injury, they also fuel inflammaging, tissue degeneration, and the progression of age-related pathologies such as atherosclerosis, metabolic disorders, neurodegenerative diseases, and cancer. This review synthesizes current advances on the molecular mechanisms driving macrophage senescence, including persistent DNA damage, mitochondrial dysfunction, epigenetic remodeling, and cGAS-STING signaling activation. We further discuss the beneficial versus detrimental roles of senescent macrophages across organ systems and disease contexts. Finally, we explore the translational potential of macrophage-targeted interventions-including senolytics, SASP modulation, and metabolic rejuvenation-and highlight current challenges and future perspectives in harnessing macrophage senescence to combat aging and age-related diseases.