Aging reprograms the functional, epigenetic, and metabolic landscape of macrophages.

Immuno-senescence is a dominant risk factor of chronic diseases, yet the impact of aging on macrophages remain understudied, despite their involvement in age-related conditions. Here, we define macrophage aging by integrating transcriptomic, epigenetic, metabolic, and functional analyses across the lifespan. Besides aging hallmarks, we uncovered progressive changes in macrophages, including reduced responsiveness to both inflammatory and anti-inflammatory cues and an imbalanced cytokine and chemokine secretory profile. This age-driven remodeling is supported by significant rewiring of epigenetic regulators, particularly histone-modifying genes, alongside coordinated shifts in metabolism toward lipid activation and trafficking at the expense of mitochondrial redox programs. Strikingly, these alterations differ between M1- and M2-like macrophages, indicating phenotype-specific aging trajectories. Functionally, aged macrophages exhibit enhanced phagocytic capacity, diminished migratory ability, and preserved antigen presentation. Together, our findings establish that aging does not simply impair macrophages; it drives an active, multi-layered reprogramming process, providing a framework to address inflammaging and age-associated diseases.