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 remains understudied, despite their involvement in age-related conditions. Here, we examine bone marrow-derived macrophage aging by integrating transcriptomic and functional analyses across the lifespan. Besides aging hallmarks, we observed progressive changes in macrophages, including reduced responsiveness to both inflammatory and anti-inflammatory cues and an imbalanced secretory profile. This age-driven remodeling is reflected by changes in the expression of epigenetic regulators, particularly histone-modifying genes, alongside coordinated gene expression shifts 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 against tumor cells, diminished migratory ability, and preserved antigen presentation. Together, our findings establish that aging drives an active transcriptomic reprogramming in bone marrow-derived macrophages, providing a framework to address inflammaging and age-associated diseases.