Neutrophils, NETs, and efferocytosis in aging: A resolution-failure axis driving inflammaging

Population aging is a defining demographic trend of the 21st century and is accompanied by a rising prevalence of chronic diseases, functional decline, and multimorbidity that impose substantial health and socioeconomic burdens worldwide. This demographic shift is characterized by a fundamental paradox in the immune system: immunosenescence, marked by declining immune function, and inflammaging, a state of chronic low-grade inflammation. While neutrophils are essential for antimicrobial defense and immune surveillance, their broader role in maintaining tissue homeostasis during aging is increasingly recognized. Here, we examine emerging evidence that age-related alterations in neutrophil fate and functional programming, including apoptosis, NETosis, and senescence-associated states, influence macrophage behavior and contribute to persistent inflammation. Recent studies further suggest that interactions between apoptotic neutrophils and macrophages are not merely mechanisms of cellular clearance but active processes that promote macrophage metabolic and functional reprogramming toward inflammatory resolution. We discuss how aging may perturb this neutrophil-macrophage axis through altered neutrophil programming, defective efferocytosis, and impaired resolution responses, while highlighting key unresolved questions regarding senescent neutrophil biology, neutrophil-specific efferocytic signaling, and macrophage metabolic reprogramming in aging tissues. These emerging insights also identify the neutrophil-macrophage resolution axis as a potential therapeutic target for restoring tissue homeostasis and promoting healthy aging.