Immune Aging as a Failure of Programmed Cell Death Coordination

Aging profoundly reshapes the immune system, leading to increased susceptibility to infection, impaired vaccine responses, chronic inflammation, and age-associated inflammatory diseases. While immune aging has traditionally been attributed to defects in immune cell development, signaling, and metabolism, emerging evidence highlights dysregulation of programmed cell death as a central and unifying mechanism. Apoptosis, necroptosis, pyroptosis, and ferroptosis are increasingly recognized not only as terminal cellular events but also as active regulators of immune homeostasis and inflammatory signaling. In aged immune cells, coordination among these death pathways is disrupted, weakening apoptotic resolution and favoring inflammatory forms of cell death that amplify tissue damage and sustain inflammaging. In this review, we summarize current evidence on how aging remodels programmed cell death pathways in the immune system, discuss the molecular mechanisms underlying this network-level shift, and consider potential strategies for restoring immune function by modulating cell death decisions.