Beyond survival: What drives senescence in trauma, shock and sepsis?

Abstract

Cellular senescence is a conserved stress response characterized by stable growth arrest, resistance to apoptosis, and a pro-inflammatory secretome that shapes tissue repair, tumor suppression, and aging. In this review, senescence is framed in the context of trauma, hemorrhagic shock, and sepsis. Severe injuries to brain, lung, abdomen, and bone, as well as ischemia-reperfusion and hemorrhagic shock, rapidly induce p21- and p16-governed senescence-like programs that modulate neurodegeneration, fibrosis, fracture healing, and organ dysfunction. In sepsis, senescence extends beyond immunosenescence to endothelial, epithelial, and stromal compartments, intersecting with ferroptosis, mitochondrial failure, and microbiome dysbiosis, and contributing to post-sepsis syndrome. Integrating mechanistic data with high-dimensional profiling and early interventional studies, this review proposes a context- and time-dependent model in which acute "pseudosenescence" may be organ-protective, whereas persistent senescent reservoirs fuel inflammaging and chronic pathology. Future translational studies are required to define the clinical rationale for phase-specific senotherapeutic interventions in trauma, shock, and sepsis, particularly with respect to long-term outcomes beyond survival.