S100A8/A9 as a central hub in inflammaging: Cross-system mechanisms

Global population aging intensifies "inflammaging," a bidirectional link between chronic inflammation and aging-related pathology. Among them, S100A8/A9 forms a positive feedback loop of "aging-inflammation". Here, we systematically review the structure and function of S100A8/A9, including extracellularly promoting leukocyte adhesion and myeloid-derived suppressor cell aggregation, and intracellularly regulating NOD-like receptor protein 3 inflammasome, arachidonic acid metabolism, autophagy, and apoptosis. This review systematically examines system-specific roles of S100A8/A9: in tumors, it fosters immunosuppression and chemoresistance; in the nervous system, it fuels neuroinflammation and neuronal injury via neutrophil extracellular traps and ferroptosis; in the cardiovascular system, it accelerates endothelial aging and plaque instability; in metabolism, it drives adipose dysfunction and insulin resistance; and in muscle, it induces atrophy and frailty. Disease activity, S100A8/A9 expression levels, chemotherapy resistance, and poor prognosis can be used as biomarkers for early diagnosis, risk stratification, and imaging tracing. Accumulating evidence demonstrates robust correlations between elevated S100A8/A9 expression, therapeutic resistance, and adverse clinical outcomes, establishing its utility as a diagnostic biomarker for disease stratification and molecular imaging. Targeting the S100A8/A9-Toll-like receptor 4 axis or neutralizing S100A9 strategies have shown potential in animal models to reduce inflammation and delay disease progression. In conclusion, S100A8/A9 is a core molecule connecting aging, inflammation, and multi-system lesions. Interventions targeting its pathway are expected to provide new strategies for extending healthy lifespans and a theoretical basis for novel and practical anti-aging strategies.