Irisin in the aging immune landscape: A new player at the crossroads of immunosenescence and sepsis

BACKGROUND: Irisin, a muscle-secreted myokine induced by exercise, serves as a molecular bridge between muscle activity and the immune system. This interaction is particularly relevant in aging, where irisin may modulate the transition toward immunosenescence and influence host vulnerability to acute systemic insults, such as sepsis. MAIN BODY: Irisin regulates immune function and inflammation by suppressing pro-inflammatory cytokines while increasing anti-inflammatory mediators. These effects are primarily driven by the modulation of the AMPK and NF-κB signaling pathways, suggesting irisin may play a role in addressing immunosenescence by orchestrating cellular inflammatory responses. Moreover, recent evidence highlights the possible anti-senescent properties of irisin, specifically through its ability to modulate the senescence-associated secretory phenotype. Dysregulated immune responses and cellular senescence contribute to sepsis pathophysiology, and accordingly, irisin has been shown to improve cognitive impairment as well as respiratory, cardiac, and renal dysfunction in murine models of sepsis. Research indicates that increased expression of FNDC5, the membrane-bound precursor of irisin, enhances these protective effects, while clinical data reveal that low serum irisin correlates with greater sepsis severity. Consequently, decreased circulating irisin may serve as a diagnostic and prognostic biomarker for predicting mortality in septic patients. CONCLUSIONS: Irisin represents a promising link between muscle-derived signaling and immune resilience. While clinical application is currently hindered by assay variability and a need for larger human cohorts, its role in modulating both immunosenescence and acute sepsis pathophysiology marks it as a possible prognostic biomarker and a potential therapeutic target in the vulnerable aging population.