Exercise-induced irisin rescues lead-induced cognitive impairment by inhibiting prefrontal cortical senescence via SIRT3

Lead (Pb) is a pervasive environmental hazard that impairs cognitive function. However, the underlying mechanisms and non-pharmacological interventions need to be further investigated. Here, Pb-induced senescence in the prefrontal cortex was associated with cognitive impairment. We found that exercise and exercise serum ameliorated Pb-induced prefrontal cortex senescence and cognitive impairment in mice. Further analyses revealed that exercise-derived irisin alleviated cellular senescence by regulating the SIRT3 signaling pathway. Meanwhile, irisin also mediated the association between blood Pb levels and MoCA scores in humans. Together, these findings suggest that exercise alleviates Pb-induced cognitive impairment via the irisin-SIRT3 pathway and identify irisin as a potential therapeutic target.