Exercise-Induced FNDC5/Irisin Ameliorates Cognitive Impairment in Aged Mice, Associated with Antioxidant and Neurotrophic Responses

Aging contributes to neurodegeneration, predominantly characterized by increased oxidative stress, which leads to neurodegenerative changes and cognitive decline. This cognitive impairment is often associated with neuroinflammation, oxidative stress, and neuronal damage. Exercise is widely recognized for its capacity to elevate levels of irisin, a hormone derived from the cleavage of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin acts as a myokine that mediates numerous beneficial effects of physical activity on metabolic health. It has also been recognized for its neuroprotective roles, suggesting its potential to mitigate neurodegenerative processes by promoting neuronal survival, reducing oxidative stress, and enhancing synaptic plasticity. However, the specific impact of exercise on the FNDC5/irisin pathway and antioxidant mechanisms in the aged brain remains insufficiently explored. In this study, we aimed to validate the neuroprotective role of exercise-induced FNDC5/irisin against aging-related oxidative stress, glial activation, neuronal damage, and cognitive impairment in 20-month-old mice. The exercise group underwent treadmill running for 60 min daily over an 8-week period. Our findings indicated that aging mice exhibited cognitive impairment, as evidenced by the Y-maze test; however, treadmill exercise effectively alleviated this impairment. Aged mice showed the activation of microglia and astrocytes in the hippocampus, which was notably reduced by exercise. Moreover, exercise improved the levels of calbindin and irisin, which were diminished due to aging. Our study demonstrated that aging led to a decrease in the antioxidant response element system and FNDC5/irisin pathway. However, exercise effectively activated Nrf2 and FNDC5/irisin expression, subsequently enhancing levels of SOD1, GSTO1/2, Sirt1, PGC-1α, BDNF, IGF-1, and IGF-2 in the hippocampus. The exercise-induced activation of Nrf2 signaling and FNDC5/irisin has emerged as a potent mechanism for alleviating oxidative stress and neuroinflammation associated with aging. In conclusion, our findings suggest that regular exercise has the potential to alleviate cognitive impairment through the activation of PGC-1α-FNDC5/irisin signaling, the Nrf2 ARE system, and neurotrophic factors in aged mice.