Exercise rescues cognitive deterioration in naturally aged rats via PGC1α/FNDC5/irisin/AMPK signaling pathway to restore redox, endothelial, and neuronal homeostasis

Background: Aging-associated cognitive impairments become a global phenomenon, especially with the increase in life expectancy and sedentary lifestyle. Thus, the present study aimed to assess the cognitive functions in aged rats and explore the potential involvement of the endogenous exercise-induced myokine irisin in such an effect. Lastly, it was to identify the possible irisin downstream adenosine monophosphate-activated protein kinase (AMPK) signaling pathway to restore hippocampal redox and eNOS/NO/brain-derived neurotrophic factor (BDNF) homeostasis. Materials and Method: Three groups of rats were conducted; young (3-month-old), non-trained aged (20-month-old), and exercise (EX)-aged group performing swimming EX 1h/day/5 days /week for 8 weeks. Results: Our findings revealed aging was associated with impaired cognitive parameters, increased total oxidant status (TOS) with a reduction in total antioxidant capacity (TAC), eNOS/NOx, and BDNF in the aged group versus the young. Such changes were improved by EX-induced upraised PGC1α/ FNDC5/irisin/AMPK pathway. The increased irisin is positively correlated with the hippocampal TAC, eNOS, NOx, BDNF, and AMPK levels, while negatively correlated with TOS. Conclusion: Bolstering irisin/AMPK levels via training would be an approach to prevent or delay an aging-associated cognitive decline or its progression.