Promise of irisin to attenuate cognitive dysfunction in aging and Alzheimer's disease

Strategies proficient for relieving cognitive impairments in aging and Alzheimer's disease (AD) have an enor-mous impact. Regular physical exercise (PE) can prevent age-related dementia and slow down AD progression. However, such a lifestyle change is likely not achievable for individuals displaying age-related frailty. Hence, drugs or biologics that could simulate the benefits of PE have received much attention. Previous studies sug-gested that the fibronectin-domain III containing 5 (FNDC5) underlies the PE-mediated improved cognitive function. A recent study reports that PE-related cognitive benefits in aging and AD are mediated by irisin, the cleaved form of FNDC5 released into the blood after PE. Such a conclusion was apparent from the deletion of irisin through a global knockout of FNDC5, leading to the loss of PE-induced cognitive benefits or inducing memory impairments in adult or aged models. Furthermore, in AD models, peripherally administered irisin mimicked the cognitive benefits of PE by modulating neuroinflammation. This short review discusses the promise of irisin to simulate the cognitive benefits of PE in age-and AD-related dementia. In addition, critical issues such as how blood-borne irisin acts on neural cells, the role of the brain-derived neurotrophic factor in irisin-mediated cognitive benefits, and irisin's ability to inhibit neuroinflammatory cascades in aging and AD are discussed.