Circulating exosomes convey the cognitive benefits of Tai Chi: The role of miR-625-5p in prefrontal remodeling and therapeutic potential

Long-term regular exercise is effective against age-related cognitive decline. However, the mechanisms through which mind-body exercises such as Tai Chi produce these effects, and the involvement of exosome-mediated signaling between the periphery and the brain, are unknown. For this 1:1 matched observational study, cognitively normal participants aged 60 to 75 years, with a male-to-female ratio of 2:3, were recruited into the long-term regular Tai Chi group ( n = 50) and long-term irregular exercise group ( n = 50). N-back task functional magnetic resonance imaging revealed that the long-term regular Tai Chi group showed a better working memory performance than the long-term irregular exercise group. Moreover, the long-term regular Tai Chi group showed altered activation in the superior frontal gyrus and pre/postcentral gyri. By integrating microRNA sequencing and proteomic profiling of serum exosomes, we identified miR-625-5p as a significant differential factor targeting CALM1 and VDAC2, whose expression levels negatively correlated with 1-back task accuracy. To investigate causality, serum-derived exosomes from both groups were delivered intravenously to SAMP8 mice. Exosomes from the Tai Chi group improved working memory deficits and resulted in an increase in prefrontal dendritic spine density, while down-regulating miR-625-5p and up-regulating the synaptic plasticity-related proteins calmodulin 1 and voltage-dependent anion channel 2 in the prefrontal cortex. Collectively, our findings suggest that long-term Tai Chi exercise may improve cognitive function by remodeling circulating exosome cargo. The key mediator, miR-625-5p, may act via the calmodulin 1/voltage-dependent anion channel 2 pathway to orchestrate prefrontal synaptic remodeling. Exosomes derived from Tai Chi practitioners may be a potential therapy for age-related cognitive decline.