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Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2-4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.
Physical activity evokes profound physiological responses in multiple tissues across the animal kingdom and is accepted to broadly improve human health1,5. The benefits of exercise extend to patients with neurodegeneration and brain trauma6,7, possibly by reducing neuroinflammation2. Long-term voluntary exercise in mouse models ofAlzheimer's disease (AD) and related disorders improve learning and memory, and decrease neuroinflammation3,7,8. How exercise exerts these beneficial effects is poorly understood. It has been proposed that 'exercise factors'-secreted from muscle and other tissues into the bloodsubsequently signal to the brain. Factors including IGF-1 (ref. 9), VEGF10 and PF4 (ref.11) increase hippocampal neurogenesis in young mice, whereas GPDL1 rescues the age-related loss in neurogenesis and cognition in old mice12 (Extended Data Table 1). However, it is unknown whether exercise-conditioned plasma contains factors that benefit the young healthy brain, whether these factors are directly transferrable through the plasma, whether such factors mediate the anti-inflammatory effect of exercise and what the key factors are.
Runner plasma improves cognition
Given these beneficial effects of exercise on the hippocampus, we investigated whether plasma from exercising male mice (runner plasma (RP)) transferred into young non-exercising littermates can mimic running; mice without access to a running wheel in their cage generated control plasma (CP) (Fig. 1a; details of the set-up are provided in the...