Exercise has for many years been known to be among the most robust means to support a healthy and long lifespan. In a previous post, we discussed research detailing evidence that exercise facilitates the elimination of senescent cells and might provide health benefits through the reduction of systemic inflammation. Exercise is likely to act in a pleiotropic manner, benefiting a variety of organ systems through activation of multiple biological pathways, rather than through a single manner of regulation. Researchers from Stanford University School of Medicine set out to determine if the neuroprotective effects seen in exercised laboratory mice might involve circulating factors in the blood.

When considering biological systems implicated in the outcome of any intervention, the circulatory system is an ideal candidate to interrogate. Blood, in addition to transporting nutrients and facilitating respiration, carries within it numerous signaling molecules, and it has long been speculated that circulating factors in the blood might facilitate pathways responsible for maintaining a robust healthy organism—an idea dating as far back as 1615 when physician Andreas Libavius proposed transfusing blood from the young to the elderly in an attempt to restore their vitality. This idea was further examined through the heterochronic parabiosis experiments of the 1940s in which the circulatory systems of old and young animals were surgically connected. This procedure led to observed benefits in the older animals thought to be the result of shared circulatory factors. However, through the shared circulatory system, these animals also shared organ systems. As a result, the more competent organs of the young animals could have been responsible for alleviating the burden on the older animal’s organ systems. This confounding aspect has drawn rightful criticism that such experiments cannot demonstrate that a circulating factor in the blood is solely responsible for the improvements seen in older animals.

Alternatively, collecting blood from animals and providing the resultant plasma to treatment groups intravenously does not have this disadvantage. In a recent study published in Nature, researchers utilized this method to identify an important circulating factor induced by exercise and vital to the imparted benefits of improved memory and reduced neuroinflammation.

In this study, mice were housed with or without running wheels, allowing for groups of exercised or non-exercised mice. Blood from both groups was collected and processed to acquire plasma—the fraction of blood free of cells but containing proteins. Plasma from both the “runners” and “non-runners” was subsequently administered to sedentary mice. Sedentary mice that received transfusions of plasma from the exercised “runner” group showed a significant increase in neurogenesis and improvement to both memory and cognition, as well as reduced neuroinflammation compared to those that received plasma from the “non-runner” mice.

When analyzed, the hippocampus, a region of the brain highly involved in learning and memory, showed increased neurogenesis in mice given access to running wheels for 28 days. In line with the increased cellular proliferation in the hippocampus, sedentary mice treated with “runner” plasma showed improved memory and cognition when assessed via standard behavioral tests.

Comparison of the plasma proteome collected from the “runner” and “non-runner” groups revealed increased levels of clusterin, a protein known to be involved in inflammation and aging. When neuroinflammation was induced through the administration of lipopolysaccharide, mice infused with “runner” plasma demonstrated reduced inflammatory markers in the hippocampus compared to controls. However, when clusterin was removed from “runner” plasma and administered to sedentary mice, inflammation was not reduced compared to mice treated with the intact “runner” plasma. Furthermore, mice administered recombinant clusterin showed downregulation of genes known to be elevated with pro-inflammatory lipopolysaccharide treatment.

Lipopolysaccharide treatment is an acute model of neuroinflammation and differs from conditions of chronic neuroinflammation seen in Alzheimer’s disease. To gain insight into clusterin’s role in chronic neuroinflammation, APP transgenic mice (an animal model for Alzheimer’s disease) were treated with recombinant clusterin. As a result, many of the pathologically driven genes abnormally expressed in brain endothelial cells of these APP transgenic mice were reversed.

Previous studies have demonstrated that aerobic exercise supports improved cognition and exerts an anti-inflammatory effect through multiple mechanisms. This study demonstrates that aerobic exercise in wheel-running mice provides a similar outcome and that plasma from these mice can confer the same benefit to sedentary mice. The authors believe their observations are the first to demonstrate clusterin’s role in reducing neuroinflammation, a state highly correlated with increased age and neurological disease, and hope these findings aid in combating such conditions.