Blood Factors Can Transfer the Benefits of Exercise to the Aged Brain

Post by Elisa Guma

What's the science?

Exercise has been shown to be a promising intervention to mitigate age-related cognitive decline, and vulnerability to age-related neurodegenerative diseases, however it is not accessible to all elderly individuals due to poor health or physical frailty. Animal studies have shown that exercise can reverse age related decline in adult neurogenesis (the formation of new neurons) in the hippocampus and improve cognitive function. Interestingly, the transfer of blood from young mice to old has also been found to improve regeneration and cognitive function. This week in Science, Horowitz, Fan and colleagues tested the effects of systemic plasma administration derived from mice that exercise on regenerative and cognitive function in the aged brain.

How did they do it?

Blood was collected and plasma was isolated from aged 18-month-old mice who had exercised (i.e. had access to a running wheel for 6 weeks) and aged sedentary mice. The isolated plasma was injected into a separate cohort of aged mice. Following administration, hippocampal-dependent learning and memory were tested (using the radial arm water maze and contextual fear conditioning) and immunohistochemistry was performed to look for evidence of neurogenesis in the hippocampus. The authors also investigated whether the benefits of exercise observed in mice at younger ages could also be transferred to the aged mice through circulating blood factors.

Next, the authors measured soluble protein levels in the plasma of exercised and sedentary mice to try to understand what might be driving the beneficial effects of exercise. Once their protein of interest was identified, they characterized its expression levels in various organs of the body, including the liver, lung, fat, spleen, skin kidney, heart, muscle, cortex, hippocampus, and cerebellum. They then overexpressed the peptide in the liver (using hydrodynamic tail vein injection) and tested its ability to improve neurogenesis and cognitive performance in aged mice. In order to gain further mechanistic insight, the authors investigated the ability of the peptide to cross the blood-brain barrier, as well as the importance of enzymatic activity associated with the peptide in effects on cognition and neurogenesis.

What did they find?

When plasma from exercised mice was given to sedentary mice, there was an increase in newly born neurons and improved performance in hippocampal-dependent learning. These data indicate that plasma from exercised aged animals can transfer the beneficial effects of exercise to the regenerative capacity of the aged hippocampus and hippocampal-dependent learning and memory. They observed similar improvements when plasma from exercised mature mice (6-7 months) was administered to aged mice.

Analysis of plasma identified 30 factors in the exercised aged mice and 33 in the exercised mature mice that had greater expression than in the sedentary mice, of which 63% and 67% respectively were expressed in the liver. They identified two proteins that were overrepresented, but chose to focus on one — glycosylphosphatidylinositol (GPI)l-specific phospholipase D1 (Glpd1) (an enzyme in the liver that cleaves GPI) — as it hadn’t previously been associated with aging, neurogenesis, or cognition. The authors confirmed that Gpld1 was increased in exercised mice and that its expression levels were correlated with improved cognitive performance. Further, they demonstrated that its overexpression in the liver of aged animals improved adult neurogenesis and cognitive function. Gpld1 was found not to cross the blood-brain barrier readily, and to have low expression levels in the brain. Finally, the authors demonstrated that the peptide must be catalytically active and cleave GPI in order to induce beneficial effects on neurogenesis and cognition.

What's the impact?

The authors identified a novel role for the liver-derived factor Gpld1 as a mediator for the beneficial effects of exercise on the aged mouse brain. This provides exciting evidence for a potential liver-to-brain axis in which circulating blood factors transmit the beneficial effects of exercise to the brain. Finally, these data point to promising avenues for intervention in the aging population, as the beneficial effects of exercise could be distributed broadly across tissues via circulating blood factors.

Horowitz & Fan et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science (2020). Access the original scientific publication here.