July 28, 2020
Written by: Claudia Lopez-Lloreda
What if you could get the benefits of exercising without actually exercising? Although this may sound like a pseudoscientific advertisement, it’s what a group of scientists at the University of California, San Francisco did in a recent study1. They transfused blood from mice that had exercised into aged mice and found that it also transferred the cognitive benefits that come with exercising.
The health benefits associated with exercise have been recorded by controlled studies and by anecdotal evidence. Specifically, research shows that exercise can improve cognitive function and slow down the loss of brain matter and cognitive function seen with age2. Since learning and memory worsen with age, most studies focus on a brain area crucial for these processes: the hippocampus. For example, one study found that moderate-intensity aerobic exercise (walking 10 to 40 minutes) 3 days a week increased hippocampal volume and cognitive function in older adults3. The intervention also increased levels of a protein called BDNF, a molecule involved in the birth of new neurons.
The beneficial effects of exercise on the cognitive function of the elderly are clear. But for older adults to be able to exercise, they must be healthy enough to do so. This makes it difficult or impossible for older adults with disabilities or physical frailty to implement this intervention to improve brain health. To get around this barrier, a group of researchers decided to test whether the beneficial effects could be passed through blood transfusions in an animal model.
Like humans, aged mice suffer from loss of cognitive function due to the detrimental effects of aging. And again, paralleling what happens in humans, exercise can reverse these age-related declines4. Interestingly, the administration of blood plasma from young animals also improves these age-related deficits 5. So, the scientists asked what would happen if they combined these two interventions.
The researchers allowed aged mice to use a running wheel as they pleased for 6 weeks and then collected their blood. They isolated and transfused plasma from both sedentary (mice who lacked access to a running wheel) and exercised mice into aged mice eight times over the span of three weeks. They saw that administration of plasma from exercised mice rescued age-related cognitive impairments, while the administration of plasma from sedentary mice had no effect.
When they looked into the mice’s brains, the researchers found that aged mice that had received the transfusion with plasma from exercised mice had increased numbers of mature neurons when compared to those treated with plasma from sedentary mice. These neurons also had markers that indicated they were new cells, meaning there was increased neurogenesis, or new birth of neurons. Additionally, plasma from exercised mice increased the neurogenesis-stimulating molecule BDNF.
Seeing as plasma from exercised mice had such a beneficial effect, the scientists wanted to dissect which molecules were responsible for this result. Using a technique that identifies chemicals within a sample, they found that the levels of 30 molecules increased in the plasma of exercised mice. One of these factors, Gpdl1, seemed to be involved in important pathways regulating metabolism.
The levels of Gpdl1 in the plasma positively correlated with improvement in cognitive performance, meaning that with increased Gpdl1, there was greater improvement. Surprisingly, older humans who were active had increased Gpdl1 levels, suggesting this molecule may also be mediating the beneficial effects of exercise in humans.
To pinpoint exactly where this molecule was coming from, the researchers examined Gpdl1 levels in different organs and found that it was highly expressed in the liver. Knowing this, the scientists decided to increase the levels of Gpdl1 in the liver to see if this modulation would be enough to mimic the effects seen by plasma from exercised mice. They were correct: increasing the expression of this molecule in the livers of sedentary, aged mice increased neurogenesis in the hippocampus and improved learning and memory.
As these downstream effects mostly depend on the activity of Gpdl1, the researchers asked what would happen if they abolished this activity. They did this by expressing a form of Gpdl1 that was inactive, meaning it could not carry out its enzymatic activity. The scientists found that by expressing this broken form of Gpdl1, they no longer saw the beneficial effects on neurogenesis and learning and memory. This means that Gpdl1 activity is necessary for the benefits of the plasma of exercised mice.
However, the scientists found that this liver-derived Gpdl1 was not getting into the brain. So how exactly was it exerting its effect on cognitive function? To answer this question, they examined processes that occur downstream, or as a consequence, of Gpdl1 function. They found that increased systemic Gpdl1 led to a decrease of two specific proteins, plasminogen and vitronectin, which are involved in coagulation (the formation of blood clots) and the complement system (part of the immune system). While more research is needed to examine whether these two proteins are mediating the beneficial effects of Gpdl1, the authors of the study suspect they may be the link between Gpdl1 and better brain health in mice.
This finding is important because it helps us understand the biology behind how exercise provides benefits to cognitive function. In the future, studies could see if the protein Gpdl1 by itself can provide similar benefits of exercise in older adults.
- Horowitz, A. M., Fan, X., Bieri, G., Smith, L. K., Sanchez-Diaz, C. I., Schroer, A. B., … Villeda, S. A. (2020). Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science, 369(6500), 167–173. https://doi.org/10.1126/science.aaw2622
- Mandolesi, L., Polverino, A., Montuori, S., Foti, F., Ferraioli, G., Sorrentino, P., & Sorrentino, G. (2018). Effects of Physical Exercise on Cognitive Functioning and Wellbeing: Biological and Psychological Benefits. Frontiers in Psychology, 9. https://doi.org/10.3389/fpsyg.2018.00509
- Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., … Kramer, A. F. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences, 108(7), 3017–3022. https://doi.org/10.1073/pnas.1015950108
- Praag, H. V., Shubert, T., Zhao, C., & Gage, F. (2005). Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice. Journal of Neuroscience, 25(38), 8680–8685. https://doi.org/10.1523/jneurosci.1731-05.2005
- Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., … Wyss-Coray, T. (2014). Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine, 20(6), 659–663. https://doi.org/10.1038/nm.3569
Cover image from PickPik.