Scientists have found that infusing old mice with cerebrospinal fluid obtained from young mice improves their memory by increasing proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) [1].
The fountain of brain youth
It has been known for years that blood from young animals can alleviate or even reverse some age-related changes, including cognitive changes, in old animals [2]. However, very little research has been done done relating to cerebrospinal fluid (CSF), which helps nourish and maintain our brain cells.
Similarly to blood, CSF composition changes with age [3], but scientists still know very little about the contribution of these changes to aging. One study has shown that in humans, CSF from young healthy donors increases neuronal viability [4]. Another one found that CSF from people with multiple sclerosis is toxic to neurons in vitro [5].
Oligodendrocytes: the electricians of the brain
In this new study, researchers infused 20-month-old mice with CSF drawn from young mice. Three weeks later, the researchers analyzed the mice’s memory by using a simple test that checks how well the mice remember stimuli associated with discomfort in the past. The researchers found that the mice who received a transfusion of young CSF performed significantly better than controls.
The scientists then ran a transcriptomic analysis of the hippocampus and identified 271 genes that were differentially expressed following the procedure. They found that genes related to oligodendrocytes, especially to their differentiation, were the most significantly upregulated.
Oligodendrocytes create myelin sheaths that envelop the axons of brain neurons. These sheaths provide insulation (just like with electric wires), reducing ion leakage and ensuring rapid signal conduction. Myelionogenesis mostly happens during early development but continues throughout life, and it is thought to be extremely important for memory and learning.
Oligodendrocytes, in turn, differentiate from OPCs. One recent study showed that oligodendrogenesis is drastically reduced with age and that increasing it can improve learning and memory in aged mice [6].
Serum response factor and the cytoskeleton
The researchers found that young CSF induced a 2.35-fold surge in the percentage of proliferating OPCs in the hippocampus. Further experiments revealed an expected increase in the number of myelinated axons. An increase in proliferation was also observed in vitro, in cultured cells treated with young CSF.
One of the proteins most upregulated by young CSF was serum response factor (SRF), a ubiquitous transcription factor that is present not just in the brain but also in skeletal muscle and the heart. Wherever it is expressed, SRF is known to increase cell motility, proliferation, and differentiation by promoting the formation of actin filaments that the cytoskeleton is mostly made from. The researchers found that CSF treatment significantly improves cytoskeleton building in OPCs.
SRF knockout, on the other hand, eliminated the gains in OPC proliferation induced by young CSF. These results strongly suggest that the effect of young CSF is mediated by SRF and specifically by SRF-induced cytoskeleton growth.
The missing link
Something in young CSF was boosting the production of SRF, but there are hundreds of proteins that could be responsible for this. After another battery of experiments, the researchers formed a list of 35 potential SRF inducers and then narrowed their search down to fibroblast growth factor 17 (Fgf17), which responded most strongly to changes in the dose of young CSF. Interestingly, the levels of Fgf17 in human CSF decrease with age.
Fgf17 supplementation induced proliferation and differentiation of OPCs in vitro, just like the treatment with young CSF did. Similar results were then obtained in vivo, in aged hippocampi. Fgf17 was also shown to improve memory in mice. Infusing young mice with Fgf17-blocking antibodies impaired their performance in cognitive tests. In vitro, blocking Fgf17 inhibited the increase in proliferation caused by young CSF.
Conclusion
While the rejuvenating properties of young blood are more widely known, the finding that oligodendrogenesis and memory function in the aged brain can be improved by young CSF opens an entirely new avenue of research into brain aging. Importantly, although both blood and CSF consist of hundreds of components, scientists can isolate the ones responsible for particular outcomes (such as Fgf17) and turn them into therapeutic targets. Unfortunately, only one type of memory test was used in this study, and more research will be required to determine how effective this approach is on other types of cognition.
Literature
[1] Iram, T., Kern, F., Kaur, A., Myneni, S., Morningstar, A. R., Shin, H., … & Wyss-Coray, T. (2022). Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature, 1-7.
[2] 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.
[3] Chen, C. P., Chen, R. L., & Preston, J. E. (2012). The influence of ageing in the cerebrospinal fluid concentrations of proteins that are derived from the choroid plexus, brain, and plasma. Experimental gerontology, 47(4), 323-328.
[4] Schwarz, N., Hedrich, U., Schwarz, H., PA, H., Dammeier, N., Auffenberg, E., … & Koch, H. (2017). Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Scientific reports, 7(1), 1-12.
[5] Schwarz, N., Hedrich, U., Schwarz, H., PA, H., Dammeier, N., Auffenberg, E., … & Koch, H. (2017). Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Scientific reports, 7(1), 1-12.
[6] Wang, F., Ren, S. Y., Chen, J. F., Liu, K., Li, R. X., Li, Z. F., … & Mei, F. (2020). Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory. Nature neuroscience, 23(4), 481-486.
