Researchers have for some time investigated the effects of transfusing materials from young animals to old animals, largely blood fractions such as blood plasma, but also other line items such as samples of the gut microbiome, thymic tissue, and so forth. The work on blood and plasma transfusions from young to old has proven disappointing in comparison to parabiosis, in the sense that results have been mixed, both in mice and in human trials. Transferring gut microbes to rejuvenate the aged intestinal microbiome looks much more promising.
In today's research materials, scientists report on a more challenging procedure, the transfer of cerebrospinal fluid between mice. Young cerebrospinal fluid improves brain function in old mice, leading to benefits to memory. Based on watching more than a decade of debate over the mechanisms involved in the way in which young blood may benefit old animals, a debate that is still very much ongoing, I expect that it will no doubt be some years before the scientific community comes to a good understanding of the mechanisms involved in improvements to cognitive function resulting from exposure to young cerebrospinal fluid.
Cerebrospinal fluid (CSF) from young mice can improve memory function in older mice. A direct brain infusion of young CSF probably improves the conductivity of the neurons in ageing mice, which improves the process of making and recalling memories. The researchers also isolated a protein from the CSF cocktail that another analysis had suggested was a compelling candidate for improving memory: fibroblast growth factor 17 (Fgf17). Infusion of Fgf17 had a similar memory-restoring effect to infusing CSF. Furthermore, giving the mice an antibody that blocked Fgf17's function impaired the rodents' memory ability.
It took more than a year to perfect the process of collecting CSF and infusing it into another brain. Collection is extremely challenging, and has to be done with precision. Any blood contamination will ruin the fluid. Pressure in the brain is a delicate balance, so infusion must be slow and in a specific location within the brain: the cerebral ventricle. The delicate procedure might pose challenges for use in people.
Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures.
We identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.