For the first time! Injection of young cerebrospinal fluid may reverse brain aging

Normally, our brains don't get water, but there is water in it, about 150 to 270 milliliters. The water is colorless, transparent and like plasma. Also known as cerebrospinal fluid, it fills the brain and spinal cord and is produced by the choroid plexus of the lateral ventricle, the third and fourth ventricles. In order to maintain volume stability, excess cerebrospinal fluid will also be excreted by the spinal cord.

The water in the brain

The journal Science published a study on the cleaning ability of cerebrospinal fluid in 2013 and 2019 respectively. The two studies complement each other and found that when people fall asleep at night, the cerebrospinal fluid that normally fills around the brain tissue conforms to the sleep cycle and enters the brain tissue through small channels. They are like "detergents", constantly flowing through and scouring the nerve tissue, bringing out harmful proteins such as beta-amyloid that accumulate in it during the day.

A fuller explanation of the function of cerebrospinal fluid comes from a comprehensive study in 2020, which holds that cerebrospinal fluid is not only a liquid buffer, ion buffer and waste pool that protects the brain, but also a part of the central nervous system. it allows us to have a more comprehensive understanding of this particular, intelligent system.

Cerebrospinal fluid develops and ages along with the brain tissue. In the early stage of development, signal molecules carried in cerebrospinal fluid can promote the proliferation and differentiation of neural progenitor cells. Cerebrospinal fluid also changes as people age, most notably an increase in inflammatory proteins and a decrease in growth factors (such as brain-derived neurotrophic factor BDNF). BDNF can enhance the synaptic plasticity (conducive to memory formation) and promote neurogenesis, neuronal development and differentiation in the hippocampus and other brain regions. Thus it can be seen that after aging, the fluid environment in the brain is more and more unfavorable to the survival of neurons.

If the aging cerebrospinal fluid is replaced with young cerebrospinal fluid, can individual memory and other brain functions be improved, or can brain aging be reversed? A recent study published in the journal Nature answers this question in detail. Tony Wyss-Coray, the study's correspondent and a neuroscientist at Stanford University in the United States, began to study brain aging in the 1990s, when he realized that the most direct effect on the brain was cerebrospinal fluid, but the technology at that time did not allow him to conduct cerebrospinal fluid-related research directly.

Wyss-Coray then turned to another kind of liquid in the human body-blood. In 2014, he and his colleagues made a startling discovery: when the blood systems of old and young mice were connected, young blood could improve the brain function of old mice. In the recent new study, the lead author, Tal Iram, used elaborate surgical techniques to make cerebrospinal fluid research possible. While reversing brain aging, these groundbreaking studies also reveal molecules that really play a key role, which may help us treat a variety of brain diseases associated with aging.

Inject young cerebrospinal fluid

In the new study, the source of cerebrospinal fluid was 10-week-old mice, which had just reached adulthood, while the recipients were 20-month-old mice, who had reached middle and old age. The researchers obtained about 90 microliters of cerebrospinal fluid (in which immune cells have been removed) from the brains of young mice and injected them into the brains of older mice at a rate of 0.5 microliters per hour over a period of seven days. A total of eight elderly mice went through this process, which is called the YM-CSF group. To be clear, the cerebrospinal fluid of adult mice is usually about 40 microliters and is updated at a rate of 1.98 microliters per hour. Thus it can be seen that the cerebrospinal fluid of old mice is not completely replaced by the cerebrospinal fluid of young mice. As a control, nine elderly mice were injected with artificial cerebrospinal fluid (aCSF group).

In order to test the learning and long-term memory ability of the hippocampus of elderly mice, as early as two days before the beginning of the above process, the elderly mice were subjected to foot shock accompanied by sound and flash, and as the first day of the experiment, cerebrospinal fluid was injected on the following 3-10 days, and the electric shock experiment was repeated 3 weeks later. If the mice can think of an electric shock immediately after hearing the sound and seeing the flash, it means that they have formed a long-term memory.

As a result, the old mice in the YM-CSF group did remember the experiment three weeks ago, and their bodies stiffened faster in fear when they sensed sound and flash. The stiffness rate of the aCSF group was almost the same as that of the old mice tested for the first time, and they did not remember. This phenomenon suggests that young cerebrospinal fluid does make older mice better at learning and long-term memory.

The thickness of the myelin sheath on the axon determines the speed of electrical signal transmission and has a critical impact on brain processing, integration of information, as well as learning and memory processes. The loss of myelin is also associated with decreased cognitive ability and a variety of diseases, such as multiple sclerosis.

The increased gene expression in the experiment also showed that after changes, the components of cerebrospinal fluid could promote the differentiation of these cells in aged mice and increase the plasticity of mature oligodendrocytes. However, from the perspective of the whole brain of mice, the change caused by cerebrospinal fluid was not obvious, but the effect on the hippocampus was more obvious, in which the number of proliferated oligodendrocytes increased by 2.35 times.

The effects of cerebrospinal fluid (CSF) of healthy young people (24.6 years old) and old people (69 years old) on old mice were also tested. The cerebrospinal fluid of young and young mice had the same ability to promote the proliferation of oligodendrocytes, while the effect of cerebrospinal fluid of the elderly was only half that of the former two. As oligodendrocytes mature, the density of myelin sheath in the hippocampus will increase, and so will the number of axons wrapped. All these fully indicate that some components in young cerebrospinal fluid may promote the proliferation, differentiation and maturation of oligodendrocytes, or counteract the effects of inhibitors (present in the cerebrospinal fluid of aged mice).

One hundred at a time

To identify the substances that play a key role, the researchers began to culture mouse oligodendrocytes in young cerebrospinal fluid (from three donors) and labeled the cells' newly produced RNA. Under the induction of cerebrospinal fluid, blood effector factor (serum response factor,SRF) is the first large amount of expression in cells. This transcription factor exists widely in skeletal muscle, heart and neurons and can induce cell proliferation, migration and differentiation. The researchers found that oligodendrocyte proliferation is triggered by SRF and its downstream signaling pathways. In addition, SRF can also down-regulate some genes related to aging and Alzheimer's disease.

There may be hundreds of proteins in cerebrospinal fluid that can induce cells to produce SRF and the subsequent process, so what is the most critical molecule? Combined with the experimental data and the cerebrospinal fluid proteome database, the researchers obtained 35 potential SRF inducing molecules and tested the induction ability of these proteins one by one. The results showed that fibroblast growth factor 8 (Fgf8) and Fgf17 were significantly related to the induction activity of SRF. In the above experiments, the researchers found that a single injection of young cerebr