Five years ago, Tal Iram, a young neuroscientist at Stanford University, approached her supervisor with a bold proposal: She wanted to extract fluid from the brain cavities of young mice and inject it into the brains of older mice, to test whether the transfers could rejuvenate. aged rodents.
His supervisor, Tony Wyss-Coray, was famous for showing that giving blood from younger animals to older animals could counteract and even reverse some effects of aging. But the idea of ​​testing this principle with cerebrospinal fluid, the hard-to-reach fluid that bathes the brain and spinal cord, struck him as a technical feat so challenging that attempting it bordered on recklessness.
“When we discussed it initially, I said, ‘It’s so hard, I’m not sure it’s going to work,'” Wyss-Coray said.
Iram persevered, working for a year just to figure out how to collect the colorless fluid from the mice. On Wednesday, she reported the tantalizing results in the journal Nature: One week of infusions of young cerebrospinal fluid improved the memory of older mice.
The finding was the latest indication that making brains resistant to the relentless changes of old age may depend less on interfering with specific disease processes and more on trying to restore the brain’s environment to something closer to its youthful state.
“This underlines the idea that cerebrospinal fluid can be used as a means of manipulating the brain,” said Iram.
Turning that insight into a treatment for humans, however, is a more formidable challenge, the study authors said. Previous work on how young blood can reverse some signs of aging led to recent clinical trials in which blood donations from younger people were filtered and applied to patients with Alzheimer’s or Parkinson’s disease.
But it’s still unclear exactly how successful these treatments might be, let alone how widely they can be used, the scientists said.
The difficulties of working with cerebrospinal fluid are more pronounced than those related to blood. Infusing a young person’s fluid into an older patient is probably not possible; extracting the fluid usually requires a spinal tap, and scientists say there are ethical questions about how to collect enough cerebrospinal fluid for infusions.
While there are theoretically other ways to achieve similar benefits — such as providing a critical fluid protein that the researchers have identified or making a small molecule that mimics that protein — these approaches have their own challenges.
Cerebrospinal fluid has become a logical target for researchers interested in aging. It nourishes brain cells and its composition changes with age. Unlike blood, fluid is close to the brain.​
For years, scientists have viewed the fluid primarily as a way of recording the changes associated with aging, rather than combating its effects. Cerebrospinal fluid tests, for example, have helped identify abnormal protein levels in patients with significant memory loss who have developed Alzheimer’s. Scientists knew there were health-promoting proteins in the cerebrospinal fluid, too, but pinpointing their precise locations and effects seemed impossible.
For one, the scientists said, it was difficult to track changes in the fluid, which the body continually replenished. And collecting it from mice, avoiding contamination of the fluid with traces of blood, was extremely difficult.
“The field has lagged decades behind other areas of neuroscience,” said Maria Lehtinen, who studies cerebrospinal fluid at Children’s Hospital Boston and is a co-author of a Nature commentary on the new mouse study. “In large part, this is due to technical limitations in studying a fluid that is deep inside the brain and is continually being replaced.”
To infuse young cerebrospinal fluid into old mice, Iram drilled a small hole in their skulls and implanted a pump under the skin in their upper back. For comparison, a separate group of old mice was infused with artificial cerebrospinal fluid.
A few weeks later, the mice were exposed to signals — a sound and a flashing light — that they had previously learned to associate with foot shocks. The animals that received the young cerebrospinal fluid infusion tended to freeze longer, suggesting they had preserved stronger memories of the original foot shocks.
“This is a very interesting study that I think is scientifically sound,” said Matt Kaeberlein, a biologist who studies aging at the University of Washington and was not involved in the research. “This adds to the growing body of evidence that it is possible, perhaps surprisingly easy, to restore function in aged tissues by targeting the mechanisms of biological aging.”
Iram tried to determine how the young cerebrospinal fluid was helping to preserve memory by analyzing the hippocampus, the part of the brain dedicated to memory formation and storage. Treating the old mice with the fluid, she found, had a strong effect on cells that act as precursors to oligodendrocytes, which produce layers of fat known as myelin, which insulate nerve fibers and ensure strong signal connections between neurons.
The study authors focused on a specific protein in young cerebrospinal fluid that appeared to play a part in triggering the series of events that led to stronger nerve isolation. Known as fibroblast growth factor 17, or FGF17, the protein can be infused into older cerebrospinal fluid and can partially replicate the effects of younger fluid, the study found.
Even more impressive, blocking the protein in young mice appeared to impair their brain function, offering stronger evidence that FGF17 affects cognition and changes with age.
The study strengthened the case that failures in myelin formation were related to age-associated memory loss.
Some scientists said that knowing one of the proteins responsible for the effects of young spinal fluid could open the door to possible treatments based on this protein. At the same time, recent technological advances have brought scientists closer to observing changes in cerebrospinal fluid in real time, helping them “peel away the layers of complexity and mystery that surround this fluid,” Lehtinen said.
