Spinal fluid from young mice sharpened memories of older rodents

Five years ago, Tal Iram, a young neuroscientist at Stanford University, approached her supervisor with a daring proposal: She wanted to extract fluid from the brain cavities of young mice and to infuse it into the brains of older mice, testing whether the transfers could rejuvenate the ageing rodents.

Her supervisor, Tony Wyss-Coray, famously had shown that giving old animals blood from younger ones could counteract and even reverse some of the effects of ageing. But the idea of testing that principle with cerebrospinal fluid, the hard-to-reach liquid that bathes the brain and spinal cord, struck him as such a daunting technical feat that trying it bordered on foolhardy.

“When we discussed this initially, I said, ‘This is so difficult that I’m not sure this is going to work,’ ” Wyss-Coray said.

Iram persevered, working for a year just to figure out how to collect the colourless liquid from mice. On Wednesday, she reported the tantalising results in the journal Nature: A week of infusions of young cerebrospinal fluid improved the memories of older mice.

The finding was the latest indication that making brains resistant to the unrelenting changes of older age might 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.

“It highlights this notion that cerebrospinal fluid could be used as a medium to manipulate the brain,” Iram said.

Turning that insight into a treatment for humans, though, is a more formidable challenge, the authors of the study said. The earlier studies about how young blood can reverse some signs of ageing have led to recent clinical trials in which blood donations from younger people were filtered and given to patients with Alzheimer’s or Parkinson’s disease.

But exactly how successful those treatments might be, much less how widely they can be used, remains unclear, scientists said. And the difficulties of working with cerebrospinal fluid are steeper than those involved with blood. Infusing the fluid of a young human into an older patient is probably not possible; extracting the liquid generally requires a spinal tap, and scientists say that there are ethical questions about how to collect enough cerebrospinal fluid for infusions.

While there are theoretically other ways of achieving similar benefits — such as delivering a critical protein in the fluid that the researchers identified or making a small molecule that mimics that protein — those approaches face their own challenges.

Jeffery Haines, a biochemist who has studied cerebrospinal fluid and multiple sclerosis at Mount Sinai Medical Center in New York, said that the study had elegantly identified how certain ingredients in the fluid might promote memory. But he said the general public’s appetite for anti-aging drugs was outpacing the science.

“In general, people are looking for the Holy Grail of ageing, and they think there is going to be a magical factor that’s being secreted that’s just going to reverse this thing,” he said. “I don’t think it’s that simple.”

Cerebrospinal fluid made for a logical target for researchers interested in ageing. It nourishes brain cells, and its composition changes with age. Unlike blood, the fluid sits close to the brain.

But for years, scientists saw the fluid largely as a way of recording changes associated with ageing, rather than countering its effects. Tests of cerebrospinal fluid, for example, have helped to identify levels of abnormal proteins in patients with significant memory loss who went on to develop Alzheimer’s disease. Scientists knew that there were also health-promoting proteins in cerebrospinal fluid, but identifying their locations and precise effects seemed out of reach.

For one thing, scientists said, it was difficult to track changes in the fluid, which the body continuously replenished. And collecting it from mice while avoiding contaminating the fluid with even trace amounts of their blood was extremely challenging.

“The field has lagged decades behind other areas of neuroscience,” said Maria Lehtinen, who studies cerebrospinal fluid at Boston Children’s Hospital and is the co-author of a commentary in Nature about the new mouse study. “Largely this is because of the technical limitations in studying a fluid that’s deep inside the brain, and that turns over continuously.”

Iram was undaunted. She set about taking the liquid from 10-week-old mice, cutting above their necks and drawing out fluid from a tiny cavity near the back of the brain while trying not to puncture any blood vessels or poke the brain itself.

When she was successful, Iram said, the result was about 10 microliters of cerebrospinal fluid — roughly one-fifth of the size of a drop of water. To collect enough for infusions, she had to do the procedure on many hundreds of mice, taming the technical challenges that Wyss-Coray had warned of by sheer force of repetition.

“I like doing these types of studies that require a lot of perseverance,” Iram said. “I just set on a goal, and I don’t stop.”

To infuse the young cerebrospinal fluid into old mice, Iram drilled a tiny hole in their skulls and implanted a pump below the skin on their upper backs. For comparison, a separate group of old mice was infused with artificial cerebrospinal fluid.

A few weeks later, the mice were exposed to cues — a tone and a flashing light — that they had earlier learned to associate with shocks to their feet. The animals that had received the young cerebrospinal fluid infusion tended to freeze for longer, suggesting that they had preserved stronger memories of the original foot shocks.

“This is a very cool study that looks scientifically solid to me,” said Matt Kaeberlein, a biologist who studies ageing at the University of Washington and was not involved in the research. “This adds to the growing body of evidence that it’s possible, perhaps surprisingly easy, to restore function in aged tissues by targeting the mechanisms of biological ageing.”

Iram tried to determine how the young cerebrospinal fluid was helping to preserve memory by analysing the hippocampus, a portion 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 that insulate nerve fibres and ensure strong signal connections between neurons.

The authors of the study homed in on a particular protein in the young cerebrospinal fluid that appeared involved in setting off the chain of events that led to stronger nerve insulation. Known as fibroblast growth factor 17, or FGF17, the protein could be infused into older cerebrospinal fluid and could partially replicate the effects of young fluid, the study found.

Even more strikingly, 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 breakdowns in myelin formation were related to age-associated memory loss. That is something of a departure from the long-standing focus on the fatty insulation in the context of diseases like multiple sclerosis.

Some scientists said that knowing one of the proteins responsible for the effects of young spinal fluid could open the door to potential treatments based on that protein. At the same time, recent technological advances have brought scientists closer to observing changes in cerebrospinal fluid in real time, helping them “peel back the layers of complexity and mystery surrounding this fluid,” Lehtinen said.

Still, scientists cautioned that those treatments would not materialise anytime soon. Among the difficulties are understanding what other proteins might be involved and figuring out how to harness their effects without causing separate problems.

But Wyss-Coray said that the study filled a critical gap in the understanding of how the brain’s environment changes as people age.

“The question is, ‘How can you maintain cognitive health until you die? How can you make the brain resilient to this relentless degeneration of the body?’ ” he said, “and what a growing number of studies show is that as we learn more about the ageing process itself, maybe we can slow down aspects of ageing and maintain tissue integrity or even rejuvenate tissues.”

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