Dracula may have had it right: Young blood can restore an aging body. Scientists have discovered that blood from a 3-month-old mouse can coax the brain of an older mouse into making new brain cells. The team has not yet identified the rejuvenating factor, but they have found a blood-borne compound that seems to promote brain aging.
As the body ages, the brain gradually becomes more sluggish. Even in people lucky enough to dodge neurodegenerative disorders such as Alzheimer's disease, fewer new neurons are created from stem cells in the brain, and the activity of existing neurons weakens. Neuroscientist Tony Wyss-Coray of Stanford University School of Medicine in Palo Alto, California, suspected that the changes could be mediated by factors in the blood.
Previous research has shown that giving young blood to older mice boosts their immune system and muscle function. Wyss-Coray wondered whether the same might be true in the brain. Although the so-called blood-brain barrier blocks many large molecules from entering the brain from the bloodstream, the barrier isn't sealed tight everywhere, which might allow some compounds to get through. It's leakiest at places where there are brain stem cells, suggesting that these neuron precursors may have interaction with the circulatory system.
Wyss-Coray's team measured neurogenesis, the creation of new neurons from stem cells, in mice that were 3 months old and mice that were almost 2 years old and considered adults. Then they surgically connected the circulatory systems of pairs of young and old mice. The number of new cells in one region of the brain's hippocampus, related to memory formation, went from fewer than 400 to almost 1000 in the older mice. In the younger mice, it dropped by almost a quarter, the scientists report today in Nature. "It worked in both directions," says Wyss-Coray. "The age of the blood has a special effect on the brain."
When the researchers gave young mice daily injections of older blood, not only did neurogenesis decrease, but their learning and memory scores in a water maze test got worse. They made more than twice the number of mistakes in the maze after a day of training and a day of testing.
To isolate the compound responsible for these changes, Wyss-Coray and his colleagues focused on 66 blood-borne chemicals. They identified 17 that increased in concentration as a mouse aged. One of them, a protein called CCL11, was enough to slow neurogenesis when injected into the bloodstream on its own. The researchers haven't yet found a compound that does the reverse—turning up neurogenesis. But finding more neurogenesis in old mice given young blood suggests that it exists.
The findings offer a proof of principle that neurogenesis can be controlled through the blood, a paradigm-shifting idea for treating neurodegenerative disease, Wyss-Coray says. "The big implication here is that we can potentially affect brain aging and degradation, even dementia, by targeting factors in the periphery rather than having to target the brain directly."
Richard Ransohoff, a neuroscientist at the Cleveland Clinic in Ohio, says the new study is a leap toward understanding how neurogenesis is controlled in the adult brain. "I think it's very exciting to know that the aging stem cell population can remain responsive to environmental cues." But more work is needed to fully understand how all the cues work, he says, and whether the findings hold true in people.
"One of the next steps is to take these factors and measure them in aging humans," Ransohoff says. "You might take patients with neurodegenerative diseases and see how the factors are different, or follow how they change over time in people with early cases of disease."
Wyss-Coray plans to start out by analyzing more blood-borne factors in mice. His team is planning a screen of hundreds more factors to see what else may be controlling the aging of the brain.