A blood-borne immune factor present in elderly mice contributes to signs of mental decline when injected into young mice, and inhibiting it restores youthfulness in old mice, according to an article published online today (August 31) in Nature. The study implies that it may be possible to change some of the symptoms of aging in the brain by altering the levels of immune factors in the blood.
"This is a really phenomenal, complete study," Sally Temple, a developmental neuroscientist and scientific director of the New York Neural Stem Cell Institute, who was not involved in the research, wrote in an email. "These experiments were particularly convincing because they addressed the issues at multiple levels, from proteomics analysis, to electrophysiology, to mouse behavior, and the authors conducted careful controls for each step."
Researchers have recently shown that the hippocampus, the part of the brain involved in creating new memories, loses function and stops producing new neurons as it ages. This decline can be partially reversed when animals exercise regularly, which is known to stimulate circulation and the release of metabolites and chemicals in the blood, leading Tony Wyss-Coray from Stanford University School of Medicine to wonder if there was a blood-borne factor that might contribute to these changes.
To find out, he and his colleagues stitched the flank of a young mouse together with the flank of an old mouse, creating a conjoined-twin-like effect that allowed the blood of the two mice to mingle and exchange. They then looked at the numbers of new neurons forming in the brains of both mice, and found that the young animals showed a decrease in neurogenesis, while the old ones showed more new growth, as compared to young and old animals stitched to similarly aged partners.
"There seemed to be rejuvenation in the old brain," said Wyss-Coray. When the researchers took only the blood plasma (with no cells) of old mice, and injected it into young mice, they saw a similar decrease in neurogenesis, suggesting an extracellular blood protein was responsible. The neurological changes correlated with inferior performance on a battery of memory tests and mazes: the mice with old blood plasma did not form as robust memories, nor did they remember the solution to a maze as well as normal young mice—impairments commonly observed in old mice.
To identify what it was in the plasma that caused the effect, the researchers compared the concentrations of blood proteins in the conjoined animals. Of six candidate proteins whose levels that changed after the mice were stitched together, a chemokine called CCL11, or eotaxin, demonstrated the biggest change, said Wyss-Coray.
"The factor [CCL11] is a surprising character,” said Richard Ransohoff from the Cleveland Clinic Lerner College of Medicine. “It's a chemokine that has zero prior neurobiology," he added, known only for its role in attracting eosinophils—immune cells that play a major role in allergy and asthma. But sure enough, when the researchers injected the chemokine into young mice, they again saw a decrease in the formation of new neurons—an effect that was reversed with an injection of a CCL11-blocking antibody. Wyss-Coray and colleagues also looked at how CCL11 changes with age, and saw that its blood-levels increased both in mice and in humans as they aged.
The big question now, said neuroscientist Fred Gage from the Salk Institute, is "how this molecule might affect the decline in neurogenesis." While CCL11 could be directly inhibiting the growth of new neurons, Gage said the effect is more likely to be indirect, given the observed "effects are fairly modest." CCL11 may be acting by triggering immune cells in the brain, such as microglia, to produce inflammatory factors that inhibit new neuronal growth, for example. Another question is whether CCL11 will play a similar role in other mouse strains and other organisms, said Ransohoff, as mouse immunology has been known to differ between strains of inbred mice. "I'd be surprised if this was a universal factor," he said.
Wyss-Coray agrees that this study opens a floodgate of new questions. But he's encouraged by the possibilities. For example, "if we could rejuvenate or maintain the brain in general," he said, it might delay some of the detrimental effects that cause dementia or Alzheimer's.
S. A. Villeda et al., "The ageing systemic milieu negatively regulates neurogenesis and cognitive function," Nature, 477:90-96, doi:10.1038/nature10357, 2011.