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Scientists with VA and Stanford University report this month in Nature on a handful of bloodborne proteins that hinder the brain from making new neurons and whose levels rise with age. If researchers can learn how to block the proteins, this could translate into therapies to help people thwart the mental effects of aging.
The lab study used a variety of methods to identify factors in the blood that influence the production of new cells in the hippocampus, a brain region crucial for learning and memory. In one phase of the study, researchers joined the circulatory systems of young and old mice: The exchange of blood turned back the clock in the brains of the old mice and had an opposite effect on the young mice.
"We have a model by which we can promote brain aging in young mice by giving them blood from old mice, and rejuvenate old mouse brains by giving old mice blood from young mice," says senior author Tony Wyss-Coray, PhD. Wyss-Coray is the associate director of the Center for Tissue Regeneration, Repair and Restoration at the VA Palo Alto Healthcare System.
Among other memory tests, young mice infused with old blood became less able to recall the location of an underwater platform they could rest on to avoid treading water.
To zero in on the factors in the blood responsible for the effect, the researchers tested scores of proteins linked to the immune system. They found six whose levels were naturally higher in older mice—and artificially elevated in young mice that were exposed to "old" blood.
The single protein that turned out to be the biggest damper on neuron production is known as CCL11, or eotaxin. The researchers took samples of blood and cerebrospinal fluid from healthy people between ages 20 and 90 and confirmed that CCL11 levels drop with age.
Wyss-Coray says the pharmaceutical industry makes several small molecules that can potentially block the action of CCL11. The molecules were used to develop new drugs for asthma, but the drugs proved ineffective in clinical trials. He says his group is now testing whether the molecules might have a beneficial effect on the brain.
The surgical technique used in the study, whereby a young mouse was joined to an old one to merge their blood systems, was pioneered in the early 2000s by VA-Stanford researcher Thomas Rando, MD, PhD, one of the authors on the current study. The method is known as parabiosis.
One question raised by the findings: What about an older patient who receives a blood transfusion from a younger person? Would he experience a boost in mental abilities, similar to going back 40 or 50 years in a time machine?
"A clinician at a recent conference told me there are case reports of people showing cognitive improvement after receiving blood transfusions for unrelated conditions," shares Wyss-Coray. Though the notion might seem far-fetched, could future therapies—say, for early Alzheimer's disease—be based on blood-switching techniques? Wyss-Coray says, "I do think it's possible we would see a benefit, but I wouldn't want to raise hopes for this now."
Meanwhile, his lab continues to search for other key proteins, particularly ones that exert effects opposite to those of CCL11. Such proteins, in theory, could serve as anti-aging potions for the brain.
"We hope to find new ones that could be given systemically and affect the brain directly," he says.
Wyss-Coray and Rando are also with the Geriatric Research, Education and Clinical Center at the Palo Alto VA. Besides VA, funding for the research was provided by the National Institutes of Health and the California Institute for Regenerative Medicine.
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