Exposing older mice to young mouse blood has reversed some effects of aging on the brain, restoring some mental capabilities. A new study suggests that factors circulating in young mouse blood could reverse impairments in age-related learning, memory, and neuron function.
Previous studies have shown that blood-borne factors in old mice can impair cognitive function in young mice. A team led by Saul Villeda from University of California, San Francisco, and Tony Wyss-Coray of Stanford wanted to see if there are systemic factors in young blood that can reverse these age-related impairments. They infused plasma -- the part of blood without cells -- from 3-month-old mice into 18-month-old mice, the equivalent of mid to late middle age.
Repeated injections improved their performance in learning and memory tasks. In one test, mice had to locate a submerged platform in a water-filled tank using memory cues. In another, the mice were trained to freeze when dropped into a specific environment; the better they recognized that environment, the longer they'd freeze. Compared with mice given a placebo, the old mice with young blood injections performed about 50 percent better on both tests, and their brain cells had 20 percent more dendrites. In both the tests, heating the blood before injecting it completely negates these effects. The heat alters the structure of the proteins -- suggesting a circulating heat-sensitive factor is behind these positive effects.
“This could have been done 20 years ago,” Wyss-Coray says in a news release. “You don’t need to know anything about how the brain works. You just give an old mouse young blood and see if the animal is smarter than before. It’s just that nobody did it.”
To check for improvements in learning and memory within nerve circuits and individual nerve cells, the team turned to a slightly more sophisticated technique called parabiosis: surgically conjoining mice’s circulatory systems. (This method dates back 150 years.) Members of such pairs, called parabiotic mice, share a pooled blood supply. The team paid especial attention to the hippocampus, which is critical for forming certain types of memories -- in particular, recollection and recognition of spatial patterns. “That’s what you need to use when, for example, you try to find your car in a parking lot or navigate around a city without using your GPS system,” Wyss-Coray explains.
When they compared hippocampi from old mice joined with young mice to hippocampi from old mice paired with other old mice, they found consistent differences in a variety of measures important for encoding of new experiences for retention in the cerebral cortex. The hippocampi of older mice in old-young pairs resembled those of younger mice: They made greater amounts of specific substances hippocampal cells produce when learning is taking place. Their hippocampal nerve cells also showed an elevated ability to strengthen the connections between one nerve cell and another.
“There are factors present in blood from young mice that can recharge an old mouse’s brain so that it functions more like a younger one,” Wyss-Coray says. These enhancements are mediated, at least in part, by the activation of a protein -- cyclic AMP response element binding protein (Creb) -- in the hippocampus. The team’s now looking for what those factors might be and where they originate.
The hippocampus is altered by experience, and it’s also extremely vulnerable to the normal aging process. With Alzheimer’s, for example, hippocampal deterioration is accelerated. “We know that detrimental anatomical and functional changes occur in the hippocampus as mice and people get older,” Villeda says in a news release. “This is just from natural aging. We’re all heading in that direction.”
He adds: “We’ve shown that at least some age-related impairments in brain function are reversible. They’re not final."
The work was published in Nature Medicine this week.
Image: Nature Medicine
