Umbilical cord blood from human newborns boosts the brain function and cognitive performance of old mice, a new study shows.
Researchers identified a protein, abundant in human cord blood but decreasingly so with advancing age, that has the same effect when injected into the animals.
“To me it’s remarkable that something in your blood can influence the way you think.”
The findings could lead to new treatments for age-associated declines in mental ability.
“Neuroscientists have ignored it and are still ignoring it, but to me it’s remarkable that something in your blood can influence the way you think,” says Tony Wyss-Coray, professor of neurology and neurological sciences at Stanford University and a senior research career scientist at the Veterans Affairs Palo Alto Health Care System.
In an earlier study, Wyss-Coray’s lab showed that direct infusion of young mice’s plasma, the cell-free portion of blood, benefited old mice. Those benefits extended beyond biochemistry and physiology to actual performance on tests of memory and learning.
The new study, published in the journal Nature, marks the first demonstration that human plasma can aid older mice’s memory and learning, which researchers say would seem to increase the likelihood that it could have a similar beneficial effect in people. Also promising from a drug-development standpoint is the idea that a single protein appears largely capable of mimicking those benefits.
Comparing blood plasma from 19- to 24-year-olds, 61- to 82-year-olds, and umbilical cords, researchers identified age-associated changes in a number of proteins.
Investigators suspected these changes might affect the hippocampus, which in both mice and humans is critical for converting experiences into long-term memories. In particular, the hippocampus is essential for helping you remember spatial information, such as how to find your way back to the car you parked in a multilevel structure several hours ago, and information about autobiographical events, such as what you ate for breakfast.
For largely unknown reasons, the hippocampus is especially vulnerable to normal aging, Wyss-Coray says. “With advancing age, the hippocampus degenerates, loses nerve cells, and shrinks.” The capacity to learn and remember falters in lockstep. Hippocampal deterioration is also an early manifestation of Alzheimer’s disease.
To distinguish the effects of old, young, and “youngest” human blood on hippocampal function, researchers used immune-deficient laboratory mice that could be given repeated injections of human plasma without experiencing negative immune reactions. Experiments undertaken before injecting human plasma into the mice showed that, like their immune-competent peers, these mice’s hippocampal activity, integrity, and regenerative capacity dropped off in old age—indeed, a bit faster.
Old immune-deficient mice didn’t perform as well as younger ones on tests of memory and learning. One such test, the Barnes maze, employs a table, about 4 feet in diameter and 1.3 feet high, that is brightly lit and open to the surrounding environment—two factors that make mice feel insecure. The table is also full of holes, one of which is attached to a tube in which a scared mouse can find darkness and safety.
The other holes offer only a drop to the floor from a height that would not physically harm a mouse but is enough deter one. Which hole has a burrowing tube attached to it can change from one session to the next. Visual cues to its location can also transfer to help guide the mouse to the escape hole, memory permitting.
When the older mice received human umbilical-cord blood plasma every fourth day for two weeks, many measures of hippocampal function noticeably improved. Plasma from older people, on the other hand, didn’t help at all, while young-adult plasma induced an intermediate effect.
Further, older mice’s performance on the Barnes maze and other tests was stellar in comparison with mice of the same age who got injections of saline instead of plasma.
So what made the difference?
Something in umbilical cord blood was making old brains act younger. To find out what it was, researchers gauged plasma-protein levels in humans and mice from different age groups, in search of proteins that the two species share in common and whose levels change similarly with age.
One protein in particular grabbed their attention: In a laboratory test designed to discern a substance’s ability to enhance nerve-cell activity in the brain, it triggered this activity to a great degree. The protein, called tissue inhibitor of metalloproteases 2, or TIMP2, belongs to a well-known family of four TIMPs that regulate the activity of other proteins whose function is to chop up yet other proteins occupying the matrix in which cells are embedded.
Injecting TIMP2 by itself into elderly mice largely duplicated the beneficial effects of umbilical-cord plasma. It even restored these mice’s nesting capacity: an instinctive penchant, largely lost in old age, for using available materials, such as cotton wads supplied by the researchers, to build nests in which mice typically prefer to sleep. But old mice that were given human cord plasma depleted of TIMP2 derived no learning and memory benefits. And administering TIMP2-neutralizing antibodies to young normal mice, who ordinarily perform well on memory tests, obliterated their prowess.
“TIMP2’s effects in the brain have been studied a little, but not much and not in aging,” says lead author Joseph Castellano, a former postdoctoral scholar who is now an instructor of neurology and neurological sciences.
“In our study, it mimicked the memory and learning effects we were getting with cord plasma. And it appeared to do that by improving hippocampal function.”
Stanford’s Office of Technology Licensing has filed for patents related to the findings in the study. Alkahest, a biotechnology company based in San Carlos, California, in which Castellano and Wyss-Coray hold equity and which Wyss-Coray cofounded, has licensed rights to this intellectual property.
The National Institute on Aging, the Jane Coffin Childs Foundation, the Simons Foundation, the US Department of Veterans Affairs, the Glenn Foundation for Medical Research, the Stanford Brain Rejuvenation Project, and Stanford’s Department of Neurology and Neurological Sciences funded the work.
Source: Stanford University