To me, it’s remarkable that something in your blood can influence the way you think.

For largely unknown reasons, the hippocampus is especially vulnerable to normal aging, said Wyss-Coray. “With advancing age, the hippocampus degenerates, loses nerve cells and shrinks,” he said. 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, the 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 performed more poorly than 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 be changed from one session to the next. Visual cues to its location can also be transferred to help guide the mouse to the escape hole, memory permitting.

Improvements in hippocampal function

When the older mice received human umbilical-cord blood plasma every fourth day for two weeks, many measures of hippocampal function improved notably. Plasma from older people, on the other hand, didn’t help at all, while young-adult plasma induced an intermediate effect. And 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.

Something in umbilical cord blood was making old brains act younger. To find out what it was, Wyss-Coray and his colleagues 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,” said Castellano. “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 co-founded, has licensed rights to this intellectual property.

Other Stanford co-authors of the study are former graduate student Kira Mosher, PhD; former research assistant Rachelle Abbey; research technician Alisha McBride; research scientist Daniela Berdnik, PhD; research associate Jadon Shen; research nurse manager Martha Tingle, RN; former mass-spectroscopy specialist Izumi Hinkson, PhD; Xinmin Xie, MD, PhD, a consulting associate professor of anesthesiology, perioperative and pain medicine; Michelle James, PhD, assistant professor of radiology and of neurology and neurological sciences; and Martin Angst, MD, professor of anesthesiology, perioperative and pain medicine.

The study was funded by the National Institute on Aging (grants K99AG051711, AG045034, DP1AG053015 and AG040877), the Jane Coffin Childs Foundation, the Simons Foundation, the U.S. Department of Veterans Affairs, the Glenn Foundation for Medical Research and the Stanford Neurosciences Institute's Brain Rejuvenation Project.

Stanford’s Department of Neurology and Neurological Sciences also supported the work.