The brains of older mice act younger when exposed to human umbilical cord blood.
The research, published in Nature, has the potential to lead to new treatments for age-associated declines in mental ability.
Aging drives changes in neuronal and cognitive function, which affect signals between the brain and other areas of the body, as well as thinking, understanding, learning, and remembering. The decline of these abilities is linked with many neurological disorders.
A previous study demonstrated that when young mice's plasma - the cell-free part of blood - was injected into old mice, their performance in memory and learning tests improved.
The new study demonstrates that human plasma can also improve the memory and learning of older mice. Moreover, as the biological and behavioral characteristics of mice closely resemble those of humans, the discovery increases the likelihood that younger plasma would benefit older people's cognitive ability.
Specifically, the team pinpointed a protein in the umbilical cord plasma - which is abundant in human umbilical cord blood but decreases with age - that was capable of mimicking the rejuvenating effect on old mice's brain function without the need to inject the rest of the plasma. This single protein could prove useful from a drug development perspective.
"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 the study's senior author, Tony Wyss-Coray, Ph.D., a professor of neurology and neurological sciences as well as a senior research career scientist at the Veterans Affairs Palo Alto Health Care System in California. The lead author of the study was Joseph Castellano, Ph.D., an instructor of neurology and neurological sciences.
Umbilical cord plasma significantly improved hippocampal function
Wyss-Coray, Castellano, and colleagues compared umbilical cords, blood plasma from 19- to 24-year olds, and blood plasma from 61- to 82-year olds in order to identify changes that are associated with age in a number of proteins.
The researchers suspected that these age-associated changes might have an effect on the hippocampus, the brain structure critical for "converting experiences into long-term memories" in both humans and mice. The hippocampus is particularly vulnerable to the normal aging process, although the exact mechanisms behind its vulnerability are largely unknown.
"With advancing age, the hippocampus degenerates, loses nerve cells, and shrinks," explains Wyss-Coray. The ability to remember and learn are negatively impacted as a result. The deterioration of the hippocampus is also connected with an early appearance of Alzheimer's disease.
The researchers tested the effect of old and young human blood, as well as the most youthful human blood of all - umbilical cord blood - on the hippocampal function of mice. Older mice received injections of plasma from older adults, younger adults, and human umbilical cord every fourth day for 2 weeks.
Human umbilical cord plasma significantly improved hippocampal function. In fact, the performance of the mice from the umbilical cord group was stellar compared with that of mice of the same age that received a sham injection of saline as opposed to plasma, according to the researchers.
Plasma from older adults had no effect on measures of hippocampal function, and plasma from younger adults slightly improved hippocampal function.
Immune-deficient mice were used in the study to prevent the mice experiencing negative immune reactions from the repeated injections of human plasma. Before the injections of human plasma commenced, experiments were undertaken to show that the hippocampal integrity, activity, and regenerative capacity of the immune-deficient mice declined in old age the same as they would in immune-competent mice.
Tests were also conducted to show that younger mice performed better in memory and learning tasks than older mice.
TIMP2 enhanced nerve-cell activity, restored nesting instinct in mice
The researchers aimed to isolate the factor in umbilical cord blood that was making the old brains act younger. To do this, the team evaluated plasma-protein levels in humans and mice from different age groups. They looked for proteins that human and mice have in common, and whose levels fluctuate similarly as they age.
One protein, called tissue inhibitor of metalloproteases 2 (TIMP2), was identified that enhanced nerve-cell activity in the brain in a laboratory experiment.
When TIMP2 was injected into older mice by itself, the protein replicated the positive effects of the umbilical cord plasma. Furthermore, the nesting instinct of the mice, usually lost in old age, was restored.
Older mice that were given umbilical cord plasma deprived of TIMP2 displayed no valuable change in learning and memory. Similarly, younger mice that were administered TIMP2-neutralizing antibodies experienced a significant decline in their ability to perform well in memory tests.
"TIMP2's effects in the brain have been studied a little, but not much and not in aging. 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."
Joseph Castellano, Ph.D.
"Together our results argue that systemic factors present early in life may be beneficial for revitalization of aged tissue and that TIMP2, a protein enriched during development, represents such a restorative factor for the aged hippocampus," the authors conclude.