For centuries, people have yearned for an elixir capable of restoring youth to their aging bodies and minds. It sounds like pure fantasy, but, in recent years, researchers have shown that the blood of young mice can exert a regenerative effect when transfused into older animals. Now, one of the NIH-funded teams that brought us those exciting findings has taken an early step toward extending them to humans.
In their latest work published in Nature, the researchers showed that blood plasma collected from the umbilical cords of newborn infants possesses some impressive rejuvenating effects [1]. When the human plasma was infused into the bloodstream of old mice, it produced marked improvements in learning and memory. Additional experiments traced many of those cognitive benefits to a specific protein called TIMP2—an unexpected discovery that could pave the way for the development of brain-boosting drugs to slow the effects of aging.
When babies are born, a teaspoon or so of blood plasma remains in their umbilical cords that often gets discarded as medical waste. For the team led by Joseph Castellano and Tony Wyss-Coray of Stanford University, Palo Alto, CA, that youthful plasma seemed an obvious place to look for human proteins that might rejuvenate the aging brain.
At four-day intervals over the next two weeks, the team infused the human cord plasma into older mice. They wanted to see if it could revitalize the hippocampus, a part of the brain involved in learning and memory, in much the same way that blood from young mice had done in previous experiments [2]. (By the way, the strain of mice used in these studies had compromised immune systems that prevented their bodies from rejecting the human material.)
To help them gauge the effects of the cord plasma, the researchers also infused similar older mice with human plasma from either young adults (aged 19-24) or elderly donors (aged 61-82). The mice that received plasma from the elderly donors showed little change in gene expression. But those given cord and young adult plasma had a boost in the activity of genes that encourage neurons to grow and form new connections for learning.
Where things got real intriguing was that the cord plasma alone specifically increased the activity of genes playing important roles in memory formation. Most notable was an increase in a gene called c-Fos, which is linked to long-term memory storage and declines with age.
But did this interesting genetic profile translate to improved memories and learning? Sure enough, it did. Mice given the cord plasma outperformed the other mice in a battery of learning and memory tests, and impressively so.
The researchers compiled a long list of human plasma proteins that vary with age and might explain the cord plasma’s rejuvenating power. To narrow it down further, they searched for proteins on the list that shift in mice with age and also when older mice are infused with young mouse blood. That yielded about 30 proteins. At the top of the list was a total surprise called TIMP2. While the protein has been studied in other contexts, next to nothing was known about its role in the aging brain.
Further study confirmed a decline in TIMP2 with age in the hippocampus. The researchers also found that injections of TIMP2 into mice led to improvements in learning and memory similar to those seen with the cord plasma. And when the researchers treated aged mice with cord plasma that had the TIMP2 protein removed, the treatment lost its brain-rejuvenating effects.
These findings help to confirm that proteins naturally present early in life could help to revitalize aged tissue. Based on these latest findings, TIMP2 holds promise for further study and perhaps even therapeutic development. Such a treatment might ultimately benefit people experiencing normal aging, as well as those with neurodegenerative conditions such as Alzheimer’s disease. We need not get too far ahead of ourselves here. But might the elusive elixir of youth that people have long pined for been inside us all along?
References:
[1] Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Nature. 2017 April 19. [Epub ahead of print]
[2] Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Nat Med. 2014 May 4.
Links:
Cognitive Health and Older Adults (NIA/NIH)
Understanding Memory Loss (National Institute on Aging/NIH)
Wyss-Coray Lab (Stanford University, Palo Alto, CA)
NIH Support: National Institute on Aging