An injection of “new blood” is a phrase long used as a metaphor for the revitalizing effect of fresh minds on a stagnant organization. But research now suggests it also applies in a literal sense. In a development that calls to mind both vampire lore and stories of bathing in blood, young blood appears to in fact rejuvenate old brains.
Researchers at Stanford University led by neuroscientist Tony Wyss-Coray showed in a 2014 study that infusions of blood from young mice reversed cognitive and neurological impairments seen in old ones. They used a somewhat bizarre technique in which two mice were sutured together in such as way that they shared a circulatory system (known as parabiosis), and found old mice joined to their youthful counterparts showed changes in gene activity in a brain region called the hippocampus as well as increased neural connections and enhanced “synaptic plasticity”—a mechanism believed to underlie learning and memory in which the strength of neural connections change in response to experience. They also gave old mice infusions of young blood plasma (the liquid component of blood containing proteins and hormones but no cells), which significantly improved their performance in learning and memory tests.
These findings may have profound implications if they can be replicated in humans. As life expectancy has increased, the burden of both normal age-related cognitive decline and neurodegenerative diseases such as Alzheimer's has become one of the biggest public health challenges worldwide. The hippocampus—a region crucially involved in forming “episodic” memories (event recall) and spatial memory (for physical navigation)—is especially affected by aging, with accompanying declines in the ability to learn and remember; it also deteriorates early on when afflicted by Alzheimer’s.
In the new study, published Wednesday in Nature, Wyss-Coray and colleagues go further by showing plasma from human umbilical cords and young adults also has beneficial effects in old mice, which is a small step toward testing the approach in humans. “This suggests there are factors [or components] in the blood of young organisms, including humans, that can rejuvenate an old brain and make it work more like a younger one,” Wyss-Coray says. “It brings us a bit closer [to humans] because it shows human blood has the same factors.” They also identified a protein that seems to be important for producing these benefits, providing a new focus for efforts to develop treatments for cognitive decline. “They have isolated one druggable target that appears to rejuvenate age-related cognitive decline in the hippocampus,” says biologist Eric Blalock of the University of Kentucky who was not involved in the study. “It's fairly exciting.”
The team took plasma from human umbilical cords as well as from younger and older people (ages 19 to 24 and 61 to 82). They found levels of numerous proteins differed according to the plasma source age. They gave aging mice (engineered to have deficient immune systems that would not adversely react to human plasma) infusions of the three types of plasma every fourth day for two weeks. The researchers found: cord plasma increased the activity of several genes linked to neural plasticity and memory; young adult plasma activated a subset of the same genes; and older adult plasma had no effect on gene expression. The researchers then measured electrical activity in the hippocampi of mice treated with each type of plasma or a saline solution, which showed cord plasma promoted a type of synaptic plasticity called “long-term potentiation,” or LTP, widely believed to be the neural basis of memory.
The researchers then showed the benefits extended to behavior. They used a fear-conditioning task, in which mice have to remember enclosures where they received electric shocks, and a maze task, which involves remembering one hole out of many where they can safely hide. Mice treated with cord plasma performed significantly better on both tasks, compared with the animals infused with saline. “What makes this important is it’s showing effects on behaviors that depend on the hippocampus; behavior that we know changes with age,” Blalock says, and those changes “can be reversed by this treatment.”
To track down what might be producing these effects, the team compiled a list of plasma proteins common to both mice and humans whose levels decline with age. They then tested some of the best candidates, finding two that affected neural plasticity. One (CSF2) was already known to reverse cognitive impairment and toxic protein buildup in mice that develop Alzheimer's disease, so they focused on the second, TIMP2, whose role in the aging brain had not been studied.
The researchers used radioactive labeling to show TIMP2 injected intravenously crosses the blood–brain barrier. They then injected the protein into elderly mice with normal immune systems, and found this reproduced the beneficial effects of cord plasma on both memory performance and LTP in the hippocampus whereas mice engineered to lack TIMP2 showed reduced LTP. These results show TIMP2 is sufficient to produce beneficial effects. So to also demonstrate TIMP2 is necessary for memory function, they injected regular young mice with TIMP2-neutralizing antibodies. This made young mice perform very poorly in a spatial memory task. Finally they showed old (immunodeficient) mice treated with cord plasma from which TIMP2 had been removed presented none of the improvements in memory performance seen using normal plasma. “We were surprised by this,” Wyss-Coray says. “I didn't expect it would be that clear-cut.”
TIMP2 is one of a family of proteins that regulate the activity of a class of enzymes, which in turn regulate many different proteins. “Maybe that’s why TIMP2 is so powerful,” Wyss-Coray says. “It doesn’t just have one function but regulates a broad network of proteins and their activities.” Yet as compelling as the results are, Wyss-Coray does not think TIMP2 is the whole story. “It would be too good to be true if this was the only factor, but it’s probably quite important,” Wyss-Coray says. Blalock agrees: “It's certainly a reasonable target,” he says.
The study leaves many open questions, which the team is working on. “We're trying to find out where these factors are produced in the body, why they decrease with age and could we potentially regulate [them]?” Wyss-Coray says. “How do factors from the blood talk to the brain? Do they interact with blood vessels in the brain, regulate neurons directly or regulate support cells?” Wyss-Coray and his colleagues are also hunting down other factors. Previously they found that in addition to old mice benefiting from young blood, young mice exposed to old blood suffered memory declines, suggesting old blood may contain “aging” factors. “We want to know what these are because one could potentially inhibit [these] factors to have beneficial effects as well,” Wyss-Coray says. “There are still lots of questions open at the basic biological level.”
There are also immediate medical implications. “The findings allow us to move forward and directly test human plasma infusions in people,” Wyss-Coray says. “The next steps are to go into safety trials, then larger efficacy trials.” Last year a Monterey Calif.–based company called Ambrosia launched the first U.S. clinical trial to test the anti-aging effect of young blood in people, but participants had to pay to participate, raising ethical questions. Wyss-Coray was critical of this trial, but Alkahest, a company he co-founded, recently completed its own more rigorous small safety trial on 18 Alzheimer's patients with “no adverse side effects.” An advantage of this therapy is that toxicology testing is largely unnecessary. “Plasma is a human product so you don't have to go through toxicology studies in animals,” Wyss-Coray says. “If we find a human plasma fraction that’s beneficial, you could potentially use this in a few years whereas a typical drug development plan is five to 10 years.” It may also be possible, he adds, “to produce these factors synthetically or develop small molecules that mimic the activity, but that takes much longer.”