When a baby is born, the now-useless umbilical cord is usually thrown away. But sometimes, it finds renewed purpose. Parents can decide to donate the blood from the cord to blood banks, which freeze the stem cells within so they can eventually be used to treat people with various cancers and genetic disorders. In the process, plasma—the liquid portion of blood—is usually ignored. But neuroscientist Tony Wyss-Coray thinks this liquid has a purpose, too.
His team at Stanford University School of Medicine has found that plasma from human umbilical cords can rejuvenate the brains of old mice—specifically in an area called the hippocampus that’s vital for learning and memory. Using actual cord plasma “is not something you’d ever want to develop as a treatment,” he says. “It’s very cumbersome and difficult to collect.” But he hopes that by identifying specific beneficial molecules in the fluid, he can develop treatments for conditions like Alzheimer’s. Already, his team has identified a possible candidate—a protein called TIMP2 that seems to underlie many of the improvements in their experiments.
This is the latest in a line of provocative studies involving lab rodents. Collectively, they suggest that it may be possible to revitalize several aging organs—the brain included—by injecting individuals with molecules that are abundant in young blood, but that decline as we age. “The mounting evidence is incredibly exciting,” says Sara Burke, a neuroscientist at the University of Florida who studies age-related memory loss. She wants to know if this approach could enhance the function of other brain areas that become vulnerable in old age, like the prefrontal cortex which governs planning, decision-making and other complex skills.
But Leigh Turner, a bioethicist at the University of Minnesota, adds a word of caution. “It’s not difficult to find innovative findings in mice,” he says. “Any time we’re talking about preliminary research in mouse models, we want to be careful about assuming that we’ll see the same outcomes in human diseases that have historically been very hard to treat.” Wyss-Coray agrees. “It will be important to know if plasma is indeed beneficial in any form in humans and whether TIMP2 could be produced synthetically to mimic beneficial effects.”
He’s also the first to admit that it sounds “creepy” to revive old organs with young blood—an act with echoes of vampirism, supervillainy, and historical apocrypha. The non-fictitious version of this practice has equally macabre roots. In 1863, French physiologist Paul Bert surgically stitched together the blood supplies of two mice, with a technique called parabiosis that has since been used to study cancer, the immune system, organ transplants—and aging. And in 1956, researchers at Cornell University did the first parabiosis experiments on rats of different ages. It was largely anecdotal work but it hinted that the older animal might benefit from the younger blood in its veins.
Despite a few promising follow-ups, the technique mostly fell out of favor. But in 2005, Irina Conboy and Thomas Rando resurrected it to show that young blood could jumpstart aged stem cells, restoring their youthful ability to divide and regenerate tissues. They focused on muscles and the liver, while another team found benefits for the heart. And in 2011, Wyss-Coray, who was Rando’s lab neighbor, showed that the brain also benefits. His student Saul Villeda found that blood from an old mouse could repress the activity of neural stem cells in its young conjoined partner. But the young mouse’s blood had the opposite effect, triggering a burst of new neurons in the hippocampus of the elder animal.
And blood alone could do the trick. In 2014, Villeda abandoned parabiosis and simply injected old mice with the plasma from younger ones. Their hippocampal neurons became better at forming new connections, and the mice started acing mental tests in the style of much younger animals. They could better recognize a place where they had received an electric shock, and more accurately remember the location of a hidden platform submerged by water. Something in the blood—some molecules that become depleted in old age—were giving the aged stem cells a kickstart.
Spurred by these successes, in January 2014, Wyss-Coray set up a company called Alkahest to identify such molecules. Later that year, the company launched a small clinical trial to see if young plasma could be safely delivered to Alzheimer’s patients.
Meanwhile, Wyss-Coray started looking at even younger plasma. His team collected fresh samples from cords that had been discarded after scheduled Cesarean-sections, and team member Joseph Castellano injected this liquid into old mice, every four days for two weeks. He found that it led to the same kinds of improvements seen in previous studies, and even more potently so than plasma from young donors, aged 19 to 24.
The protein TIMP2 could reproduce many of these benefits on its own, allowing mice to more quickly find the escape hole in a maze, or recognize that an object in their enclosure had been moved. But when Castellano stripped TIMP2 out of the plasma before injecting it into the mice, these benefits disappeared.
It’s not clear why TIMP2 is so important. It works by blocking a group of enzymes called MMPs that influence the movement of cells, the closing of wounds, and—in the brain—the reshaping of neural networks. “That might be why we saw such a prominent effect,” says Wyss-Coray. “TIMP2 doesn’t just have a single task. It has a very broad effect, which makes it challenging to understand exactly how it works.”
It might also make it difficult to use TIMP2 for medical purposes—it might have positive effects, but unplanned negative ones, too. And Irina Conboy, whose work kickstarted this new wave of young-blood studies, is dubious that TIMP2 matters at all. They “have no direct proof that the proteins from the cord plasma itself went to the brain and did anything positive,” she says. The team only showed that purified TIMP2 can reach the brains of injected mice. Wyss-Coray counters that getting the proof Conboy demands is unfeasible—he’d have to purify TIMP2 from plasma, chemically label it, and add it back in.
Conboy also notes that several studies find higher TIMP2 levels in people with Alzheimer’s, which would mean more of the protein is unlikely to benefit such patients. “The premise that this is a miracle molecule that you can inject into people who are losing their memory is contradicted by what has already been published,” she says. Again, Wyss-Coray disagrees. In his work, the protein is twice as concentrated in cord plasma as in young blood, and its levels remain constant in later life.
Finally, Conboy says that TIMP2 might have unintended side effects. The enzymes it blocks—the MMPs—are like machetes that clear pathways for migrating cells by hacking their way through connective tissue. And neurons in the hippocampus need to migrate; if you stop them from doing so, you might cause more problems than you solve.
This debate echoes others within this small body of research. In 2013, Amy Wagers and Richard Lee from Harvard University showed that a protein called GDF11, which was apparently abundant in young blood, could rejuvenate old muscle. But other teams failed to reproduce the results. Wagers reportedly stands by her results, although Thomas Rando told Science magazine that “GDF11 does not go down with age.”
Meanwhile, last year, Conboy’s team swapped the blood of pairs of mice without actually stitching them together, and found negative effects in the younger animals but no improvements in the older ones. It’s more that old blood harms than young blood helps, she argued. In past experiments, the young plasma may just have diluted harmful factors in the old blood. But Wyss-Coray thinks her data don’t support that conclusion, and says that Conboy has become “bitter” towards others in the field. Conboy, meanwhile, suggests that Wyss-Coray’s team is being swayed by their own “financial interests to put forward these claims that young fluids can be medicine.”
With a feud already brewing within such a small community, Wyss-Coray hopes for... er... an infusion of fresh blood. “There are quite a few studies in the pipeline,” he says. “I hope that more people will work on this. There are way more questions than answers.”
Then, there’s the attention from outside academia. Wyss-Coray isn’t that bothered about tech billionaire Peter Thiel, who, according to a report from Inc., is “very, very interested in young people’s blood.” He’s more concerned by a startup called Ambrosia, which is offering transfusions of young plasma for the price of $8,000. “They’re treating anybody—people with Lyme disease, Alzheimer’s, people who are old and rich, whoever wants to get treated,” says Wyss Coray. “They claim they’re doing a clinical trial but I think every serious scientist agrees that this is abuse of the term. I think that they’re harming the whole field.”
“[Ambrosia] is an early indicator of how research like this might manifest in a direct-to-consumer marketplace,” says Turner, who studies the marketing of unproven cell-based treatments. But he says scientists in the field must shoulder some responsibility for that. “The Alkahest website has a painting of the fountain of youth, and Wyss-Coray’s TED talk references the fountain, too. When you have rhetoric like that, it’s easy to see how it can be mobilized.”
More legitimate trials are taking place in South Korea to look for any anti-aging effects of cord blood, and in San Francisco to see if young plasma can help with a brain disorder called progressive supranuclear palsy. Meanwhile, the Alkahest Alzheimer’s trial is finished but hasn’t published its results yet. Wyss-Coray, who was not directly involved with the trail, says that Alkahest’s ultimate strategy is to look for specific proteins or fractions of plasma that can be injected into patients, rather than going for wholesale transfusions.
In the meantime, he worries that the public underestimates how many unknowns there still are, and how much work he and others still have to do. “I’ve given many talks to general audiences and when I say we’re trying to get more money to understand how this works, people often say, ‘Why do you need to understand more? We know it works.’ There’s this mythology that blood is the essence of life and young blood has this power to rejuvenate people.” And those beliefs are certainly aging well.
