Eternal youth is among humanity’s oldest quests. For centuries, from the British Isles to Japan, people searched for fountains and elixirs. In ancient China, wealthy individuals consumed potions made from gemstones to metabolize the endurance of jade or cinnabar, or from gold to keep from “tarnishing.” But in Europe, a touted panacea was human blood, bought fresh from executioners during Medieval and Renaissance times, or—much earlier, in ancient Greece—harvested from virgins and gladiators. As has so often been the case, the Hellenic people were on to something.
The first murmurings that young blood might mitigate the effects of aging echoed through the scientific community in 2005. A team of Stanford researchers had paired old mice with young mice, linking their circulatory systems, and within five weeks, the muscle and liver tissues of the old mice began to resemble those of the young mice. The common belief that aging results from simple wear and tear suddenly seemed questionable. Rather, the body’s cells appeared to receive signals from the young blood telling them to regenerate.
The gold standard of science is reproducibility, and over the next 15 years, trials repeatedly showed health improvements in old mice dosed with young blood. Few scientists questioned its restorative effects, but many asked which of its components were responsible and who would be the first to distill those and bring them to market.
“Just a couple decades ago, if you postulated that you could slow down or reverse aging, you were really out there,” says Stanford professor of neurology and neurological sciences Tony Wyss-Coray, “but now, just in the past 10 years, there are so many interventions—genetic interventions, diets, environmental interventions—that show that you can slow down aging or even reverse aging, measured with many different tools.”
In recent years, life-extension therapies have hit the mainstream. Unlike their enthusiasts who promise the imminence of biological immortality, Wyss-Coray stands out for the rigor with which he has researched how young blood affects the brain. Chosen by Time in 2018 as one of 50 people transforming health care, the 55-year-old Swiss-born American is also a skeptic. “I am not one of these researchers who would take a drug they work on because they believe in it so much,” he says. He points out that trial after clinical trial with humans—many of which were based on promising mouse experiments—has failed. Yet through his work at Stanford and Alkahest, the biotech company he co-founded, he has brought us closer to understanding how young blood can rejuvenate the brain and which of its components do so. (Hint: They’re not specific to virgins or gladiators, or even mice.)
Making Cells Young
Parabiosis (“living beside”), a state in which two organisms share physiological systems, as in conjoined twins, was surgically induced for the first time by French zoologist Paul Bert in 1864. As a proof of concept, he linked the circulatory systems of two rats. The technique won him some attention but largely fell out of use until the 1950s, when researchers joined rats to evaluate whether the metabolic needs of one affected the other. (They did.) During that same period, Clive McCay, a gerontologist at Cornell, devised heterochronic (“different in time”) parabiosis, in which old rats were conjoined with young rats, which resulted in minor increases in life span for the old rats. Half a century later, the technique was revived, this time at Stanford under the leadership of Thomas Rando, professor of neurology, and Irving Weissman, MD ’65, professor of developmental biology. “We had been studying the decline in tissue regeneration with age,” Rando recalls, “and we had been trying to understand the mechanisms by which specifically the stem cells in old animals failed to engage in tissue repair like stem cells from young animals.”
The results were startling: Old mice soon exhibited significantly enhanced repair of muscle and liver tissue. Something in young blood was activating stem cells, the cells responsible for tissue repair. The aged cells themselves began rejuvenating—a word that Rando uses cautiously, since measuring a cell’s biological age is difficult. “But certainly what we seem to be doing,” he says, “is conferring youthful properties to old cells.”
The regeneration appeared to involve epigenetics. “What makes a liver cell different from a skin cell,” Rando says, “is not the DNA—the DNA is the same—it’s the epigenome reading that DNA in a different way. We have evidence that with age you get the same kind of thing happening, where the DNA is essentially the same but the readout of that DNA is different, and it’s possible to reprogram that so that the old cell becomes younger by the way it reads its DNA.”
The Plasma Swap
Wyss-Coray joined Stanford’s faculty in 2002, recruited by Rando, who was spearheading a research program on aging and age-related diseases. Wyss-Coray had completed his PhD in immunology at the University of Bern and a postdoc at Scripps Research Institute and the Gladstone Institute and was developing ways to diagnose Alzheimer’s—a disease to which he had a personal connection through his father-in-law. “I saw how he disappeared,” Wyss-Coray recalls, “and how in the end there was just a shell.”
Wyss-Coray had conducted his research with mice engineered to express Alzheimer’s symptoms, but the lack of progress in diagnosing and treating the disease in humans frustrated him. At Stanford, he focused on how to detect the disease in people. “You can’t study the brain at the molecular level unless a person has died,” he says. “But you can probe the blood. The idea is that if something happens in the brain, it will leave molecular signatures in the blood.”
‘Just a couple decades ago, if you postulated that you could slow down or reverse aging, you were really out there.’
When he analyzed human blood for clear markers specific to the disease, he found them as well as biomarkers of old age—which appeared to grow stronger as a patient’s Alzheimer’s advanced. “The aging connection,” he says, “came from following the trail to understand Alzheimer’s and realizing that the strongest signature we kept seeing was an aging signature.” After publishing these results in 2007, he increasingly found himself being invited to conferences on aging, a field in which he’d previously held no ambitions.
Rando and Wyss-Coray then combined their efforts to investigate how heterochronic parabiosis affects the brain. In a 2011 paper in Nature, they showed that young mice infused with the blood of old mice had impaired learning and memory. In 2014, in Nature Medicine, Wyss-Coray’s lab went further, publishing a paper that stated: “Exposure of an aged animal to young blood can counteract and reverse preexisting effects of brain aging.”
During this time, Wyss-Coray’s lab showed that parabiosis wasn’t necessary to conduct these experiments. Plasma—the liquid part of the blood—could simply be injected. It didn’t even have to come from the same species. “If we take plasma from old people and put it into young mice,” he says, “we make the brains of mice more inflamed, we reduce stem cell activity, and we impair cognitive function. If we take plasma from young people and put it in an old mouse, that old mouse has more stem cell activity, has less inflammation and their memory function is better.”
While Rando and Wyss-Coray were conducting their research, Amy Wagers, a postdoc with the 2005 Rando-Weissman research team who is now professor of stem cell and regenerative biology at Harvard, was doing her own investigation into heterochronic parabiosis. In 2013 and 2014, her lab published research showing that parabiosis promoted muscle regeneration in older mice and made their enlarged and inefficient hearts resemble those of young mice.
Speaking of the chronic diseases prevalent in older individuals, Wagers says, “A hypothesis that’s being tested not just by my lab but by many around the world is that the common denominator is aging, that there are fundamental mechanisms of aging that are seeding these diseases. Often there’s a confounding of life-span extension and strategies targeted at improving the health of older individuals. It’s entirely possible those two things will be connected, but it’s also possible that they are not. You could have an impact on health without changing life expectancy. And that, I think, would also be a win.”
Now, Wait a Minute
Around this time, the idea that young blood had rejuvenating qualities started generating excitement in Silicon Valley, where start-ups began charging tens or hundreds of thousands of dollars for plasma transfusions. Cashing in on the buzz, HBO’s Silicon Valley featured a scene in which Gavin Belson—chief innovation officer and tech supervillain—watches a PowerPoint presentation while receiving blood from his “transfusion associate.” Even Joe & the Juice, a global chain of juice bars with several locations in Palo Alto, got in on the fun, including “Young Blood” on its menu (it contains celery, lemon and apple).
The FDA, responding to companies bringing young blood to market before either the mechanism underlying its short-term effects or its overall long-term impact was understood, issued a warning in February 2019, stating that “some patients are being preyed upon by unscrupulous actors touting treatments of plasma from young donors as cures and remedies. Such treatments have no proven clinical benefits for the uses for which these clinics are advertising them and are potentially harmful.”
Wyss-Coray sees premature commercialization of young blood overshadowing the research aims of Alkahest, which he co-founded in 2014 and on whose board he and Rando serve. “We are very different,” he says. “We use clinical trials to demonstrate whether this really works. In a clinical trial, you cannot charge the subject.”
The challenge now was legitimizing what had previously looked to be one of the most promising breakthroughs in the field of aging.
The Philosopher’s Sponge?
The story of Alkahest begins with Chen Din Hwa, a philanthropist in Hong Kong who owned the Nan Fung Group—one of the city’s largest privately held property developers. In 2009, at the age of 86, Din Hwa learned he had Alzheimer’s and also began receiving blood transfusions for cancer. His grandson, Vincent Cheung, who holds a bachelor’s in molecular and cell biology from UC Berkeley, noticed that after each transfusion, his grandfather’s lucidity temporarily increased. When he shared this observation with Karoly Nikolich, a family friend who was an adjunct professor of psychiatry and behavioral sciences at Stanford and had a long history of involvement in biotech, Nikolich told him about Wyss-Coray’s work. Not long afterward, the Nan Fung Group expressed interest in seeding a company.
Din Hwa died in 2012, but two years later, Alkahest was founded, with Nikolich as CEO and Wyss-Coray as chair of the scientific advisory board. The company’s name came from Wyss-Coray’s readings on Paracelsus, the 16th-century Swiss alchemist who claimed to have invented alkahest—a universal solvent that could dissolve any substance to its individual parts. It was supposed to be the philosopher’s stone—a centuries-old notion of a material that could transmute base metals to gold and restore youth.
“Here we have plasma,” Wyss-Coray says, “which is this complex soup, and if we can figure out the rules and the individual components, we understand life, if you will.” But invoking Paracelsus conveyed a subtler message. “Paracelsus is credited as the founder of pharmacology because he discovered, or claimed to discover, that the dose makes the toxin. It depends on how much you take of anything whether it kills you or it has a beneficial effect.”
‘[T]he dose makes the toxin. It depends on how much you take of anything whether it kills you or it has a beneficial effect.’
To avoid incorrect dosing, Alkahest used an albumin-rich plasma fraction that contained many proteins commonly found in young blood and that had already received FDA approval for transfusions, which facilitated the rapid start of clinical trials. (Due to the demand for millions of transfusions each year, donated blood is separated into the fractions that recipients need—only the red or the white blood cells, the plasma, or specific plasma proteins.)
While Alkahest does not disclose the reasoning behind the proteins it chooses for treatment, albumin has been of special interest due to its ability to stabilize other factors, preventing them from degrading. “Albumin is a sponge protein that’s the most abundant protein in the blood,” Wyss-Coray explains. “It binds a lot of different factors and acts as an antioxidant to some extent, and with age, it changes its function and it’s not as effective.”
In August 2019, Alkahest completed a six-month phase 2 trial. (Only after phase 3—a much longer trial with a larger cohort and a control group—does the FDA give approval.) Forty patients with mild to moderate Alzheimer’s who had been treated with the plasma fraction over a period of six months showed no significant decline in cognitive function. “If you look at historic controls of people who have Alzheimer’s disease,” Wyss-Coray says, “they go down very gradually on average, so there’s a noticeable effect from the normal decline to no decline at all.”
Wyss-Coray also embarked on another study that would help legitimize the use of blood plasma in treating cognitive decline. The vessels nourishing our gray matter are highly impermeable compared with those elsewhere, and historically, this blood-brain barrier was thought to keep out many elements in the blood, allowing only water and essential nutrients to pass through—not the types of blood factors that might cause regeneration. “It’s still an enigma what this blood-brain barrier is,” Wyss-Coray says. “We’re basically postulating all you need to do to make the brain function better and have less inflammation and more stem cell activity is change the composition of the blood. And the first reaction from neuroscientists is, ‘Are you crazy? These factors can’t get into the brain.’ ”
Using molecular-labeling techniques, Wyss-Coray’s lab tagged thousands of protein species in plasma and then injected it into mice. When the researchers looked at the mice’s brain tissue under the microscope, they saw tagged proteins inside the blood-brain barrier and in the neurons themselves. There was no longer any question that the blood was sending molecular signals to the brain.
Just a Matter of Time
Understanding aging scientifically demands a system of biological measurement. Chronological age is an imprecise gauge of health, as a quick comparison of vigor among octogenarians, much less among people in their 30s or 40s, would reveal. Precisely assessing the protein composition of plasma at different ages, however, might provide a yardstick for life span.
“When I started 15 years ago, I was looking at about 100 proteins in the blood, and now I can look at almost 3,000 different proteins,” Wyss-Coray says, emphasizing how advances in technology have benefited his research. Recently, in a study of 4,263 people aged 18 to 95, his team measured how the blood’s protein content changes with age, then created an aging clock. The team discovered that people’s biological age is generally within three years of their chronological age, with the exception of those who are unusually healthy or unhealthy.
The largest change in blood proteins takes place around 78 years old, when the concentrations of approximately 1,000 proteins decrease or increase. Smaller waves occur around 60 and even around 34. “That’s super interesting to us,” Wyss-Coray says, “because it suggests that the aging process is uneven, that the proteins that change then are not the same ones that change later. So you can start to ask what the biological processes are that change at an early age in people. How do they affect aging 20, 30, 50 years down the line? And if you want to have an impact on aging, would you actually have to intervene much earlier?”
Remember Me
Wyss-Coray and his wife, Christina, the clinical coordinator at Stanford’s Alzheimer’s Disease Research Center, have two grown daughters—an urban planner and a PhD student in biology at Stanford—and a 16-year-old son. Wyss-Coray observes the rapidity with which his youngest child learns to use a new computer or phone. “I get frustrated when I see how quickly he picks up this stuff,” he says and laughs. “I start to feel aging, and it gets annoying, especially cognitive aging—that your brain is not as fast.”
He acknowledges the ticking clock but remains skeptical of solving aging for his generation. “I’m too realistic,” he says. “We still have a limited understanding of biology in general. For a lot of these proteins, we know very little about them.”
By mapping proteins associated with aging, he has come closer to identifying which of young blood’s ingredients have regenerative potential. Still, the reasons that proteins are created at certain ages and how they affect the rest of the body remain poorly understood. He points out that while the life span of worms has been dramatically extended in labs, the same techniques haven’t worked in humans or even mice, and he reiterates that mouse studies of the brain rarely produce results in humans. “Many clinical trials start with good, solid preclinical data—otherwise, you wouldn’t put $100 million into a phase 3 trial. And yet they fail, one after another.”
Aside from the feasibility of life extension, Wyss-Coray also weighs the ethical considerations. Given the global demand for plasma and the already limited supply for people critically in need, synthetic plasma proteins would have to be made and might be available only for the wealthy. “There are huge socioeconomic implications,” he says. “If we all of a sudden find something that prolongs life span to 120 in the average population, I don’t think we could deal with that. There aren’t enough resources, and the population would increase so rapidly that we could probably not cope with it without starting to kill each other or having massive famines.”
In light of these concerns, Wyss-Coray’s focus is on treating diseases and allowing people to have healthy lives (what both Rando and Wagers refer to as increasing “health span” rather than life span). As Alkahest raises funds for a phase 3 study on mild to moderate Alzheimer’s, it is running other trials investigating the impact of young plasma on Parkinson’s, severe Alzheimer’s and recovery after surgery. It is still years away from definitively knowing whether young blood can treat age-related cognitive diseases.
As for Wyss-Coray’s own cognitive decline, would he eventually consider using plasma to prevent it if the trials are successful? He hesitates and then says, “If the phase 3 data shows a positive effect? Yeah.”
Deni Ellis Béchard is a senior writer at Stanford. Email him at dbechard@stanford.edu.
