This story was originally published in our Jul/Aug 2023 issue as “Young Blood.” Click here to subscribe to read more stories like this one.

Are you ready for a Super Age-Reducing supplement, a revolutionary, clinically proven, all-natural remedy guaranteed to make you look 20 years younger and 30 pounds lighter — or your money back?

We’ve all seen some variation of this message: another hard sell for a product that promises the benefits of youth or exercise (or something else) in a pill.

But what if legitimate researchers were actually developing drugs that could one day do what those sketchy late-night infomercials and YouTube videos have been claiming for years? That is exactly what scientists at leading universities across the U.S. are doing, by searching for factors circulating in our own blood that appear to confer the healthful benefits of youth and exercise.

The first breakthrough came in 2014, when Tony Wyss-Coray and colleagues at Stanford University surgically connected the bloodstreams of an old mouse and a young mouse in a process called heterochronic parabiosis. As they reported in Nature Medicine, the procedure caused the old brain to function more like a younger one, generating more new brain cells and improving the ability to learn and remember.

Then, in 2020, Saul Villeda of the University of California, San Francisco, published a paper in Science showing that the long-established cognitive benefits of exercise could likewise be conferred by injecting the blood of elderly, exercising mice into the bloodstream of their elderly, sedentary littermates. Even more extraordinarily, he found that a single enzyme, called GPLD1, was responsible for transmitting most of those benefits. When administered to the aged, less active mice, the enzyme reproduced most of the neurocognitive benefits seen in aged exercisers. Older humans who exercise were likewise found to have higher levels of GPLD1 than their sedentary counterparts.

 But GPLD1 is just one of many blood factors shown to confer the benefits of youth or exercise. In August of 2021, Harvard University’s Christiane Wrann reported in Nature Metabolism that the hormone irisin “is sufficient to confer the benefits of exercise on cognitive function.” And in December of 2021, Wyss-Coray published a study in Nature, this time showing that the protein clusterin confers to sedentary mice most of the benefits seen in mice who exercise.

None of these three scientists started their careers with any interest in human biology. Yet in diverting from the paths they originally envisioned for themselves, each has brought scientific credibility to something long considered to be in the realm of science fiction — or those bogus infomercials.

 The National Institutes of Health, meanwhile, is spending $170 million on a study designed to search more systematically for ways to measure the benefits of physical exercise in chemical molecules within our bodies. And in January 2022, one of the most richly financed startups in history, Altos Labs, announced that it was starting out with $3 billion in funding to study rejuvenation and develop anti-aging techniques.

Let’s be clear: When it comes to the blood factors being studied, not one of these substances has yet been given to a single human being, let alone to dozens or hundreds in a randomized clinical trial. Nearly all the evidence so far is based on studies of mice. Nevertheless, Villeda, Wrann, Wyss-Coray and others press forward, seeking to discern with scientific rigor what Mayan myths and stories of vampires have suggested for centuries: that the secrets of life flow within our veins.

Enzyme for Exercise

“My story is bizarre,” says Saul Villeda. “My parents came here illegally in the ’70s from Guatemala. I was born in East L.A. My dad was a janitor for a convalescent hospital. I thought I would grow up to be a mechanic.”

But by his senior year in high school, he was accepted to numerous universities, and attended the University of California, Los Angeles. The professor teaching Villeda’s first upper-division class, in developmental neurobiology, invited him to volunteer in her laboratory, and then encouraged him to apply to graduate school. He went to Stanford and ended up in the laboratory of Wyss-Coray, who was studying blood biomarkers for Alzheimer’s disease.

“It was exciting,” Villeda says, “I was interested in looking for blood factors linked to aging that were not just biomarkers, but that you could manipulate and affect the aging process. That’s where parabiosis came in.”

Villeda, Wyss-Coray and colleagues later came up with the idea of repeatedly injecting blood plasma from old mice into young mice, rather than surgically connecting them. The results, described in a 2011 paper in Nature, showed that the young mice treated with blood serum from old mice performed worse on tests of learning and memory. Something in the blood of the old mice was transforming the young mice into mental geezers.

In 2014, they published their extraordinary follow-up, this time showing that blood serum from young mice, when repeatedly injected into old mice, not only improved their learning and memory, but also increased the rate at which their neurons matured and synapses grew.

“The reaction to that paper was insane, absolutely insane,” Villeda says. “I was interviewed on CNN and Fox News. The idea that there’s something in young blood that is beneficial, all of a sudden people are talking about ‘vampire therapy.’ But at its core, it’s such a simple concept. Even my mom was not surprised by that. In Guatemala, the Mayan culture is predominant. Our ancestors performed sacrifices of young people to give the king virility.”

Given the unlikely and ethically questionable prospect of turning the blood of young people into a kind of drug for old people, Villeda, Wyss-Coray and others instead turned to the question of identifying what properties in young blood made it so beneficial.

In 2020, Villeda published his answer in Science. By then running his own laboratory at UCSF, he reported that blood levels of the liver enzyme glycosylphosphatidylinositol-specific phospholipase D1, or GLPD1, increase after exercise. That enzyme was also elevated in older mice whose cognitive function was unusually good for their age — an observation similarly seen in active, healthy older humans. What’s more, raising the blood levels of GPLD1 in old mice improved their ability to learn and remember.

The discovery was significant enough that Villeda and two of his co-authors filed for a patent on the use of GPLD1 for treating or preventing the cognitive effects of aging. “We’re not going to take a 75-year-old and turn him into a 21-year-old,” Villeda is quick to note. Even so, that hasn’t stopped the search by other scientists for other blood factors to convey the benefits of youth or exercise — including one favored by Villeda’s mentor, Wyss-Coray.

Cognition and Clusterin

“My plan was to be a plant biologist,” says Tony Wyss-Coray. Growing up in a rural village in Switzerland, he studied at the same high school that Albert Einstein attended a century before. It was here that he fell in love with nature in general and plant life in particular.

“I was a total geek,” he confesses. “I would collect all the plants and figure out their names. In high school, I did a research project on a society of orchids that grow in the Jura Mountains.”

However, influenced by a charismatic college professor who taught immunology, Wyss-Coray ended up pursuing that field for his Ph.D. at the University of Bern. Then he decided to research the immune system of the brain, something that few immunologists or neurologists had ever focused on.

Eventually landing at UCSF, he pursued the study of how inflammation in the brain is associated with Alzheimer’s disease, while his wife, a nurse, worked at the university’s dementia clinic. It was there, in the late 1990s, that he and his wife began noticing that her father was becoming increasingly forgetful and disoriented. Eventually he was diagnosed with a mixed dementia, Alzheimer’s disease with Lewy body dementia. “At the end he was just a shell,” Wyss-Coray says.

Wyss-Coray felt that after 20 years of studying the disease, he had nothing to offer his father-in-law. That explains in part why he was open to the unlikely idea of his star student, Villeda, to see what would happen if they switched the blood serum of young and old mice.

“I like to do stuff that is not too obvious,” he says. “There are people who want to understand the minute details of something. Other people, and that’s my personality, they look for bigger risks, bigger stories.”

After Wyss-Coray moved to Stanford, he published his Nature paper in December of 2021 describing the effects of the protein clusterin. Decades of research had already shown that clusterin plays a role in regulating inflammation. Wyss-Coray’s paper, however, described something new.

Wyss-Coray’s team first found that blood from mice that exercised could convey cognitive benefits when given to sedentary mice; they then filtered the blood serum to see which proteins appeared to be most strongly associated with the effect. That turned out to be clusterin. When they removed the protein from the test serum, the benefits for sedentary mice vanished. When injected into the bloodstreams of mice bred to develop an Alzheimer’s-like syndrome, it dampened their brains’ inflammation. And when U.S. military veterans with mild cognitive impairment spent six months engaged in physical exercise, their levels of clusterin increased along with their cognitive status.

By now, dozens of scientific studies of GPLD1 have been published, as have hundreds of both clusterin and irisin. But FDA approval of any blood factors associated with youth or exercise remains years away.

“People get antsy when you tell them they have to wait, but the complexity of this field is astronomical,” Wyss-Coray says. “I believe that these are all true findings. But making a drug out of that is a huge challenge.” Nevertheless, he has started a company, Alcahest, to search for fractions of blood plasma from young people that convey the benefits of youth and exercise. (Villeda has signed on as a scientific advisor.)

Hope in a Hormone

“I actually trained as a veterinarian,” Christiane Wrann says. A competitive equestrian in her youth, she competed on a team with others as their horses literally danced. At the age of 12, her team won second place in a competition in her native Germany.

“I would come home from school, do my homework, then take my bike to the riding club from 3 to 8 p.m.,” she says. “I was really into it.”

When one of her horses suffered a tendon injury in the left foreleg, Wrann found herself wondering why some horses develop illnesses or injuries as they age, and how to treat them. So, she went to veterinary school in Hannover, then came to the U.S. for postdoctoral work, joining the Harvard lab of biochemist Bruce Spiegelman in August of 2011.

“Bruce was one of the international leaders on the effects of exercise,” she says. “His was one of the first labs to come up with this idea: Can you capture exercise in a protein or hormone?”

In a paper published in Nature in January of 2012, Spiegelman’s team described their discovery of the hormone irisin. Blood levels of irisin rise, they found, during exercise, thereby stimulating white fat to turn into its more healthful cousin, brown fat. “Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise,” they concluded.

Wrann decided to focus on those other disorders, in particular the neurological variety. A decade of research later, she had her own lab at Harvard when she published her blockbuster paper in Nature Metabolism. Irisin “is sufficient to confer the benefits of exercise on cognitive function,” she and colleagues reported. They called it a potential drug for treating cognitive disorders, including Alzheimer’s.

But even if irisin could confer all the benefits of exercise, she points out, that still won’t eliminate the risk of cognitive decline and Alzheimer’s. As a leader in the Program in Neuroprotection in Exercise at Massachusetts General Hospital, Wrann has heard many variations on the same story: “My husband always ate well, he exercised, but he still got dementia.”

“Nothing in life is a hundred percent,” she adds. “Exercise helps, but can it cure dementia? No.” Wrann’s hope with irisin, however, is that it might actually increase the odds of remaining cognitively healthy for those unable to exercise.

Like Villeda and Wyss-Coray, she too holds a patent — related to irisin — and has co-founded a company, Aevum Therapeutics, to develop drugs to harness the effects of exercise in order to treat neurodegenerative and neuromuscular disorders. While such drugs remain in the future, one thing seems certain: When they’re released, they won’t be the stuff of late-night infomercials.

Understanding Klotho

By no means are irisin, GLPD1 and clusterin the only blood factors shown to convey the benefits of youth and exercise; they might not even be the most potent ones. The hormone Klotho, for instance, was discovered in 1997 by a Japanese cardiologist who found that a mutation caused some mice to age prematurely. Enhancing Klotho levels, he found, increased their lifespan. In 2015, other research showed that the hormone also enhances learning and memory in mice — even young ones.

The lead author of that paper, Dena Dubal, who now holds the endowed chair in Aging and Neurodegenerative Disease at UCSF, says that efforts to develop Klotho into a drug are “moving, feels like inching, toward clinical trials in humans.” But much remains to be learned, she says, especially about how the different factors might work together.

“Could clusterin increase GLPD1?” she wonders. “Could irisin increase Klotho? Is there a master regulator?”

No matter how the science sorts out, Dubal says, “it’s hard to believe that all the benefits of exercise could be packaged in a pill. But if we had a pill that homes in on the brain benefits of exercise, maybe our aging population could be a lot better off.”