Restore Youthfulness & Vitality to the Aging Brain & Body | Dr. Tony Wyss-Coray

Andrew Huberman introduces Dr. Tony Wyss-Coray, a professor of neurology at Stanford School of Medicine, as a researcher who looks for factors that can help prevent and reverse organ degeneration and aging. According to Huberman, the episode covers proteins that circulate at high levels in young blood and decline with age, factors released into the blood after exercise, the claim that aging is nonlinear and speeds up at certain life phases, and the claim that different organs age at different rates. He describes Wyss-Coray as a tool developer for measuring and reversing aging, not someone talking about a molecule that might become a drug someday.

When Huberman credits him with the first serious experiment moving young blood into an older organism, Wyss-Coray corrects the record: his group was not first. They collaborated with Tom Rando, the colleague who recruited him to Stanford and who brought back a surgical model called parabiosis. In parabiosis, an old mouse and a young mouse are joined so that their circulation exchanges blood. Rando used the model to study muscle stem cells. In old age, muscle deteriorates and fails to regenerate. When the young circulation reached old muscle, that muscle regenerated and "looked almost like a young muscle."

Rando also saw effects in other tissues, including the brain, and that is where the collaboration started. Wyss-Coray had a second reason to be interested. In separate human studies looking for blood signatures of Alzheimer's disease, his group found proteins that correlated with the disease or even predicted it. The largest difference they saw, though, was between younger and older people. That raised the question he says biologists always have to ask: "Is this cause or effect?" Blood proteins could change in response to an aging brain, or they could help drive brain aging.

Because for the first time, we could take an old brain, and we could give factors from a young organism and ask, "Is that going to change the age of the brain?" And that's indeed what it did.

In the old mice that received young factors, he reports several measured changes: brain stem cells were reactivated, inflammation fell, and neurons showed more electrical activity. He calls the improvement in memory function the most important result. He presents the question of whether this applies to humans as something the field is still trying to translate.

Huberman states the conceptual shift directly. He usually thinks of blood-borne factors "as a readout, not as a medicine," and Wyss-Coray is describing them as medicine. Wyss-Coray agrees that this is the core of the work. Many proteins in the blood, and probably other molecules, do more than reflect the state of the body. They actively influence how it works.

His evidence is a dataset he often shows in talks. His group measured 3,000 proteins in several thousand people and plotted the levels by color. The shift from young to old is large enough that you could pick one sample and say, "This person must be about that old." He accepts that some blood factors clearly change how cells and organs function. He also states what is still unknown: which factors matter most, and which could be used to slow aging or keep the body healthy for life.

To test this in humans, Wyss-Coray's group started a company, Alkahest. The first step was still in mice. They injected blood from young or old people into mice and found that young human blood could mimic the effects of young mouse blood, which suggests that humans and mice share similar factors.

Next they worked closely with Grifols, a company that makes clinical medicines from donated plasma. Grifols pools thousands of donations and separates them into products, such as antibodies for immunodeficient or immunosuppressed patients and albumin, the main protein in blood, for patients who have lost a lot of blood. This manufacturing process let the team test different plasma fractions in mice and find some that were more powerful than others. They then ran clinical trials that infused these fractions into patients with Alzheimer's disease and Parkinson's disease. Wyss-Coray says the trials were small but "looked promising." He links the results to an older observation that people who receive blood transfusions often say they feel invigorated or that their mind cleared.

He also cites a separate Grifols study in Alzheimer's patients that was blinded and placebo-controlled. Patients first had their plasma removed, a procedure called therapeutic plasma exchange, and then received albumin, which also contains other factors. He says the study showed clear, significant benefits in 500 patients. He describes the field as still working out its next steps. The goal is a large clinical study strong enough to show that the approach works and could get FDA approval.

Asked whether he has done therapeutic plasma exchange himself, Wyss-Coray says he hasn't, though he knows people who have. Companies now offer it. He describes a small placebo-controlled trial of 40 healthy older people run by Circulate Therapeutics. Using epigenetic clocks, which estimate how old the body or an organ is, the trial found that some organs, or the body overall, looked younger, along with some improvements in function. He frames the result cautiously:

Not dramatic, but suggesting that there might be something there.

Huberman separates two possible ways young blood could work. Older blood might carry damage-related factors from injuries such as a heart attack or hip fracture, or from small injuries people never notice, and young blood might simply lack them. Alternatively, young blood might supply something that actively promotes youthfulness. He argues that a therapy would ultimately need to tell these two mechanisms apart.

Wyss-Coray's short answer is "it's all of the above." Many inflammatory proteins rise with age. His group identified some of them, and in old mice, knocking those proteins out or neutralizing them improved cognition. Young blood also contains natural factors that inhibit these harmful ones, along with growth factors that stimulate cells and may help maintain stem cells. The open problem is which factors matter most, and what is the smallest set, or cocktail, that would still have an effect.

Or it's the fountain of youth that lives in us, but it dries out as we get older. But it also accumulates. There's also an accumulation of bad stuff, so it's not just a loss of that fountain.

Newer tools let researchers measure gene expression in every cell of an old mouse after it receives young blood. Wyss-Coray says almost every cell changes its behavior, but cells respond differently, as expected, because they carry different receptors. Stem cells appear to be frequent targets, which he says confirms the original findings with an unbiased method. Mitochondria, the energy-producing units inside cells, also appear to be key targets of the rejuvenating effects.

He is direct about the limits. Finding which factor to supply or block would mean knocking out genes one by one inside a living animal with CRISPR tools, and that cannot yet be done easily in vivo. Over the past 10 years, researchers have kept describing individual factors. He says the field has not found a good method for combining multiple factors to get an amplified benefit that mimics what nature does.

When Huberman asks whether he should bank his own blood, Wyss-Coray says it isn't necessary for this kind of research. People differ clearly, but young people's blood has broadly similar concentrations of these factors. Every sample his group used was pooled from multiple donors, and the pooled blood still had the beneficial effect.

Huberman asks whether the Dracula legend reflects this science and mentions bloodletting as a historically dubious practice. He contrasts it with giving blood today, which can lower iron load and helps hospital blood banks. Wyss-Coray suggests the legend may come from people recognizing blood as an essential fluid and perhaps linking it to youthfulness, but he says, "I don't know exactly how." He notes that nobody has ever fed young blood to mice. For that to work, the factors would have to survive stomach acid and be absorbed. He says he wouldn't be surprised if some did and had beneficial effects, but the experiment has not been done. He adds that leeches release blood-thinning factors and suggests they must have done something, or people would probably not have used them. Huberman stresses that he is not promoting drinking blood.

Huberman points out that blood infusion reaches the whole circulation, while organs differ in how open they are to it. For example, the brain has a blood-brain barrier and the gonads have a blood-gonad barrier. He asks whether organs age in parallel. Wyss-Coray says that, contrary to the intuition that an organism ages in sync, organs do not. He credits Monica Driscoll as, he thinks, the first to show this, in worms: at the ultrastructural level, some organs looked more aged than others.

Molecular tools now allow this to be studied in single cells and within organs. In mice, researchers collect tissues from different animals every few weeks or months and track how each tissue changes over time. Some tissues stay stable for a long time and then decline. Others decline steadily from early adulthood. Still others stay intact almost until the animal dies. This leads to a question about individuals: one person's heart may age faster than the rest of their body, while in another person it may be the lung or the brain. Wyss-Coray says that "that's indeed what we seem to be seeing."