Vampires know the fountain of youth is in your blood – Heterochronic parabiosis

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Know-it-all Vampire, by Peggy

Old Mice

“A PUDGY BLACK MOUSE snuffles around a tiny tower of Legos, turns away, then comes back to snuffle again. He’s 18 months old—a senior citizen, in rodent terms. And it’s getting tough to keep it all straight. Do these blocks seem familiar to him? Has he seen this thing before?”

“He’s a bit muddled, but that’s not his fault. Few new neurons are being born inside his itty-bitty brain. The cells that once exuberantly branched, sending lush offshoots to interweave and connect with others, are now sparse and barren.”

“This Lego test indirectly measures those physical changes by monitoring his behavior. When mice of a certain age become forgetful, they spend more time checking out little trinkets they’ve seen before—objects that should warrant only a quick “Oh yeah, that thing again” glance. Cameras and laser-based detectors mounted on the ceiling capture and quantify those pauses and vacillations.”

“Alana Horowitz, the University of California, San Francisco graduate student conducting this FaceTime lab tour, puts her phone camera right up to the mouse’s muzzle. His eyes are bleary, like an old barfly’s. He probably hasn’t groomed himself recently, she says. His coat looks shabby and worn. You’ve likely never looked an elderly mouse in the face, but if you did, all of this—the thinning fur, the dim eyes, the hesitation—would be depressingly familiar. He inspires pity. Like sands through the hourglass, little fella.”

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“But in this lab, headed up by neurobiologist Saul Villeda, nobody is sighing and moping over graybeard mice. Here, aging is not a sad fate to bemoan; it’s a problem to be solved. And for mice, at least, this team has already figured out how to reverse the damage time brings.”

How to  rejuvenate mice

“The secret is somewhere within those tiny veins. In a series of studies over the last 15 years, Villeda and others …..have shown that, when infused with blood from young mice, old ones heal faster, move quicker, think better, remember more. The experiments reverse almost every indicator of aging the teams have probed so far: It fixes signs of heart failure, improves bone healing, regrows pancreatic cells, and speeds spinal cord repair. “It sounds sensational, almost like pseudoscience,” says Villeda. It’s some of the most provocative aging research in decades.”

“These studies, which use a peculiar surgical method called parabiosis that turns mice into literal blood brothers, show that aging is not inevitable. It is not time’s arrow. It’s biology, and therefore something we could theoretically change. The attempt to turn back the clock in living bodies “is probably the most revolutionary experiment that biologists have done,” says Stanford professor of neurology Tony Wyss-Coray…. “It supports this notion that it is possible to reassemble and fix things that we thought are doomed to die.”’

“Benjamin Button-ing, of course, isn’t natural. But Villeda counters that getting old isn’t either: “It is the most artificial construct.” Previously, only a very few rare individuals reached 90 or 100. Now, in wealthy nations, it’s becoming downright common. With antibiotics, vaccines, public health measures, and a steady food supply, the industrialized world made the long, slow goodbye of aging commonplace—and, along with it, the consequences, such as brittle bones, Alzheimer’s disease, diabetes, and heart failure. Young-blood research, like some gory fairy tale, whispers to us that there could one day be a magic pill that can fix it all. The plot twist: That bloody fountain of youth was inside our bodies all along.”

It is not known why this works. And it would be too dangerous to use blood itself for anti-aging treatments. What may be possible is that we find what it is in the blood that causes the rejuvenation and turn these into medicines.

Villeda’s and associates are trying to use parabiosis to help the aging brain. They are also looking the effects on the aging brain of exercise and fasting. They want to know if these affect the blood.

The bloody history

“THE IDEA THAT BLOOD can impart vigor and vitality has a long and stomach-turning history. Pliny the Elder, writing in first-century Rome, describes people with epilepsy guzzling the gore of wounded gladiators. Similar motifs reappear frequently in European lore: The sickly 15th-century pope Innocent VIII allegedly traded blood with three shepherd boys; all four died shortly thereafter.”

“Once British physician William Harvey mapped the circulatory system in 1628, swapping fluids became a fad. Across France and England, enterprising proto-scientists linked animals to animals and animals to people, and on and bloody on. Their hypothesis was that blood could remodel the flesh. In 1666, for instance, the legendary natural philosopher Robert Boyle proposed that introducing blood from a cowardly dog into a fierce one might temper the savage beast’s nature.”

“In 1667, London’s Royal Society hosted a public experiment in which a surgeon paid a man suffering from mental illness to be linked to a living sheep for a few moments via feather quills and silver pipes. Perhaps the gentle lamb’s essence might ease his agitation, was the thinking. Afterward the fellow indeed “found himself very well,” at least according to the surgeon, and he allegedly went on to spend his fee in the tavern. (The sheep’s feelings were not recorded.)”

However when a Frenchman died after a transfusion, these practices slowed, and an end was put to the practice by pope Innocent XI. 

“A new round of transfusion science emerged in the early 19th century, this one with much more scientific rigor. These experiments helped establish the first real knowledge about how to keep injured soldiers from bleeding out or mothers from dying in labor. But it wasn’t until 1864 that a Parisian physician working on skin grafts developed true parabiosis: a sustained commingling of the blood supplies of two living creatures.”

“Knowing that the red stuff flows through every organ and tissue, scientists have used the technique ever since to study bodywide states like obesity and systemic diseases like radiation sickness. If you divert blood from a sickly animal into a healthy one, and that one also becomes ill, it suggests some soluble factor in the blood plays a role. That knowledge, in turn, helps you narrow down what causes the illness or condition. For example, in 1958, scientists linked up rats from a strain prone to tooth decay to rodents from another strain that’s naturally resistant to cavities, to test whether something in the blood might account for the differences. In this case, at least, blood swapping made no difference.”

“Heterochronic parabiosis, in which researchers pair two animals at different points in the lifespan, was first used to study aging in the 1950s. But by the 1990s, it was largely forgotten—until Stanford put it back on the map.”

Aging alters everything.

“The hair grows gray, the bones weaken, the heart falters. Inside cells, DNA replication glitches and stutters, and proteins clump up into sticky globs. Meanwhile, natural repair mechanisms like adult stem cells no longer scurry to replace dead or injured tissues. All this happens more or less in sync, as if some systemwide signal has told the whole body to go down the tubes.”

“This organized process of decrepitude was still largely an enigma in 1993, when biologist Cynthia Kenyon, then at UCSF, discovered that mutating just one gene in a roundworm doubled its lifespan. Her finding helped launch the modern study of aging, but it soon became clear that a one-gene or one-protein approach wasn’t going to work, at least not for mammals.”

“But what is it that coordinates this systemic ruin? Fellow Stanford neurologist Thomas Rando reasoned that it made sense to look in the blood, that witch’s brew of biochemical whatnot that bathes the body, pinkie toe to pointer finger. Mostly water, nutrients, and red blood cells, what runs through our veins also transports a huge variety of signaling molecules that coordinate metabolism, immune responses, fight-or-flight reactions, and myriad other activities.”

Frankenmice

“On the theory that blood-borne factors might orchestrate the transitions of aging, Rando and two postdocs in his lab, Michael and Irina Conboy, turned to heterochronic parabiosis. In the creepy but simple procedure, the surgeon slits two anesthetized mice down their flanks, then sutures and staples them together, side by side. Because these lab animals are so inbred, their immune systems don’t attack one another. As the incisions heal, their blood vessels connect, and the two share a supply.”

“Conjoined, the Frankenmice learn to eat together, make their little nests together, and ramble around as if they’re in a three-legged race. Their bodies begin to change. The old mouse’s fur gets thicker and silkier. It scrapes together its bedding more quickly. The junior partner loses speed, becomes tentative.”

“The authors had brain data too, but it was too preliminary to be included in the paper. By 2005, the long-held dogma that adult brains cannot make new cells had softened: Research had shown that certain regions, including the hippocampus, could generate new neurons, but claims of actually restoring function still raised most eyebrows sky-high.”

Brains as well as bodies

“Villeda did the tiny surgeries and collected evidence. Soon, he could see that new brain cells were in fact surging in old mice. And they looked great.”

“When a neuron is born in an old brain, it’s [usually] scrunched up,” he says, balling up his fist. “In these old brains they looked just like the young ones, beautiful,” he continues, stretching out his fingers. Those cells eagerly extended their long tendrils to make connections—the synapses that enable learning, memory, thinking, and everything else an elderly mind often struggles with.”

” Villeda demonstrated that the access to young blood not only remodeled old nerve cells so that they looked and responded like younger neurons but also improved aged mouse learning and memory.”

Rejuvination

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Rejuvinated Mouse, by Peggy

“Wagers and others at places like Columbia Medical Center soon showed that parabiosis could improve the function of heart, bone, and other tissues. These teams worked together to establish a working definition of what really qualifies as rejuvenation, including changes in DNA modification, gene activation, or protein levels characteristic of younger bodies.”

“Villeda .. also collected plasma—blood with the cells removed—from young mice,  and transfused it into older ones. The effect was the same, strongly suggesting that whatever the magic was, it was something dissolved in the fluid itself, some code or key that signaled a fresh start.”

Get SEWED to someone ?

“JUST TO GET THIS OUT OF THE WAY: Nobody’s sewing humans together. Our immune systems would wallop one another, with potentially deadly consequences …Transfusing seniors with young blood isn’t practical either; people would probably need repeat treatments, with each bringing a risk of infection, allergic reaction, and even injury to the lungs … ……….”

Heterochronic parabiosis may not lead to a longer life, it just reverses some decline.

Some are already selling the blood of others

“Of course there are those already selling the plasma of young people. There are plans to charge large amount for doing this, but no studies as yet. Since this is a treatment in use for some rare autoimmune diseases and coagulation problems, the service is legal as long as they make no claims that can’t be backed up. Companies have, however, make such claims, ad the FDA stopped it in 2019.”

 “Everyone recognizes this is an incredibly important experiment,” says Eric Verdin, CEO of the Buck Institute for Research on Aging, who closely follows parabiosis. “What has been lagging is: How do you translate these discoveries?”

The path forward

“The most straightforward path would be to pinpoint a pro-aging factor in old blood,…that a drug could block. Many groups have identified such elements. Villeda and his collaborators, for instance, found that a protein called CCL11 increases in aged humans and mice and is correlated with reduced brain cell birth.”

“The other obvious tactic is to identify youthful plasma’s secret formula and optimize it. The Conboys’ research suggests the hormone oxytocin might be a candidate; Wagers has identified the protein GDF11. Combination therapies are also under consideration; the biotech company Wyss-Coray founded is exploring mixtures of hundreds of blood-borne proteins as therapies for a variety of age-related diseases. Villeda is on its board.”

“It’s also possible that the rejuvenating effects seen in experiments don’t arise from one magic ingredient, or even from some combination of a dozen or a hundred compounds, but happen simply because the procedure dilutes some unknown harmful substances that accumulate in old blood. From this perspective, there’s no particular need for young stuff: Any form of plasma replacement will do.” 

“Their (the Conboys) recent experiments, published in the journal Aging, replaced half the blood of some old mice with a mix of salt water and purified albumin (the main protein in plasma), which successfully rejuvenated the rodents’ hearts, livers, and brains. They too are starting a company and are aiming for human clinical trials to determine if simply flushing out the bloodstream can help with problems like frailty and declining cognition.”

“…Villeda and others are rushing forward with a bigger project: cracking all the other codes that might be written in blood.”

” It’s well known that exercise can reduce some of the effects of aging on the brain, increasing blood flow to the organ and boosting cell birth in one of the few regions that produce new neurons. Shelly Fan, a postdoc in Villeda’s lab wanted to see whether plasma from an active animal could transmit those benefits to a sedentary one. “

“Mature mice were allowed to sprint as much as they wanted on little exercise wheels for six weeks (these critters typically like a nice, brisk jog). She then collected their plasma and delivered it to aged couch-potato equivalents. These older animals’ brains produced extra new neurons, and they aced memory tests. The paper was published in Science in summer 2020.”

“The surprise was that the effects seemed to flow through the liver, which ramped up several factors including an enzyme called GPLD1 that is also plentiful in active elderly humans. Rando and Wyss-Coray, with others…. found that serum (plasma with clotting factors and platelets removed) taken from exercising older mice restarted the systems responsible for muscle repair……..”

Soon we may all want to be vampires . . . of one sort or another . . . 

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