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I DISCOVER the French bistro tucked into a strip mall that wraps around a parking lot it shares with a hardware shop and a barber. The man I am meeting has asked to come here instead of the clinic because he doesn’t want to do an interview while being transfused.

I am led to a booth where I find him drinking a glass of wine, wearing the blazer-and-T-shirt uniform common among venture capitalists. His youthful looks have an enhanced, slightly uncanny cast, but I am still shocked when he tells me he is 65. To protect his privacy, he chooses to be identified for this article as JR.

JR is a minor celebrity in these parts. It is the fifth time this year that he has flown in from Atlanta to have the treatment. Monterey doesn’t get a lot of traffic from people like him.

You might think of the Californian coast as a homogeneous stretch of sun-drenched sand and rich people. But things change around the middle of the state. Driving there from San Francisco, you quickly lose the sun behind a permanent blanket of fog. The central coast is long and flat, with glimpses of iron grey choppy waves behind squat buildings.

So it’s a bit odd that this is the epicentre of a phenomenon rocking Silicon Valley: young blood treatments. JR is one of about 100 people who have each paid $8000 to join a controversial trial, offering them infusions of blood plasma from donors aged between 16 and 25 in a bid to turn back the clock. Participants have come from much further afield, including Russia and Australia.

It’s not hard to see why. After a spate of recent trials showed astonishing rejuvenation in old mice, the notion of filling your veins with the blood of the young has gone from creaky vampire myth to the latest tool in Silicon Valley’s quest to “disrupt death”.

Now start-ups, universities and pharmaceutical companies are clambering to commercialise the potential of young blood. and are rumoured to be partaking behind the scenes. The idea’s popularity is sparking fears of red markets and a dystopian future in which the old steal youth from the young, and no longer just metaphorically.

Scratch beneath the hype, however, and we may have been looking at young blood the wrong way round. Within a few years, new insights could usher in a safer, more effective way for blood to stop the inevitable declines of ageing.

Mystery ingredients

Vampire tales aside, we have suspected since the mid-19th century that young blood has rejuvenating powers, thanks to a grim surgical technique known as parabiosis. Scientists would stitch together two animals, usually rats – like twins conjoined only at the skin – and wait a week for capillaries to form and fuse their blood supplies. The new plumbing seemed to change the old rats, making them physically and cognitively resemble their younger partners. By 1972, research began to suggest that after being conjoined, .

In the early 2000s, researchers at Stanford University in California revisited the technique, this time with a view to reversing specific ailments of ageing. They damaged the livers and muscles of old mice before connecting each one up to an undamaged mouse. Those with young partners healed well. old partners did not. Similar results emerged with regard to heart health, then age-related cognitive declines.

What was it in blood that was having these rejuvenating effects? The prime suspect seems to be plasma, the yellow liquid that out after donation. Components like red blood cells are used for medical transfusions, but the plasma often goes spare.

Plasma is rich in all sorts of proteins and other compounds, which could hold the key to what makes young people young and old people old. Not that we know what all these components are. But we do know that their amounts and ratios change as we age. For example, old blood has higher levels of inflammatory compounds that damage tissues they reach. Inflammation has been linked to cancer, heart disease and depression. Younger blood, by contrast, is characterised by a higher concentration of stimulating and restorative factors.

An amazing discovery, but to be medically relevant, we must deliver young blood without having to stitch pensioners to 20-year-olds. So in 2014, a team led by , a neuroscientist at Stanford University, injected middle-aged mice with plasma from young mice. Sure enough, after three weeks they had anatomical improvements in the brain and a cognitive boost, compared with mice given a placebo. Every other system they tested fared similarly.

The plasma didn’t even need to come from the same species – old mice became just as sprightly when the injection came from young humans. “We saw these astounding effects,” Wyss-Coray told 91av in 2014. “The human blood had beneficial effects on every organ we’ve studied so far.”

Wyss-Coray had the proof he needed to start a human trial. In October 2014, his start-up, Alkahest, began recruiting participants for a trial at Stanford School of Medicine, using young blood in people with late stage Alzheimer’s disease. The following year, Bundang CHA General Hospital in South Korea trial to compare the anti-ageing effects of cord blood, young plasma and placebo on markers of frailty in ageing. Both trials were met with enthusiasm. Wyss-Coray was invited to give lectures, including at the World Economic Forum and a .

Then there’s the Ambrosia trial, which JR is taking part in. Ambrosia is a start-up headquartered in Washington DC. The trial didn’t need regulatory approval because plasma is treatment to replace missing proteins in people with rare genetic diseases. And there’s no placebo arm to it. All you need to join is a date of birth that makes you over 35 – and a spare $8000.

For your money, you are infused with 2 litres of plasma left over from young people who have donated to blood centres (see “Blood myths”). Unlike the trials looking at young blood’s effects on specific diseases, Ambrosia has a softer target: the general malaise of being old. In addition to measuring changes in about 100 biomarkers in blood, the firm is also “looking for general improvements”, says Jesse Karmazin, who runs the start-up.

The methodology falls short of the normal standards of scientific rigour, so it’s unsurprising that scientists and ethicists have accused Karmazin’s team of taking advantage of public excitement around the idea.”I don’t think the Ambrosia trial can be called a trial at all, since they treat healthy people and they have no clear read-outs,” Wyss-Coray says.

This makes any findings virtually unpublishable, which may explain why Karmazin announced his first results to a room full of technologists at the Silicon Valley Code Conference in May instead of at a medical conference or in a journal. The numbers were as unverifiable as they were impressive: one month after treatment, 70 participants saw reductions in blood factors associated with risk of cancer, Alzheimer’s disease and heart disease, and reductions in cholesterol were on par with those from statin therapy.

Karmazin says this could explain his observations during the trial: a woman with chronic fatigue syndrome is now able to get out of bed and live normally; another participant, who had early stage Alzheimer’s when he enrolled, no longer meets the clinical criteria for having the disease.

“Whatever is in young blood is causing changes that appear to make the ageing process reverse,” Karmazin told me. Even healthy participants “just have more energy”.

JR agrees. “I do feel it a bit,” he says. “I am starting to run again now.” However, although Karmazin says that the effects in the blood are identical regardless of participant age, JR says his 39-year-old girlfriend feels no different after two treatments. As for his youthful looks, JR says he tries out many of the therapies his company invests in.

Not that any of this should be taken at face value. Many of Ambrosia’s claimed improvements could be down to the placebo effect. Even so, the numbers are proof enough for Karmazin. He originally 600 participants. However, the results have made him so optimistic that he is expanding the business. When I travelled to Monterey in June, Karmazin had just opened his third clinic, and thanks to recent infusions of investor cash, he is planning a total of six in the US in 2018.

I ended up in Monterey because, for the past year, I’ve been preparing myself to enrol in the trial too.

As it did with much of the public, the idea of the glittering Silicon Valley “blood spa” captured my imagination. The reality of this clinic is somewhat different, though. The one-storey building shares an intersection with a flaking self-storage facility and a pockmarked parking lot.

The interior is also modest; patients pass through a wood-panelled kitchen on their way to the reception. In the main room, a row of armchairs, each with an IV drip stand, faces a window overlooking washed-out scenery that culminates with the Pacific Ocean, barely discernible under the fog. Most of the elderly clients occupying those chairs are not getting plasma, but IV fluids.

When I visit, the trial is being run by Craig Wright, Karmazin’s erstwhile partner. Karmazin has a medical degree but not a licence to practise, so he teamed up with Wright, an immunologist formerly at Walter Reed Army Medical Center in Washington DC, who is licensed to run one of the West Coast’s few non-hospital affiliated infusion clinics.

Although at 67 he could be retired, Wright maintains the clinic to look after his patients. “Healthcare in this country doesn’t give a crap about old people,” he says. One of his clients has dementia that used to regularly put him into the emergency room for dehydration. Another, after several rounds battling lymphoma, had a compromised immune system that left her struggling with recurring infections.

Eventually Wright enrolled her in the Ambrosia trial. Her infections went away.

“Whatever is in young blood is causing changes that appear to reverse ageing”

But by the time I get to the clinic, I am rethinking whether I want to go through with this. Wright and I go into his office so he can give me the consent form. I tell him I’m starting to reconsider, and I am surprised to find he doesn’t try to talk me round. “You need to think long and hard before you do this,” he says. For some of his older, sicker patients, plasma has proved beneficial. For younger would-be participants like me, however, he lists a litany of potential side effects.

Risks with plasma transfusion include transfusion-related acute lung injury, which is fatal; transfusion-associated circulatory overload; and allergic reactions. Rare complications include catching an infectious disease: blood products carry a greater than 1 in a million chance of HIV transmission. That’s too risky for JR, who tells me that before every treatment he takes a dose of the HIV prophylactic PrEP.

Karmazin had previously assured me that none of the risks associated with plasma transfusion exceed 1 or 2 per cent, a statistic borne out in the trial: in his Code presentation, he told the room that of his participants had reported any negative effects. “Not one.”

Complications

But when I meet up with JR and Wright on the second day of my visit, both are visibly shaken. A participant had arrived earlier that day from Moscow to get the infusion. As he started on his second unit of plasma, the man had an anaphylactic reaction. His face and tongue swelled up, and he developed a rash all over his body. “Even the whites of his eyes turned red. He was in a lot of trouble,” says JR. Wright administered emergency treatment to stabilise him and sent him back to his hotel.

I am astonished that my visit has coincided with the first complication of the treatment. There’s an uncomfortable silence as JR and Wright exchange glances. “It’s not the first one,” says Wright. When I press him for more information, he demurs. “You’ll have to talk to Jesse.”

When I call Karmazin, he clarifies that there was also an eyelid rash and a case of pneumonia that was probably already in place before the patient got the treatment. But in later conversations with Wright, he tells me of worse cases. Without published data, it’s imporssible to get to the bottom of it.

Either way, those are the known knowns. There are also known unknowns associated with injecting material from someone who is genetically different to yourself, says , a co-author on the early Stanford work that put young blood on the map, and now at the University of California, Berkeley.

There could be risks of developing autoimmune disorders. And some fear that pumping stimulating proteins into people for years could lead to cancer. “If you keep infusing blood, the risk of reactions goes up,” says , an immunologist at California Pacific Medical Center in San Francisco. “Many of these people are just eager to get younger – they don’t have a particular disease, so it’s not justified.”

It’s easy to criticise Ambrosia for charging people to receive an unproven procedure (see “Why does it cost $8000?”, below), but there is also no evidence yet that the other trials are yielding anything more promising. Alkahest began recruiting volunteers for its Alzheimer’s trial in 2014, but there have been no publications yet. Wyss-Coray plans to announce results in November.

Because there’s so much uncertainty hanging over both risk and reward, others are looking for a shortcut. Identify one or more “silver bullets” in plasma to reverse the effects of ageing, and it might be possible to develop a safe, convenient pill.

For a while, the chief candidate was GDF11, a rejuvenating protein that decreases in abundance as we age. In 2013, Amy Wagers of Harvard University reported that of GDF11 restored the muscle size, endurance and grip strength of old mice to levels seen in a much younger individual.

Then there’s the protein osteopontin, which seems to keep blood cells young and provide an immune boost. And now a protein called TIMP2 from umbilical cord plasma has been shown to .

Attractive as this option is, it needs a reality check. “There’s a lot of hype around single protein factors,” says , who also works on plasma at Stanford. “But one plus one is not always two in biology. We don’t know which constituents are working together, or how.”

Indeed, there was an initial flurry of enthusiasm over GDF11, but multiple labs have Wagers’s result.

Besides, it could be that the curative powers of young plasma were a red herring all along. Many conclusions have been drawn about the power of young blood, but most of these come from parabiosis.

The problem is, parabiosis isn’t just about blood. There are other reasons the older mice might have benefited from the deal. “These old mice suddenly had access to much more than just young blood,” says Conboy: a young liver to filter toxins, a young heart to pump harder, young lungs and all the rest. Not to mention the environmental enrichment. “They were now getting dragged around by the young mice instead of sitting in a corner all day,” she says.

“New clinics will offer 30-minute treatments for $500 a pop”

So Conboy set out to tease out the effects of blood from those of being joined to another mouse. Funded by Google’s life-extension biotech arm Calico, among others, she developed an experiment in which a pump ferried half the blood from one individual into another. “We were transplanting half the blood supply into the old mouse, not just a bit of plasma,” she says. “If you tried this in a human, it would be fatal.”

The young blood for the old mice, certainly less than had been found in parabiosis. But what surprised Conboy was the to the young mice. “After a single exchange, the mice got dumber,” she says, and markers of inflammation increased.

What did this mean? For one thing, it suggested that anything good in young blood is swiftly overpowered by the bad in old blood.

It also suggests that young blood didn’t cause any rejuvenating effects in the trials – if anything, it just diluted the bad stuff. This makes its benefits temporary at best. It would also help explain Karmazin’s observations that customers will need to come back for regular top-ups.

To see real benefits from a young person’s blood, then, you’d probably need to stitch yourself to the poor soul for a few weeks – a red market perhaps, but not a convenient one.

That’s not to say the whole endeavour should be scrapped. We just need to turn the thinking about young blood on its head, says Conboy: instead of trying to isolate what’s good about young blood and add it, we could isolate what’s so damaging about old blood, and get it out.

Conboy is now working on a different approach with the anti-ageing start-up Unity Biotechnology, which is backed by Amazon founder Jeff Bezos’s investment company. They are developing a blood-exchange device, a kind of dialysis machine for old age, which cycles your blood through a filter that washes a laundry list of harmful compounds out of the plasma before returning it to you. This would carry no immune effects or disease risks, because it’s your own blood. No regulatory approval is needed, because dialysis filters that remove proteins from plasma are already in use, for example to remove cholesterol in people with certain hereditary diseases.

They are also developing sensors to notify you when levels of bad biomarkers are getting too high – a decrepitude meter to tell you when it’s time for a decrepitude wash.

The filters have already been tested in mouse blood in vitro, and Unity says it is about to publish the data. The firm hopes that human trials will start in 5 years.

Even so, this isn’t a procedure you would take lightly. “It’s not a pleasant experience to have your blood filtered,” says Douglas Kiel at Harvard’s Institute for Aging Research. “Just talk to dialysis patients.”

Still, Conboy and Yousef think that if we can crack the problem of old blood, a brave new world awaits. They even envisage a time when, rather than removing the bad stuff in blood, you could treat it at source (see “Roots of bad blood”). They have evidence that the blood components responsible for ageing could be released by senescent cells. Tackle this, and you might be able to restore a 75-year-old body to functioning like a 35-year-old, they say. “Our age is not set in stone,” says Conboy.

Until we see whether the blood-purifying-filter route stands up to scrutiny, what about plasma? Karmazin plans to streamline his services. His new clinics will no longer charge $8000 or infuse 2 litres over two days: instead, he tells me, he is already trialling a procedure that takes just a few hours. His aim is to eventually offer smaller amounts of plasma over 30 minutes, for $500 a pop.

Ultimately, it was these plans that drove a wedge between Karmazin and Wright, who developed the original protocol and deemed the new, quicker treatments too risky. He stopped working for Ambrosia in July, a month after my visit.

And even without the risks, any effects – placebo or not – are modest, acknowledges JR. “This isn’t a silver bullet. You feel a little better. You sleep better. But you don’t come away feeling like your life has changed.” Still, he says plaintively, “if I can just get 10 more healthy years of living…”.