Could ‘young’ blood stop us getting old?

In the early 2000s a group of scientists at Stanford University, California, revived a grisly procedure used in the 1950s known as parabiosis. They paired living mice, young with old, peeled back their skin and stitched together their sides so the two animals shared the same blood circulatory system. A month later, they found signs of rejuvenation in the muscles and livers of the old mice. The findings, published in 2005, turned the minds of scientists, entrepreneurs and the public to the potential of young blood to rejuvenate ageing people. By 2016, enough interest had grown to prompt a US-based startup called Ambrosia to start offering pricey infusions of young plasma – the cell-free component of blood. The procedure came under fire from the US Food and Drug Administration early last year both for its lack of proven clinical benefit and for potential safety issues; Ambrosia closed, though it has recently reopened.

Meanwhile, a clutch of scientific startups are trying to discover the secrets of parabiosis and use them to tackle age-related disease. By identifying factors in plasma that change with age, they aim to create therapies that either supplement what’s beneficial in young blood or to inhibit what’s detrimental in old. One is even beginning to report early clinical trial results.

“There’s still a long way to go – blood is complicated,” says Aubrey de Grey, who leads the nonprofit Sens (strategies for engineered negligible senescence) Research Foundation. “But there are many excellent labs focused on this, so I am optimistic about progress.”

While no one thinks that altering one or more blood factors will be the sole answer to ageing, blood has the potential advantage of cutting across various ageing mechanisms, allowing several of them to be modulated at once.

Alkahest

Alkahest’s pristine laboratories sit just off the freeway connecting San Francisco to Silicon Valley. The company was co-founded in 2014 by Tony Wyss-Coray, a neurologist at Stanford University, after he published papers showing that the rejuvenating effect of parabiosis extended to the mouse brain. Old mice showed improved performance on cognitive tasks, and grew new neurons. His studies also showed that it was young plasma that had the beneficial effect, with proteins in that plasma largely responsible.

Alkahest, which has about 80 employees and more than $41.5m in funding, has clinical trials under way and is reporting its first results. “We’re not just big mice,” says Steven Braithwaite, Alkahest’s chief scientific officer. “We’ve seen so much in our animal models that convinces us, but we need to learn from people.”

This August, Alkahest reported the results from a six-month trial that saw 40 patients with mild to moderate Alzheimer’s disease infused with a proprietary human plasma “fraction”. It appeared to arrest their mental decline.

The fraction was one of two that Alkahest has developed. Each contains about 500 proteins – far fewer than the 10-20,000 contained in natural human plasma. The fractions are made from pooled plasma, which allows for a homogeneous product, by Grifols, a plasma-derived medicines company that is an investor in Alkahest. The fractions contain fewer of the proteins that increase with age (and tend to be detrimental), leaving more that decrease with age (and tend to be beneficial). Donors to the plasma pool are in their early 30s, on average – much younger than intended recipients.

Alkahest believes that the fractions could affect symptoms and slow progression of neuro-degenerative diseases. Trials among patients with severe Alzheimer’s and with Parkinson’s are due to report. Following encouraging results among patients with mild to moderate Alzheimer’s, a larger trial with placebo control is planned. The company hopes that fractionated plasma treatments will be available within a decade. Yet the point, says Braithwaite, is not actually to be an enriched-plasma company. It wants to further refine those fractions, to perhaps 10 or 20 of the most beneficial proteins, and bioengineer them: no plasma needed. This is necessary, says Braithwaite, because the supply of donated plasma is always going to be limited.

Alkahest also has results showing that a drug that removes a protein from old blood could help with age-related macular degeneration (AMD). Two small six-week trials using patients with AMD – 29 who had never been treated for the disease and 26 who hadn’t responded adequately to existing treatment – showed that most maintained or improved their visual acuity as judged by how successfully they read a standard eye chart. They were treated with an antibody designed by Alkahest to block the signalling of a bad protein called Eotaxin, which Wyss-Coray found was increased in old mice and has negative effects.

Elevian

Startup Elevian also wants to commercialise parabiosis. It was co-founded in 2018 by Amy Wagers, who was on the Stanford parabiosis revival team and is now a professor of stem-cell and regenerative biology at Harvard University.

The company is based in Boston, but with an office in Silicon Valley, and is backed by $5.5m in investment, including from the firm of Peter Diamandis, a tech entrepreneur and futurist. It is working on therapies to elevate the activity of Growth Differentiation Factor 11 (GDF11) – a protein in blood plasma present in very small amounts that it believes decreases with age in mice.

Studies published in 2013 and 2014 by Wagers’s laboratory and those of the company’s other scientific co-founders, showed that old mice injected with GDF11 reproduced several of the parabiosis findings – with regeneration seen in the heart, skeletal muscle and brain. It is the only factor that has been demonstrated in old mice to have beneficial effects across a number of major organs that decline with age, notes Wagers. Elevian is working on scaling up GDF11 production before launching its first human trial. It wants first to test whether injections of the protein promote stroke recovery. “Stroke recovery is a very significant unmet medical need,” says Mark Allen, Elevian’s CEO. It is also trying to develop new molecules that could lead to less frequent GDF11 injections, and has a project using artificial intelligence to discover small molecules that could produce GDF11’s biological actions, so patients could take a pill instead.

GDF11 is controversial. It has proved hard to replicate some of the regeneration findings, calling into question its use as a therapy.

Nathan LeBrasseur, a scientist who studies ageing at the Mayo Clinic, a not-for-profit academic medical centre in Minnesota, says his lab could not find that GDF11 changed with age. “I’m challenged to see a therapeutic opportunity,” he says. “For skeletal and cardiac muscle, I have not seen compelling evidence for a beneficial effect of GDF11 beyond the initial papers, and while there is a possibility of beneficial effects of GDF11 on the brain, preventing adverse effects on muscle or heart poses a challenge.”

For Paul Robbins, a researcher who works on the biology of ageing at the University of Minnesota, the negative data doesn’t necessarily mean that the original findings are wrong. “It just means that it’s a complicated system, and the question is why it works in some hands and not in others,” he says.

Wagers acknowledges that there is much to learn about GDF11 biology. She points out that the protein is difficult to measure, because it reacts with other proteins and can exist in both active and inactive forms. But she and Allen defend the improvements seen in muscle and heart when GDF11 was supplemented. A “therapeutic window” may be at play, suggests Wagers. Too little or too much and effects are deleterious – and many conflicting studies used high doses. There is “strong data for moving forward” with Elevian’s programme, says Wagers. Her research group, sponsored by the company, is busy with additional experiments to test what they think is going on. “We’re letting the data lead us and we will report whatever the outcome is,” she says. “Controversy pushes the field forward.”

Which approach is likely to best slow or reverse age-related diseases based on parabiosis’s effects? Alkahest’s plasma fractions are the “safe bet”, says Robbins. “I can’t say that results from the clinic [to date] have been amazing [but] I think they will have something that works.” Elevian could be closer to a home run, however, if it can resolve the issues with the biology of GDF11. “If it does work as initially published it could change our treatments for ageing,” says Robbins.

For LeBrasseur, the most promising is Alkahest’s approach of fixing aged blood by inhibiting bad proteins. Aged blood appears to promote disease and impair rejuvenation, he notes: “Addressing what is causing that may be more effective than simply dripping in young factors.”

Ambrosia, plasma and the FDA

In 2016, Jesse Karmazin began offering infusions of young whole-plasma infusions as a way to help beat ageing, without published evidence that the treatment worked. By the end of 2018 Ambrosia, the US startup he co-founded, which charges $8,000 for one litre or a discounted $12,000 for two, had opened clinics in five US cities. But in January of last year, the FDA issued a general warning to consumers: plasma infusions from young people provide “no proven clinical benefit” against ageing or its diseases. And, as with any plasma product, the infusions could pose risks.

The company wasn’t warned first by the FDA. “It came out of the blue,” says Karmazin, who ceased operations out of caution and to understand the FDA’s position. Last October, after an eight-month hiatus, Ambrosia reopened as a scaled-back operation with a clinic in San Francisco. As Karmazin sees it, the law is on his side. Plasma is an approved drug; his treatment is just an off-label one, which is allowed. And while the FDA statement says that procedures such as his “should” be performed under an active Investigational New Drug (IND) application, that isn’t the same as saying they are required to be. “My lawyers are all telling me I have the legal right to do this,” he says.

Ambrosia’s approach irks many scientists trying to methodically translate the effects of parabiosis into therapies to slow or reverse ageing. It is unfortunate, says Amy Wagers of Elevian, when scientific work and Ambrosia’s approach become conflated. “I think the FDA did the right thing,” she says. Meanwhile, Karmazin says he still plans to publish the results of a clinical trial of customers given infusions that compares their biomarkers before and after (it wasn’t placebo-controlled) – but first he is getting the company back on its feet.

Whether the FDA will come after Ambrosia again is unclear. It doesn’t comment on compliance matters but said in a statement that it had not “licensed or approved any plasma product obtained from young donors for any use”.