Can a “magic” protein slow down the aging process?

This article is part of Reacheda series on young companies exploiting new sciences and technologies.

Several years ago, scientists studying aging at the Harvard Stem Cell Institute used a somewhat Frankensteinian technique known as parabiosis – surgically joining a young mouse and an old mouse so that they share blood – to see what that would happen to the heart and skeletal muscle tissue. They knew from previous research that putting young blood into old mice made them biologically younger, and that young mice exposed to old blood aged faster.

Harvard researchers Amy Wagers and Dr. Richard Lee found that the old mouse’s heart tissue had been repaired and rejuvenated, becoming young again. In fact, the size of the old mouse’s heart had shrunk to that of a young heart.

“We all wondered, what is the magic substance in the blood?” said Lee Rubin, professor of stem cells and regenerative medicine at Harvard and co-director of the neuroscience program at the Stem Cell Institute. The “magic” they identified was a protein, GDF11, one of tens of thousands produced in the human body. Dr. Rubin’s lab also found that GDF11 in mice stimulated the growth of new blood vessels in the brain and neurons in the hippocampus, a part of the brain associated with learning and memory. Dr. Wagers’ lab found that GDF11 also rejuvenates skeletal muscle tissue. The scientists’ findings were published in the journals Cell and Science in 2013 and 2014.

The next obvious question: Could GDF11 be harnessed to promote regeneration and repair in humans? In 2017, Drs. Rubin, Wagers and Lee, along with five others, founded pharmaceutical start-up Elevian with the goal of commercializing GDF11-based therapies to stop, slow or reverse diseases associated with aging. It’s a big leap from mice to humans, but one that could have far-reaching consequences.

“We are interested in proteins like GDF11 that are excreted into the bloodstream because they can cause changes throughout the body,” said Dr. Mark Allen, CEO of Elevian. “And that’s the kind of change we want.”

Dr. Allen started his first healthcare business while in medical school at the University of California, Los Angeles, and he left his residency position in 2000 to start a second. In early 2017, he and his investment partner, Sebastian Giwa, an economist, were looking to launch a new one that would develop therapies targeting the degenerative processes involved in aging. They considered two dozen potential research projects before settling on GDF11.

“I had this idea that aging itself might be a target for therapeutic intervention,” Dr. Allen said, “because if we target one aspect of the aging process, we have the potential to treat many different diseases.”

Early research into the rejuvenating properties of GDF11 has received some pushback from the scientific community. In 2015, after Dr. Wagers and Dr. Lee published their findings, a group of researchers led by David Glass, the executive director of the Novartis Institutes for Biomedical Research in Cambridge, Mass., at the time, challenged the accuracy of their findings in an article in the journal Cell Metabolism. The Harvard researchers later countered the Novartis team’s findings in another paper published later that year in the journal Circulation Research, in which the Harvard researchers cited a problem with the findings of the Novartis team.

Dr. Glass, who now works for biotech company Regeneron, said in a recent email that he stands by his original work, which showed GDF11 inhibits, rather than helps, muscle regeneration. But, he added, “our work still leaves open the possibility that there may be positive effects of GDF11 in particular contexts.”

Dr Allen said that since the initial controversy, the Elevian research team has replicated and extended their original findings in several studies, but none have yet been published in peer-reviewed journals. However, institutions unrelated to Elevian have conducted and published numerous preclinical studies demonstrating the therapeutic efficacy of rGDF11 (the laboratory-developed form of GDF11) in the treatment of age-related diseases.

The company is on track to begin human clinical trials in the first quarter of 2023 and has raised $58 million in two rounds of funding, with another round planned for mid-2023.

Elevian is one of many companies working to find ways to increase human lifespan by increasing “health span”, the period of life during which a person is generally healthy. This emerging sector of the pharmaceutical industry is often referred to as “longevity therapeutics” and includes companies like Altos Labs, which started in January with $3 billion in funding; Calico Life Sciences at Google; Biotechnology Unit; Alkahest; and Youth. About $2 billion in venture capital was invested in pharmaceutical companies focused on anti-aging in 2021, according to Longevity Technology, a market research firm and investment platform focused on the longevity industry. .

For years, researchers have searched for drugs that can extend lifespan and health. The National Institutes of Health’s Intervention Testing Program began testing drugs — some Food and Drug Administration-approved, some not — in mice 17 years ago to see if these interventions would prolong their lives. Dr. Richard A. Miller, professor of pathology at the University of Michigan and director of the Paul F. Glenn Center for Biology of Aging Research, said anti-aging therapies are often tested on mice because aging in mice is very similar to aging in humans. “Mice and people share organs, cell biology, and most varieties of neurons and neurotransmitters, and they often respond to drugs in similar ways,” he said.

A daunting challenge awaits all of these companies: bringing an anti-aging drug to market is next to impossible because the FDA does not recognize aging as a disease to be treated. And even if it were considered a disease, the clinical studies needed to prove an effective treatment would take many years.

“Clinical studies to see if certain drugs slow aging — and thus delay the many consequences of aging — would likely take a long time,” Dr. Miller said.

So the founders of Elevian determined that the fastest way to bring GDF11 to market was to target a specific medical condition.

“We thought, what is the worst disease that has no good treatment and that we could treat for the shortest time possible and show clinical effects?” says Dr. Allen. “We decided that stroke was the right one to target because it’s the number one cause of long-term disability with very limited treatment options.”

Dr. Elisabeth Breese Marsh, medical director of the comprehensive stroke program at Johns Hopkins Bayview Medical Center in Baltimore, said the best treatments for strokes caused by clots (about 87% of them) are some type of medication known as tissue plasminogen activator, or tPA, which must be given within 4.5 hours of stroke, and surgical removal of large clots.

But according to experts, only about 20% of stroke victims receive tPA, either because the stroke is not recognized early enough or because the patient is ineligible due to pre-existing conditions. The Elevian researchers said their preclinical (and not yet published) studies have shown that just a few days of treatment with GDF11 can improve recovery after stroke. They found that GDF11 reduces inflammation, improves metabolism, and stimulates the brain to regenerate blood vessels and neurons.

The next big hurdle for Elevian is scaling up its manufacturing, which requires specialized equipment and conditions. So much research is being done in biotech that contract manufacturers are “full”, Dr Allen said. “They’re busy with Covid-related work, and there’s been a lot of funding in biotech in general,” he added. “So it’s a challenge to find the space that meets our specifications.”

And, like nearly every other sector of the economy, biotech research faces supply chain issues, making it more difficult for Elevian to obtain some of the basic materials it needs to conduct its research. . But the company is moving as fast as it can, and Dr Allen said he believes the results of his work will have a profound impact on how we age and how long we live.

“By targeting the fundamental mechanisms of aging, we have the potential to treat or prevent multiple aging-related diseases and extend the span of health,” he said. “We want to make 100 the new 50.”

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