THE FOREVER BODY

A Silicon Valley scientist and entrepreneur who invented a drug to explode double chins is now working on a cure for aging

Nathaniel David’s father began suffering from the symptoms of early-onset osteoarthritis in his back during his teenage years. The 77-year-old is now stooped over, effectively crippled, and unable to move.

David started feeling muscle tightness in his back two years ago, at age 47. An MRI confirmed what he knew was his likely genetic fate: He was in the early stages of degenerative disc disease. But unlike his father, David might stay active deep into his retirement years—if his current company, Unity Biotechnology, turns out to a success.

Unity is a Bay Area-based company developing drugs to treat specific diseases that accompany aging, where David is cofounder and president, This past fall, the company announced $116 million in Series B funding from some big names, including Venrock, ARCH Venture Partners (where David is a partner), and Jeff Bezos’ venture fund Bezos Expeditions. Other investors include Mayo Clinic Ventures—Unity cofounder and Mayo Clinic researcher Jan van Deursen published some of the key science undergirding the startup—and Founders Fund, run by life-extension enthusiast Peter Thiel.

 Unity is the best bet among the growing number of companies taking aim at aging to actually get a drug to market. At an event on the “business of longevity” hosted in San Francisco last month by The Economist, Laura Deming (a biology prodigy, venture capitalist, and Thiel acolyte) singled out Unity as one of the most exciting companies in a space that’s gone from fringe science to hot new field thanks to high profile endeavors like Alphabet’s Calico. Deming’s enthusiasm is backed by money she invested through The Longevity Fund; she thinks Unity is the best bet among the growing number of companies taking aim at aging to actually get a drug to market.

The company’s approach is deceptively simple: clearing the body of senescent cells, which are trapped in a state of purgatory between division and death—they’re still alive, but they’re not making new tissues. Cells in this mode are found throughout the body, and research has shown that they can congregate in areas that start to wear with aging, like the eyes and in joints. A recent paper in Science, coauthored by Unity founders Van Deursen and Judith Campisi of the Buck Institute for Research on Aging, demonstrated that, in mice, senescent cells contribute to atherosclerosis, the buildup of plaque in the arteries.

In 2011, Van Deursen’s team at the Mayo Clinic published research in Nature showing that when scientists regularly eliminate senescent cells from mice, the animals remain youthful longer; older mice who got similar treatment appeared to stop aging, based on measures of their mobility, muscle mass, and fat storage.

These two mice are siblings, born in the same litter. (Their age is equivalent to 70 human years.) But the mouse on the right had its senescent cells regularly cleared, while the—much more sickly—one on the left did not.
These two mice are siblings, born in the same litter. (Their age is equivalent to 70 human years.) But the mouse on the right had its senescent cells regularly cleared, while the—much more sickly—one on the left did not. (Unity Biotechnology)

When David saw the paper, he knew had to talk to the authors. Within 72 hours, he and Van Deursen were discussing forming a company. “This is my sixth company,” says David, who previously started three other biotechs, as well as two energy businesses. “You get kind of pattern recognition on things that feel ‘druggable.’”

Prior to Unity, he founded Syrrx in the late 1990s as he was finishing his Ph.D. in molecular and cellular biology at the University of California, Berkeley. The company developed the Type 2 diabetes drug alogliptin, sold as Nesina in the US and Vipidia in Europe. The Japanese pharma giant Takeda bought Syrrx in 2005 for $270 million. Next, he started Achaogen, which David says is now close to getting regulatory approval to sell a new antibiotic that can be deployed against bacteria that are resistant to carbapenems. (Carbapenems are a “last resort” class of antibiotics that are still effective against multi-drug-resistant bugs typically found in hospitals—though there’s evidence to suggest bacteria are beginning to develop resistance to even them.)

David was also part of the team at Kythera Biopharmaceuticals, bought in 2015 by Allergan for $2.1 billion. Kythera’s claim to fame was the development of Kybella, a drug for double chins that literally explodes fat cells.

 “Eight weeks in indescribable medieval pain is somehow more valuable than feeling sexy again” “We go around saying that it’s morally praiseworthy to make a drug that costs $150,000 that extends people who are on salvage chemotherapy who have eight weeks to live to get them another eight weeks in horrible pain,” David says, defending Kybella’s importance. “And yet we somehow socially argue that making a woman feel beautiful again, or a man for that matter, is somehow morally less valuable than extending a human life that has really lost its high quality. Eight weeks in indescribable medieval pain is somehow more valuable than feeling sexy again, than feeling socially comfortable again.”

While the Food and Drug Administration considers double chins a reasonable therapeutic target for drug development, it doesn’t feel the same way about aging. So even though Van Duersen’s Mayo Clinic team showed this past February that clearing senescent cells from middle-aged mice led to a 20% increase in average lifespan versus control animals, Unity has to focus its therapies on certain conditions. Anyway, David bristles at the idea that Unity is an “anti-aging” company. The claim, he says, implies that biologists have already figured out what controls the fundamental ticking of the human aging clock. They haven’t. Meanwhile, David expects Unity to test its first drug, for osteoarthritis of the knee, in humans within 18 months.

Right now, patients with OA of the knee typically get cortisone injections into the joint every few months to treat the pain. Those shots appear to temporarily shut down senescent cells’ ability to secrete proteins that cause inflammation, which essentially is the immune system turning on normal tissue, resulting in damage and stiffness. UNITY’s drug will be delivered similarly through regularly scheduled injections, but would instead trigger the cells’ deaths. Since the offending cells would be gone instead of temporarily muted, their injection could be given every year or two. David says Unity’s has been shown to grow new cartilage in knees treated in a lab dish—a tantalizing first step toward maybe reversing osteoarthritis in humans.

If you had to pick one medical indication or element associated with aging to go after, says Matt Kaerberlein, an expert in the biology of aging at the University of Washington, “osteoarthritis is a great place to be. It’s a specific indication, but it’s a indication that could have a huge impact of quality of life for a lot of people.”

 David expects Unity to test its first drug, for osteoarthritis of the knee, in humans within 18 months. Other symptoms of aging could also be solved with Unity’s approach: David estimates that drugs targeting the senescent cells that play a role in glaucoma and age-related macular degeneration in the eye are about three to six months behind the osteoarthritis therapy. Unity is also developing treatments for atherosclerosis.

There are concerns about side effects. For one, senescent cells also play a role in preventing cancer: cells can go into senescence to avoid become cancerous, acting as a sort of cancer emergency brake. David says the key is to make sure that Unity’s drugs don’t “screw with the emergency brake.” In other words, the company’s therapies must avoid preventing cells from becoming senescent, and rather just eliminate them once they’ve gone down that path.

Second, senescent cells play a role in healing wounds, and are often recruited to areas in the body where there’s been trauma. Research done by Unity cofounder Campisi has shown that in animals without senescent cells, wounds take longer to heal. Amaia Lujambio, an oncologist at the Icahn School of Medicine at Mount Sinai, says that a challenge facing Unity is figuring out dosing and treatment schedules to ensure that some senescent cells are available to restore tissues. “I don’t think the drugs are going to be so potent and specific that they are going to cause too much trouble,” she says.

For David, the serial entrepreneur, the science behind Unity is simply irresistible. And the excitement in his voice is audible when he talks about people aging in calendar years without deteriorating physically‚ as he watched happen dramatically to his father. While David doesn’t believe that his company’s therapies will radically increase lifespan, he does see an opportunity to profoundly extend “health span”—body part by body part. “Rather than dying at age 83, demented and catheterized in your bed, how’d you like to die at 107 on the tennis court while winning or be killed by a jealous lover at 112?” he says. “That’s in the realm of the possible with this biology.”

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