Rewriting Life

In New Anti-Aging Strategy, Clearing Out Old Cells Increases Life Span of Mice by 25 Percent

As we get older, some of our cells stop dividing. Are these derelicts a reason we age?

Can removing old, tired-out cells extend an animal’s life span?

That’s is the conclusion of first-of-a-kind study by researchers at the Mayo Clinic, which found that mice lived about 25 percent longer on average if so-called “senescent” cells were cleared out from their bodies.

The results, reported today in Nature, outline a possible new tactic for treating diseases including glaucoma, arthritis, and heart disease and potentially extending human life, according to lead author Jan van Deursen, a molecular biologist at the Mayo Clinic in Rochester, Minnesota.

The research is already the basis of a biotechnology company called Unity, cofounded by van Deursen and Judith Campisi, of the Buck Institute for Research on Aging, who has pursued related research.

These mice are siblings born in the same litter. Both are two years old, or about 65 in human years. The mouse on the right appears younger after receiving a new anti-aging treatment.

Nathaniel David, CEO of the startup, says the company has identified drugs that can kill senescent cells in lab animals. He said it would try to develop drugs for age-related disease and eventually hopes to create treatments to postpone aging.

This study isn’t the first to make mice live longer, although it does appear to be the first time the effect was achieved by targeting senescent cells. “Life span gains have been achieved in dozens of ways in mice by changing the diet, feeding drugs,” says Steven N. Austad, a biogerontologist who is chairman of the biology department of the University of Alabama in Birmingham. "We know lots and lots of ways to do it. This is a new way."

Cells become senescent when they stop dividing. Like grumpy old men on park benches, they hang around, not doing any particular job but coloring their surroundings. According to Austad, although the cells could have some beneficial effects, they’re believed to be mostly harmful. “These are cells that don’t die, but sit there and excrete all kind of molecules that degrade tissue,” he says.

The aging discovery came about by accident, van Deursen says, while he was studying cancer in “progeroid” mice genetically engineered to become old and develop tumors unnaturally fast. What he found was that if cells were blocked from entering a state of senescence, the early symptoms of old age were mostly avoided. “I just stumbled on something really, really interesting,” he says.

That work, published in 2011, offered compelling evidence of a link between senescence and aging symptoms. What wasn’t known until today’s result was whether eliminating senescent cells would also delay aging in normal mice.

To prove that, the team relied on genetic engineering, creating breeds of mice in which they could tag, and selectively destroy, any cell expressing a biomarker of senescence. When the mice were 12 months old, equivalent to around 45 in human years, they were injected with a drug that cleared away the marked cells.

Although the maximum age the mice lived to was not greatly altered—they didn’t turn into furry Methuselas—more of the treated mice than the untreated mice lived to a ripe old age. Van Deursen says the treated mice had an improved “health span”: they remained healthy for longer and seemed to develop cancer more slowly.

Although the genetic method would be hard to use in people, drugs could be developed to kill senescent cells. Unity, which is being funded by the venture firms Arch Venture Partners and Venrock, as well as the Mayo Clinic and the Chinese drug company Wuxi, says it is exploring whether deleting senescent cells can treat specific conditions like glaucoma, although “the big dream is a drug that extends health span,” says David.

He says it’s possible to imagine a person taking a drug to clear out inactive cells once every few years, starting in early middle age when senescent cells begin to accumulate. The company didn’t disclose how much money it had collected so far, but according to SEC documents in 2013, it raised around $2 million under an earlier name, Cenexys.

Because removing senescent cells could treat a range of ailments, Unity will attempt to raise and spend large sums of money to advance drugs into studies, says Robert Nelsen, the managing director of Arch, who has played a leading role in some recent high-profile startups including Juno Therapeutics as well as Grail, a $100 million effort to develop cancer blood tests announced this year.

David and Nelsen acknowledge that the hunt for anti-aging drugs has not yet proved successful, with earlier startups like Sirtris and Elixir Pharmaceuticals eventually flopping. But the idea remains irresistible. In 2013, Google announced a spinoff called Calico that it said would investigate how to defeat aging.

Nelsen, who also backed Elixir before it failed, says the science “wasn’t ready” 10 years ago but that seeing van Deursen’s new data was a “holy crap” moment, suggesting an entirely new way to treat disease. “It looks too good to be true, which is always why you take these things forward in a scientific manner,” says Nelsen. “But it reminds me of those very simple ideas that are usually the groundbreaking ones in biology.”

It’s still unclear why organisms age at different rates, but the rules of aging don't seem fixed. Even one species of clam can live 10 times as long as another. That is what keeps scientists returning to the question of whether human life span could be altered. “We know there are knobs on this biology that can be turned, because nature has turned them,” says David.

The evidence that senescent cells are the answer is hardly decisive, and some of it is conflicting. Van Deursen says animals that have cells removed “are much more exploratory and active than animals that don’t.” However no difference was seen in other traits associated with frailty, like strength, metabolism of glucose, overall coordination, or blood counts.

Developing an anti-aging treatment also remains difficult because the FDA does not recognize aging as a disease. And since humans live longer than 70 years on average, a clinical study would take decades.

Last year, such obstacles led another company, Elysium, an MIT spinout backed by several Nobel Prize winners, to simply market a nutritional supplement instead of waiting for proof its pill really forestalls aging. Nelsen, the venture capitalist behind Unity, says he takes the Elysium pill every morning.

Unity will follow a conventional approach. Rather than pursue an anti-aging treatment right away, the company will instead try to treat recognized diseases but keep an eye out for age reversal. “I think it’s better to study disease first and then see if there are side effects that extend life span,” van Deursen says.

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