UW researchers test drug to extend dogs’ years
Originally published May 16, 2016 at 4:32 pm Updated May 17, 2016 at 6:28 am
The drug rapamycin, which lengthened the lives of laboratory mice, is being tested on dogs [at]University of Washington scientists look for alternatives to treating the individual maladies that come with age in humans.
By Amy Harmon
The New York Times
Ever since last summer, when Lynn Gemmell’s dog was inducted into the Seattle trial of a drug that has been shown to significantly lengthen the lives of laboratory mice, she has been the object of intense scrutiny among dog-park regulars.
To those who insist that Bela, 8, has turned back into a puppy — “Look how fast she’s getting that ball!” — Gemmell has tried to turn a deaf ear. Bela, a border collie-Australian shepherd mix, may have been given a placebo, for one thing.
The drug, rapamycin, which improved the heart health and appeared to delay the onset of some diseases in older mice, may not work the same magic in dogs, for another. There is also a chance it could do more harm than good.
“This is just to look for side effects, in dogs,” Gemmell told Bela’s many well-wishers.
Technically that is true. But the trial, which just concluded its pilot run in Seattle, also represents a new frontier in testing a proposition for improving human health: Rather than seeking treatments for the individual maladies that come with age, we might do better to target the biology that underlies aging itself.
While the diseases that now kill most people in developed nations — heart disease, stroke, Alzheimer’s, diabetes, cancer — have different immediate causes, age is the major risk factor for all of them. That means that even breakthroughs in these areas, no matter how vital to individuals, would yield on average four or five more years of life, epidemiologists say, and some of them likely shadowed by illness.
A drug that slows aging, the logic goes, might instead serve to delay the onset of several major diseases at once. A handful of drugs tested by federally funded laboratories in recent years appear to extend the healthy life span of mice, with rapamycin, approved by the Food and Drug Administration to treat organ transplant patients and some types of cancer so far proving the most effective.
In a 2014 study by the drug company Novartis, the drug appeared to bolster the immune system in older patients. And the early results in aging dogs suggest that rapamycin is helping them, too, said Matt Kaeberlein, a biology of aging researcher at the University of Washington who is running the study with a colleague, Daniel Promislow.
But scientists who champion the study of aging’s basic biology — they call it “geroscience” — say their field has received short shrift from the biomedical establishment. And it was not lost on the UW researchers that exposing dog lovers to the idea that aging could be delayed might generate popular support in addition to new data.
“Many of us in the biology of aging field feel like it is underfunded relative to the potential impact on human health this could have,” said Kaeberlein, who helped pay for the study with funds he received from the university for turning down a competing job offer. “If the average pet owner sees there’s a way to significantly delay aging in their pet, maybe it will begin to impact policy decisions.”
The idea that resources might be better spent trying to delay aging rather than cure diseases flies in the face of most disease-related philanthropy, not to mention the Obama administration’s proposal to spend $1 billion on a “cancer moonshot.” And many scientists say it is still too unproven to merit more investment.
Researchers in the field, in turn, say they might have more to show for themselves if they could better explain to Congress and the public why basic research on aging could be useful.
“People understand ‘my relative died of a heart attack, so I’m going to give money to that,’ ” said James L. Kirkland, a Mayo Clinic researcher. “It’s harder to grasp ‘my relative was older, that predisposes them to have a heart attack, so I should give money to research on aging.’ ”
Aging in mouse and dog years
In 2006, Kaeberlein and others demonstrated that rapamycin, the drug now being tested in dogs, suppressed one of the crucial proteins in yeast, resulting in a longer life span without removing a gene. The protein is known to be involved in cell growth. But just how its suppression works to extend life is still unclear, raising questions about potential unknown downsides.
Dogs age faster than humans, and bigger dogs age faster than smaller dogs. The 40 dogs that participated in the rapamycin trial had to be at least 6 years old and weigh at least 40 pounds.
Like Lynn Gemmell’s Bela, whose cholesterol was high, many of them were showing signs of aging: loose skin, graying muzzles, a stiffness in the joints. So were some of their owners.
“How are you going to be sure people are going to be giving this to their dog rather than taking it themselves?” Gemmell, 58, joked with Kaeberlein on her first visit to the veterinary clinic, where Bela was given a checkup and an echocardiogram to measure heart function, a marker that could conceivably register an improvement over the 10 weeks that she would be given the drug.
A research coordinator for human clinical trials at a hospital, Gemmell adopted Bela as a 12-week-old rescue without realizing how much outdoor time she would need with her. Now divorced with two grown daughters, Gemmell dons a headlamp when she returns home in the dark, and takes Bela out with a glow-in-the-dark ball and a collar light. “I wish she could live forever,” she said.
She is not alone. Over 1,500 dog owners applied to participate in the trial of rapamycin, which has its roots in a series of studies in mice, the first of which was published in 2009.
Ethical questions
Made by a type of soil bacteria, rapamycin has extended the life spans of yeast, flies and worms by about 25 percent.
But in what proved a fortuitous accident, the researchers who set out to test it in mice had trouble formulating it for easy consumption. As a result, the mice were 20 months old — the equivalent of about 60 human years — when the trial began. That the longest-lived mice survived about 12 percent longer than the control groups was the first indication that the drug could be given later in life and still be effective.
Kaeberlein said he had since achieved similar benefits by giving 20-month-old mice the drug for only three months. (The National Institute on Aging rejected his request for funding to further test that treatment.) Younger mice, given higher doses, have lived about 25 percent longer than those not given the drug, and mice of varying ages and genetic backgrounds have been slower to develop some cancers, kidney disease, obesity and symptoms of Alzheimer’s disease. In one study, their hearts functioned better for longer.
“If you do the extrapolation for people, we’re probably talking a couple of decades, with the expectation that those years are going to be spent in relatively good health,” Kaeberlein said.
Still, drugs that work in mice often fail in humans. It is also hard to ask rodents about their quality of life. The side effects, depending on the dose and duration, include mouth sores, cataracts, insulin resistance and, for males, problems with testicular function. No one knows if people, who already live a lot longer than mice, would see a proportional increase in life span.
And some researchers say there would be serious concerns in testing rapamycin, or any drug, in healthy people just to slow aging. What if a drug lengthened life for some and shortened it for others? Could anyone ethically put a healthy person into a test that might actually shorten life span?
“It’s not as simple as cancer, where patients are going to die anyway if they don’t get the drug,” said Andrew Dillin, a biology of aging researcher at the University of California, Berkeley, who recently raised the questions in Nature, a scientific journal.
Ethical concerns aside, such a trial would take decades. But dog lovers have long known that pets age about seven times as fast as they do. And Kaeberlein knew that fact would be a boon for a study of rapamycin that would have implications for both species. An owner of two dogs himself, he was determined to scrounge up the money for the pilot phase of what he and Promislow called the Dog Aging Project.
Last month, he reported at a scientific meeting that no significant side effects had been observed in the dogs, even at the highest of three doses. And compared with dogs in the control group, the hearts of those taking the drug pumped blood more efficiently at the end. The researchers would like to enroll 450 dogs for a more comprehensive five-year study, but do not yet have the money to do it.
Even if the study provided positive results on all fronts, a human trial would carry risks.
Kaeberlein, for one, said they would be worth it.
“I would argue we should be willing to tolerate some level of risk if the payoff is 20 to 30 percent increase in healthy longevity,” he said. “If we don’t do anything, we know what the outcome is going to be. You’re going to get sick and you’re going to die.”
For her part, Gemmell is not counting on anything. The other night, when she got home from work, she was ready to read her mail and have a glass of wine. But Bela greeted her as usual, ball in her mouth, ready to play.
For now, she said, this is how they both plan to stay young.
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