Dogs Test Drug Aimed at Humans’ Biggest Killer: Age
Ever since last summer, when Lynn Gemmell’s dog, Bela, was inducted into the 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!” — Ms. 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 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,” Ms. Gemmell told Bela’s many well-wishers.
Technically that is true. But the trial also represents a new frontier in testing a proposition for improving human health: Rather than only 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 treatment 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 lives of mice, with rapamycin and its derivatives, approved by the Food and Drug Administration for organ transplant patients and to treat 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.
这里的逻辑是，可以减缓衰老的药物或许能同时延迟好几种重大疾病的发生。最近几年，由美国联邦政府资助的实验室测试的几种药物似乎可以延长小鼠的健康寿命，其中雷帕霉素及其衍生物目前被证明效果最好。这种药物经过了美国食品与药品管理局(Food and Drug Administration)的批准，可以给接受器官移植的病人使用，或用来治疗某些癌症。制药公司诺华(Novartis)在2014年进行的一项研究显示，它似乎可以增强老年病人的免疫系统。在华盛顿大学(University of Washington)从事衰老生物学研究的马特·克贝尔莱茵(Matt Kaeberlein)表示，针对老年狗的早期实验结果也显示，雷帕霉素对它们有帮助。克贝尔莱茵在和同事丹尼尔·普罗米斯洛( Daniel Promislow)一起牵头进行这项研究。
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 University of Washington 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 Dr. 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 to cure diseases flies in the face of most disease-related philanthropy and 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 Dr. 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.’ ”
“人们可以理解‘我的亲人死于心梗，所以我要给这方面的研究捐钱，’”梅奥诊所(Mayo Clinic)的研究员詹姆斯·L·柯克兰博士(James L. Kirkland)说。“更难被人理解的是，‘我的亲人年纪大了，就会更容易心梗，所以我应该捐钱让他们做有关衰老的研究。’”
Most of us harbor the intuition that we age because our bodies, like our cars, our furniture, our patience, just wear out. But the best argument that life span is not hard-wired, biologists say, has long been evident: Living things age at significantly different rates.
“The squirrels in my neighborhood have a 25-year life span, but they look like rats that live two years,” said Gary Ruvkun, a pioneer in aging biology at Harvard Medical School. “If you look at what nature has selected for and allowed, it suggests that you might be able to get your hands on the various levers that change things.”
That aspiration gained traction in the 1990s and 2000s, when scientists, armed with new tools of molecular biology, homed in on the complex cellular pathways that regulate life span in many species. By removing genes that produced certain proteins, or adding genes that produced others, researchers found they could significantly extend the lives of simple laboratory organisms like budding yeast, roundworms and flies.
“It’s not just wearing out, it’s a program,” Dr. Ruvkun said. “The genetics told us that. If you can modulate it with a few simple perturbations, that’s the definition of a program.”
Since genes cannot be so easily manipulated in humans, it was significant in 2006 when Dr. 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, which just concluded its pilot run in Seattle, 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?” Ms. Gemmell, 58, joked with Dr. 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, Ms. 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, Ms. 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.
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. Made by a type of soil bacterium, 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.
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.
“它不像癌症那么简单，病人不试这种药也会死，”加州大学伯克利分校(University of California, Berkeley)的衰老生物学研究员安德鲁·迪林(Andrew Dillin)说。前不久，他在科学期刊《自然》(Nature)上提出了这些问题。
Ethical concerns aside, such a trial would take decades. But what dog lovers have long considered the sad fact that their pets age about seven times as fast as they do, Dr. Kaeberlein knew, 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 Dr. Promislow called the Dog Aging Project.
姑且不谈道德顾虑，这样的试验需要花费数十年时间。但克贝尔莱因博士知道，狗的衰老速度基本是人的七倍这一点（爱狗的人一直认为这是个可悲的事实），却可以给雷帕霉素研究带来福音。而这项研究会对人和狗都产生影响。克贝尔莱因博士本人养了两只狗，他下定决心筹到资金进行他和普罗米斯洛博士所说的狗狗衰老项目(Dog Aging Project)的初试阶段。
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 the hearts of 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.
Even if the study provided positive results on all fronts, a human trial would carry risks.
Dr. 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.”