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寻找长寿药方,科学家拿狗做试验

更新时间:2016-5-19 7:37:24 来源:纽约时报中文网 作者:佚名

Dogs Test Drug Aimed at Humans’ Biggest Killer: Age
寻找长寿药方,科学家拿狗做试验

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.

自去年夏天以来,林恩·格默尔(Lynn Gemmell)的狗贝拉(Bela)就成为遛狗公园的常客密切关注的对象。当时贝拉开始接受一项药物测试,这种药物显示可以大大延长实验室小鼠的寿命。

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.

8岁的贝拉是博德牧羊犬和澳大利亚牧羊犬杂交的后代。有些人坚称它又变成了小狗——“看她接球接得多快啊!”——格默尔尽量不去听信。一来,贝拉接受的药物或许只是安慰剂。

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.

二来,尽管这种名为雷帕霉素的药物在年龄比较大的实验室小鼠身上起到了作用,可以改善其心脏健康水平,似乎也能延迟它们患上一些疾病的时间,但它或许无法在狗身上也取得同样神奇的效果。而且,这种药也有可能弊大于利。“只是为了看看用在狗身上会有什么副作用,”格默恩告诉这些对贝拉心存好意的人。

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.

从技术层面讲,这是事实。但这项试验代表着测试改善人类健康方案的新阵地:与其只为随着衰老会患上的各种疾病寻求治疗方案,不如将目标放在有关衰老本身的生物学研究上。

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.

尽管在发达国家夺取最多生命的那些疾病——心脏病、脑卒中、阿尔茨海默病、糖尿病、癌症——有各种不同的直接起因,但衰老是罹患所有这些疾病的主要风险因素。流行病学家表示,这意味着,即便这些疾病的治疗出现突破,哪怕对个人而言有多么重大,也只会平均延长四五年的寿命,其中有些年还很可能会生活在疾病的阴影下。

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.

不过,支持衰老基础生物学——他们称为“老年科学”——研究的科学家表示,这一领域遭到了生物医学界权威人士的漠视。但华盛顿大学的研究人员注意到,向爱狗人士展示可以延缓宠物的衰老这样一种观念,或许可以为他们赢得公众的支持,也可能带来新的数据。

“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.”

“我们这些在衰老生物学领域做研究的人,有不少觉得,考虑到它对人类健康可能产生的潜在影响,这方面的研究资金是缺乏的,”克贝尔莱茵说。他自己支付了这项研究的部分花销,用的钱是华盛顿大学因他拒绝了另一个工作机会而给予的奖金。“如果很多宠物主人觉得存在一种可以大大延迟自家宠物衰老时间的方法,就可能开始会对决策产生影响。”

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.

资源或许更应该用来尝试延缓衰老而非治疗疾病这种观念,同大多数与疾病相关的慈善事业背道而驰,也与奥巴马政府提出的花10亿美元攻克癌症的“登月”计划相左。很多科学家表示,它还远远没有得到验证,不足以获得更多投资。

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.

该领域的研究人员则表示,如果他们能更清晰地向国会和大众解释有关衰老的基础研究为何很有用,或许便能更好地证明自己。

“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.

我们大多数人怀着这样一种直觉:我们之所以衰老,只是因为身体遭到了损耗,就像我们的汽车、家具和我们的耐心一样。但生物学家表示,能最好反驳生命周期不可改变这种观念的证据一直都显而易见:生物衰老的速度可以是天差地别的。

“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.”

“在我家附近生活的松鼠有25年的寿命,但和它们看起来长得差不多的老鼠只能活两年,”衰老生物学研究领域的先驱、来自哈佛医学院的加里·鲁夫库恩(Gary Ruvkun)说。“如果看看自然界选择了什么,容许什么,就能明白你或许可以获得各种能够改变现状的杠杆。”

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.

这种抱负在20世纪90年代和21世纪初获得了更多关注与支持。掌握了新的分子生物学工具的科学家开始集中精力研究复杂的细胞通路——很多物种的寿命就是由这些细胞通路控制的。通过移除生成某些蛋白质的基因,或加入生成其他蛋白质的基因,研究者们发现,他们能极大延长简单的实验室生物的寿命,比如芽殖酵母、蛔虫和苍蝇。

“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.”

“不只是逐渐损耗,而是一个程序,”鲁夫库恩说,“遗传学向我们表明了这一点。我们能施加一些简单的干预,从而对它进行调节——这就是程序。”

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.

由于人类的基因不易操纵,2006年的一项发现就显得很重要:克贝尔莱因等人发现,雷帕霉素能抑制酵母中的一种关键蛋白质,从而在不移除基因的前提下延长寿命。人们知道这种蛋白质参与细胞生长,但不清楚为什么抑制它能延长生命,因此让人担心它可能存在未知的负面作用。这种药目前正在狗身上试验。

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.

狗比人衰老得更快,大型狗比小型狗衰老得更快。参与雷帕霉素试验的40只狗都是至少6岁,体重至少40磅。这项研究刚在西雅图完成了初试阶段。

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.

林恩·格默尔的贝拉胆固醇偏高。参与实验的其他很多狗也像贝拉一样,表现出衰老的迹象:皮肤松弛,鼻口发灰,关节僵硬。它们的主人中有些也是这样。

“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.

“你怎么能确保主人把药喂给狗了,而不是自己吃了?”58岁的格默尔第一次去这家兽医诊所时跟克贝尔莱因博士开玩笑说。贝拉在那里进行体检,还做了超声心动图,以检查心脏功能。这是一个标记,可以直观显示用药10周后的改善情况。

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.

格默尔是一家医院的人类临床试验研究协调员。贝拉12周大时被人救下,格默尔收养了它,当时并不知道自己需要陪它在户外待多长时间。现在,两个女儿都已成年,已经离婚的格默尔在天黑后回到家时,可以戴着头灯,拿着在黑暗中会闪光的球带贝拉出去玩。贝拉会戴着项圈灯。“我希望她能一直活下去,”她说。

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.

1500多名狗主人申请参与雷帕霉素试验,这项试验基于一系列对小鼠做的研究,第一项研究结果发表于2009年。雷帕霉素是用一种土壤细菌做成的,能将酵母、苍蝇和蠕虫的寿命延长约25%。

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.

随后发生了一个事后看来很走运的意外情况。研究者决定在小鼠身上进行试验时,一时找不到易于吸收的配方。结果,等试验开始时,那些小鼠已经20个月大了,大致相当于人的60岁。试验中,寿命最长的老鼠比对照组的多活了约12%的时间。这首次表明,这种药在生命后期服用依然有效。

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?

不过,对小鼠有用的药物经常对人无效。而且也很难去问啮齿类动物,它们的生活质量如何。根据剂量和服药时间的不同,会产生不同的副作用,包括口疮、白内障、胰岛素阻抗,对于雄性动物来说,还会有睾丸功能失常。没有人知道,服用这种药物的话,人的寿命是否也会成比例增长——人的寿命本来已经比老鼠长很多。有些研究者说,仅仅为了延缓衰老而在健康的人身上试验雷帕霉素或其他任何药物,都会引起严重担忧。如果一种药物让有些人寿命延长,却让另一些人寿命缩短,那该怎么办?。谁能心安理得地让一个健康人参与可能缩短寿命的试验呢?

“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.

上个月,他在一次科学会议上报告称,在狗身上没有观察到明显的副作用,即使是三种剂量中最高的那一种,也没有。试验结束时,与对照组的狗的心脏相比,服药狗的心脏泵血功能更强。这些研究者想招募450只狗进行更全面的五年期研究,但目前经费不够。

Even if the study provided positive results on all fronts, a human trial would carry risks.

即使这项研究在各方面的结果都是积极的,在人身上试验仍然可能有风险。

Dr. Kaeberlein, for one, said they would be worth it.

但作为一个支持者,克贝尔莱因博士说这值得一试。

“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.”

“我要说,我们应该愿意容忍一定程度的风险,如果回报是能延长20%至30%的健康寿命,”他说,“如果我们什么都不做,我们知道结果是什么。我们会生病,会死去。”

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