尋找長壽藥方 科學家拿狗做試驗

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.

自去年夏天以來，林恩·格默爾(Lynn Gemmell)的狗貝拉(Bela)就成爲遛狗公園的常客密切關注的對象。當時貝拉開始接受一項藥物測試，這種藥物顯示可以大大延長實驗室小鼠的壽命。

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歲的貝拉是博德牧羊犬和澳大利亞牧羊犬雜交的後代。有些人堅稱它又變成了小狗——“看她接球接得多快啊！”——格默爾儘量不去聽信。一來，貝拉接受的藥物或許只是安慰劑。

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.

二來，儘管這種名爲雷帕黴素的藥物在年齡比較大的實驗室小鼠身上起到了作用，可以改善其心臟健康水平，似乎也能延遲它們患上一些疾病的時間，但它或許無法在狗身上也取得同樣神奇的效果。而且，這種藥也有可能弊大於利。“只是爲了看看用在狗身上會有什麼副作用，”格默恩告訴這些對貝拉心存好意的人。

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.

從技術層面講，這是事實。但這項試驗代表着測試改善人類健康方案的新陣地：與其只爲隨着衰老會患上的各種疾病尋求治療方案，不如將目標放在有關衰老本身的生物學研究上。

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.

儘管在發達國家奪取最多生命的那些疾病——心臟病、腦卒中、阿爾茨海默病、糖尿病、癌症——有各種不同的直接起因，但衰老是罹患所有這些疾病的主要風險因素。流行病學家表示，這意味着，即便這些疾病的治療出現突破，哪怕對個人而言有多麼重大，也只會平均延長四五年的壽命，其中有些年還很可能會生活在疾病的陰影下。

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.

這裏的邏輯是，可以減緩衰老的藥物或許能同時延遲好幾種重大疾病的發生。最近幾年，由美國聯邦政府資助的實驗室測試的幾種藥物似乎可以延長小鼠的健康壽命，其中雷帕黴素及其衍生物目前被證明效果最好。這種藥物經過了美國食品與藥品管理局(Food and Drug Administration)的批准，可以給接受器官移植的病人使用，或用來治療某些癌症。製藥公司諾華(Novartis)在2014年進行的一項研究顯示，它似乎可以增強老年病人的免疫系統。在華盛頓大學(University of Washington)從事衰老生物學研究的馬特·克貝爾萊茵(Matt Kaeberlein)表示，針對老年狗的早期實驗結果也顯示，雷帕黴素對它們有幫助。克貝爾萊茵在和同事丹尼爾·普羅米斯洛( Daniel Promislow)一起牽頭進行這項研究。

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.

不過，支持衰老基礎生物學——他們稱爲“老年科學”——研究的科學家表示，這一領域遭到了生物醫學界權威人士的漠視。但華盛頓大學的研究人員注意到，向愛狗人士展示可以延緩寵物的衰老這樣一種觀念，或許可以爲他們贏得公衆的支持，也可能帶來新的數據。

“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.”

“我們這些在衰老生物學領域做研究的人，有不少覺得，考慮到它對人類健康可能產生的潛在影響，這方面的研究資金是缺乏的，”克貝爾萊茵說。他自己支付了這項研究的部分花銷，用的錢是華盛頓大學因他拒絕了另一個工作機會而給予的獎金。“如果很多寵物主人覺得存在一種可以大大延遲自家寵物衰老時間的方法，就可能開始會對決策產生影響。”

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.

資源或許更應該用來嘗試延緩衰老而非治療疾病這種觀念，同大多數與疾病相關的慈善事業背道而馳，也與奧巴馬政府提出的花10億美元攻克癌症的“登月”計劃相左。很多科學家表示，它還遠遠沒有得到驗證，不足以獲得更多投資。

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.

該領域的研究人員則表示，如果他們能更清晰地向國會和大衆解釋有關衰老的基礎研究爲何很有用，或許便能更好地證明自己。

“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.’ ”

“人們可以理解‘我的親人死於心梗，所以我要給這方面的研究捐錢，’”梅奧診所(Mayo Clinic)的研究員詹姆斯·L·柯克蘭博士(James L. Kirkland)說。“更難被人理解的是，‘我的親人年紀大了，就會更容易心梗，所以我應該捐錢讓他們做有關衰老的研究。’”

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.

我們大多數人懷着這樣一種直覺：我們之所以衰老，只是因爲身體遭到了損耗，就像我們的汽車、傢俱和我們的耐心一樣。但生物學家表示，能最好反駁生命週期不可改變這種觀念的證據一直都顯而易見：生物衰老的速度可以是天差地別的。

“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年的壽命，但和它們看起來長得差不多的老鼠只能活兩年，”衰老生物學研究領域的先驅、來自哈佛醫學院的加里·魯夫庫恩(Gary Ruvkun)說。“如果看看自然界選擇了什麼，容許什麼，就能明白你或許可以獲得各種能夠改變現狀的槓桿。”

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.

這種抱負在20世紀90年代和21世紀初獲得了更多關注與支持。掌握了新的分子生物學工具的科學家開始集中精力研究複雜的細胞通路——很多物種的壽命就是由這些細胞通路控制的。通過移除生成某些蛋白質的基因，或加入生成其他蛋白質的基因，研究者們發現，他們能極大延長簡單的實驗室生物的壽命，比如芽殖酵母、蛔蟲和蒼蠅。

“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.”

“不只是逐漸損耗，而是一個程序，”魯夫庫恩說，“遺傳學向我們表明了這一點。我們能施加一些簡單的干預，從而對它進行調節——這就是程序。”

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.

由於人類的基因不易操縱，2006年的一項發現就顯得很重要：克貝爾萊因等人發現，雷帕黴素能抑制酵母中的一種關鍵蛋白質，從而在不移除基因的前提下延長壽命。人們知道這種蛋白質參與細胞生長，但不清楚爲什麼抑制它能延長生命，因此讓人擔心它可能存在未知的負面作用。這種藥目前正在狗身上試驗。

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。參與雷帕黴素試驗的40只狗都是至少6歲，體重至少40磅。這項研究剛在西雅圖完成了初試階段。

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·格默爾的貝拉膽固醇偏高。參與實驗的其他很多狗也像貝拉一樣，表現出衰老的跡象：皮膚鬆弛，鼻口發灰，關節僵硬。它們的主人中有些也是這樣。

“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.

“你怎麼能確保主人把藥餵給狗了，而不是自己吃了？”58歲的格默爾第一次去這家獸醫診所時跟克貝爾萊因博士開玩笑說。貝拉在那裏進行體檢，還做了超聲心動圖，以檢查心臟功能。這是一個標記，可以直觀顯示用藥10周後的改善情況。

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.

格默爾是一家醫院的人類臨牀試驗研究協調員。貝拉12周大時被人救下，格默爾收養了它，當時並不知道自己需要陪它在戶外待多長時間。現在，兩個女兒都已成年，已經離婚的格默爾在天黑後回到家時，可以戴着頭燈，拿着在黑暗中會閃光的球帶貝拉出去玩。貝拉會戴着項圈燈。“我希望她能一直活下去，”她說。

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多名狗主人申請參與雷帕黴素試驗，這項試驗基於一系列對小鼠做的研究，第一項研究結果發表於2009年。雷帕黴素是用一種土壤細菌做成的，能將酵母、蒼蠅和蠕蟲的壽命延長約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.

隨後發生了一個事後看來很走運的意外情況。研究者決定在小鼠身上進行試驗時，一時找不到易於吸收的配方。結果，等試驗開始時，那些小鼠已經20個月大了，大致相當於人的60歲。試驗中，壽命最長的老鼠比對照組的多活了約12%的時間。這首次表明，這種藥在生命後期服用依然有效。

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?

不過，對小鼠有用的藥物經常對人無效。而且也很難去問齧齒類動物，它們的生活質量如何。根據劑量和服藥時間的不同，會產生不同的副作用，包括口瘡、白內障、胰島素阻抗，對於雄性動物來說，還會有睾丸功能失常。沒有人知道，服用這種藥物的話，人的壽命是否也會成比例增長——人的壽命本來已經比老鼠長很多。有些研究者說，僅僅爲了延緩衰老而在健康的人身上試驗雷帕黴素或其他任何藥物，都會引起嚴重擔憂。如果一種藥物讓有些人壽命延長，卻讓另一些人壽命縮短，那該怎麼辦？。誰能心安理得地讓一個健康人蔘與可能縮短壽命的試驗呢？

“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.

“它不像癌症那麼簡單，病人不試這種藥也會死，”加州大學伯克利分校(University of California, Berkeley)的衰老生物學研究員安德魯·迪林(Andrew Dillin)說。前不久，他在科學期刊《自然》(Nature)上提出了這些問題。

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.

姑且不談道德顧慮，這樣的試驗需要花費數十年時間。但克貝爾萊因博士知道，狗的衰老速度基本是人的七倍這一點（愛狗的人一直認爲這是個可悲的事實），卻可以給雷帕黴素研究帶來福音。而這項研究會對人和狗都產生影響。克貝爾萊因博士本人養了兩隻狗，他下定決心籌到資金進行他和普羅米斯洛博士所說的狗狗衰老項目(Dog Aging Project)的初試階段。

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.

上個月，他在一次科學會議上報告稱，在狗身上沒有觀察到明顯的副作用，即使是三種劑量中最高的那一種，也沒有。試驗結束時，與對照組的狗的心臟相比，服藥狗的心臟泵血功能更強。這些研究者想招募450只狗進行更全面的五年期研究，但目前經費不夠。

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

即使這項研究在各方面的結果都是積極的，在人身上試驗仍然可能有風險。

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

但作爲一個支持者，克貝爾萊因博士說這值得一試。

“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.”

“我要說，我們應該願意容忍一定程度的風險，如果回報是能延長20%至30%的健康壽命，”他說，“如果我們什麼都不做，我們知道結果是什麼。我們會生病，會死去。”