尋找長壽藥方 科學(xué)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 hasbeen shown to significantly lengthen the lives oflaboratory mice, she has been the object of intensescrutiny among dog park regulars.

自去年夏天以來，林恩·格默爾(Lynn Gemmell)的狗貝拉(Bela)就成為遛狗公園的常客密切關(guān)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 intoa 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后代。有些人堅稱它又變成了小狗——“看她接球接得多快啊!”——格默爾盡量不去聽信。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 somediseases in older mice, may not work the same magic in dogs, for another. There is also achance 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，盡管這種名為雷帕霉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于利。“只是為了看看用在狗身上會有什么副作用，”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 propositionfor improving human health: Rather than only seeking treatments for the individual maladiesthat come with age, we might do better to target the biology that underlies aging itself.

從技術(shù)層面講，這是事實。但這項試驗代表著測試改善人類健康方案的新陣地：與其只為隨著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(guān)衰老本身的生物學(xué)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 factorfor all of them. That means that even treatment breakthroughs in these areas, no matter howvital to individuals, would yield on average four or five more years of life, epidemiologists say,and some of them likely shadowed by illness.

盡管在發(fā)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、癌癥——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(xué)家表示，這意味著，即便這些疾病的治療出現(xiàn)突破，哪怕對個人而言有多么重大，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 severalmajor diseases at once. A handful of drugs tested by federally funded laboratories in recentyears appear to extend the healthy lives of mice, with rapamycin and its derivatives, approvedby the Food and Drug Administration for organ transplant patients and to treat some types ofcancer, so far proving the most effective. In a 2014 study by the drug company Novartis, thedrug appeared to bolster the immune system in older patients. And the early results in agingdogs suggest that rapamycin is helping them, too, said Matt Kaeberlein, a biology of agingresearcher at the University of Washington who is running the study with a colleague, DanielPromislow.

這里的邏輯是，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(fā)生。最近幾年，由美國聯(lián)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，其中雷帕霉素及其衍生物目前被證明效果最好。這種藥物經(jīng)過了美國食品與藥品管理局(Food and Drug Administration)的批準，可以給接受器官移植的病人使用，或用來治療某些癌癥。制藥公司諾華(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(tǒng)。在華盛頓大學(xué)(University of Washington)從事衰老生物學(xué)研究的馬特·克貝爾萊茵(MattKaeberlein)表示，針對老年狗的早期實驗結(jié)果也顯示，雷帕霉素對它們有幫助?？素悹柸R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 loston the University of Washington researchers that exposing dog lovers to the idea that agingcould be delayed might generate popular support in addition to new data.

不過，支持衰老基礎(chǔ)生物學(xué)——他們稱為“老年科學(xué)”——研究的科學(xué)家表示，這一領(lǐng)域遭到了生物醫(yī)學(xué)界權(quán)威人士的漠視。但華盛頓大學(xué)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，或許可以為他們贏得公眾的支持，也可能帶來新的數(shù)據(jù)。

“Many of us in the biology of aging field feel like it is underfunded relative to the potentialimpact on human health this could have,” said Dr. Kaeberlein, who helped pay for the studywith funds he received from the university for turning down a competing job offer. “If theaverage pet owner sees there’s a way to significantly delay aging in their pet, maybe it willbegin to impact policy decisions.”

“我們這些在衰老生物學(xué)領(lǐng)域做研究的人，有不少覺得，考慮到它對人類健康可能產(chǎn)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(xué)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(chǎn)生影響。”

The idea that resources might be better spent trying to delay aging rather than to curediseases flies in the face of most disease-related philanthropy and the Obamaadministration’s proposal to spend $1 billion on a “cancer moonshot.” And many scientistssay it is still too unproven to merit more investment.

資源或許更應(yīng)該用來嘗試延緩衰老而非治療疾病這種觀念，同大多數(shù)與疾病相關(guān)的慈善事業(yè)背道而馳，也與奧巴馬政府提出的花10億美元攻克癌癥的“登月”計劃相左。很多科學(xué)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 couldbetter explain to Congress and the public why basic research on aging could be useful.

該領(lǐng)域的研究人員則表示，如果他們能更清晰地向國會和大眾解釋有關(guān)衰老的基礎(chǔ)研究為何很有用，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‘我的親人死于心梗，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(yīng)該捐錢讓他們做有關(guān)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, biologistssay, has long been evident: Living things age at significantly different rates.

我們大多數(shù)人懷著這樣一種直覺：我們之所以衰老，只是因為身體遭到了損耗，就像我們的汽車、家具和我們的耐心一樣。但生物學(xué)家表示，能最好反駁生命周期不可改變這種觀念的證據(jù)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 twoyears,” said Gary Ruvkun, a pioneer in aging biology at Harvard Medical School. “If you look atwhat nature has selected for and allowed, it suggests that you might be able to get your handson 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(xué)研究領(lǐng)域的先驅(qū)、來自哈佛醫(yī)學(xué)院的加里·魯夫庫恩(Gary Ruvkun)說。“如果看看自然界選擇了什么，容許什么，就能明白你或許可以獲得各種能夠改變現(xiàn)狀的杠桿。”

That aspiration gained traction in the 1990s and 2000s, when scientists, armed with newtools of molecular biology, homed in on the complex cellular pathways that regulate lifespan in many species. By removing genes that produced certain proteins, or adding genesthat produced others, researchers found they could significantly extend the lives of simplelaboratory 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(guān)注與支持。掌握了新的分子生物學(xué)工具的科學(xué)家開始集中精力研究復(fù)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(zhì)的基因，或加入生成其他蛋白質(zhì)的基因，研究者們發(fā)現(xiàn)，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 youcan 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(xué)向我們表明了這一點。我們能施加一些簡單的干預(yù)，從而對它進行調(diào)節(jié)——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 withoutremoving a gene. The protein is known to be involved in cell growth. But just how itssuppression works to extend life is still unclear, raising questions about potential unknowndownsides.

由于人類的基因不易操縱，2006年的一項發(fā)現(xiàn)就顯得很重要：克貝爾萊因等人發(fā)現(xiàn)，雷帕霉素能抑制酵母中的一種關(guān)鍵蛋白質(zhì)，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(zhì)參與細胞生長，但不清楚為什么抑制它能延長生命，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 thatparticipated in the rapamycin trial, which just concluded its pilot run in Seattle, had to be atleast 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。參與雷帕霉素試驗的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 ofaging: 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(xiàn)出衰老的跡象：皮膚松弛，鼻口發(fā)灰，關(guān)節(jié)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 takingit themselves?” Ms. Gemmell, 58, joked with Dr. Kaeberlein on her first visit to the veterinaryclinic, where Bela was given a checkup and an echocardiogram to measure heart function, amarker that could conceivably register an improvement over the 10 weeks that she would begiven the drug.

“你怎么能確保主人把藥喂給狗了，而不是自己吃了?”58歲的格默爾第一次去這家獸醫(yī)診所時跟克貝爾萊因博士開玩笑說。貝拉在那里進行體檢，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周后的改善情況。

A research coordinator for human clinical trials at a hospital, Ms. Gemmell adopted Bela as a12-week-old rescue without realizing how much outdoor time she would need with her. Nowdivorced with two grown daughters, Ms. Gemmell dons a headlamp when she returns home inthe dark, and takes Bela out with a glow-in-the-dark ball and a collar light. “I wish she couldlive forever,” she said.

格默爾是一家醫(yī)院的人類臨床試驗研究協(xié)調(diào)員。貝拉12周大時被人救下，格默爾收養(yǎng)了它，當時并不知道自己需要陪它在戶外待多長時間?，F(xiàn)在，兩個女兒都已成年，已經(jīng)離婚的格默爾在天黑后回到家時，可以戴著頭燈，拿著在黑暗中會閃光的球帶貝拉出去玩。貝拉會戴著項圈燈。“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 aseries of studies in mice, the first of which was published in 2009. Made by a type of soilbacterium, rapamycin has extended the life spans of yeast, flies and worms by about 25percent.

1500多名狗主人申請參與雷帕霉素試驗，這項試驗基于一系列對小鼠做的研究，第一項研究結(jié)果發(fā)表于2009年。雷帕霉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 hadtrouble formulating it for easy consumption. As a result, the mice were 20 months old — theequivalent of about 60 human years — when the trial began. That the longest-lived micesurvived about 12 percent longer than the control groups was the first indication that thedrug could be given later in life and still be effective.

隨后發(fā)生了一個事后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，一時找不到易于吸收的配方。結(jié)果，等試驗開始時，那些小鼠已經(jīng)20個月大了，大致相當于人的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 theirquality 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 knowsif 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, inhealthy people just to slow aging. What if a drug lengthened life for some and shortened it forothers? Could anyone ethically put a healthy person into a test that might actually shorten lifespan?

不過，對小鼠有用的藥物經(jīng)常對人無效。而且也很難去問嚙齒類動物，它們的生活質(zhì)量如何。根據(jù)劑量和服藥時間的不同，會產(chǎn)生不同的副作用，包括口瘡、白內(nèi)障、胰島素阻抗，對于雄性動物來說，還會有睪丸功能失常。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(jīng)比老鼠長很多。有些研究者說，僅僅為了延緩衰老而在健康的人身上試驗雷帕霉素或其他任何藥物，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，那該怎么辦?。誰能心安理得地讓一個健康人參與可能縮短壽命的試驗?zāi)?

“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, whorecently raised the questions in Nature, a scientific journal.

“它不像癌癥那么簡單，病人不試這種藥也會死，”加州大學(xué)伯克利分校(University of California, Berkeley)的衰老生物學(xué)研究員安德魯·迪林(Andrew Dillin)說。前不久，他在科學(xué)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 longconsidered the sad fact that their pets age about seven times as fast as they do, Dr. Kaeberleinknew, 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 pilotphase 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(shù)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(愛狗的人一直認為這是個可悲的事實)，卻可以給雷帕霉素研究帶來福音。而這項研究會對人和狗都產(chǎn)生影響?？素悹柸R因博士本人養(yǎng)了兩只狗，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 beenobserved in the dogs, even at the highest of three doses. And compared with the hearts of dogsin the control group, the hearts of those taking the drug pumped blood more efficiently atthe end. The researchers would like to enroll 450 dogs for a more comprehensive five-yearstudy, but do not yet have the money.

上個月，他在一次科學(xué)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(jié)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(jīng)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(jié)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.

但作為一個支持者，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 30percent increase in healthy longevity,” he said. “If we don’t do anything, we know what theoutcome is going to be. You’re going to get sick, and you’re going to die.”

“我要說，我們應(yīng)該愿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，“如果我們什么都不做，我們知道結(jié)果是什么。我們會生病，會死去。”