传说秦始皇曾派徐福带领众童男女赴浩渺的东海探寻长生不老之方；自己也曾数次御驾亲征，不辞劳苦，最终中途死在沙丘，可谓执着。更兼大明几多帝王偏信方士术人蛊惑，吃仙丹，服迷药，无非都是为了益寿延年，永享富贵。

在实验室里，在包括酵母，线虫和小鼠等动物身上已证明有多种药物可以延长它们的寿命。但是，很多很有前景的药物却在人体验证时失败了。本周，研究人员正建议用宠物狗开展延寿药物效果的研究。实验药物为rapamycin，在临床上，这种药物是肾脏器官移植后抗免疫排斥系列药物中的一员，实验发现这种药物可以给雌鼠延寿13%，雄鼠延寿9% (Nature 460, 392–395; 2009)。

但是这种化合物的延寿作用尚未在人体开展过。人体试验花费高昂、且需要很长时间才能获得结论。另外，rapamycin已经过了专利有效期，药物公司不愿在它身上投入更多。rapamycin可能引起严重副作用，因此它可能不能成为“长寿泉”（fountain of youth）药物。例如，已在肾移植的病人发现这种药物可能增加患糖尿病风险(J. Am. Soc. Nephrol. 19, 1411–1418; 2008)。但是研究人员怀疑在低剂量情况下，这种药物或许不会在健康狗上招来这些副作用。

“任何化合物都一定程度上存在副作用，关键是什么样的副作用，是否可以接受”，德州圣安东尼奥Barshop长寿与衰老研究所（Barshop Institute for Longevity and Aging Studies）的老年医学家Randy Strong说。

西雅图华盛顿大学分子生物学家Matthew Kaeberlein和Daniel Promislow建议：给予家犬低剂量rapamycin，看是否可以在狗身上发挥延寿效应，同时评估其副作用情况。他们两人邀请了众多犬类健康专家和衰老生物学家参加十月28-29日在西雅图的会议，讨论如何构思开展这一试验。

研究人员希望在大量家犬上检测rapamycin的效果，家犬通常能活8到10年，他们将在动物活到6到9岁时给药。一个前期试验将先用30只家犬，其中一半给药，研究人员将用以在较短时间内观察心脏功能和其它健康指标，这一试验将在3年内完成。研究人员不必等到试验结束，他们可以在试验进行几个月后开始观察rapamycin是否提升了心肌功能和其它的健康指标。

Rapamycin通过作用于细胞生长的某蛋白发挥作用，但至于它如何发挥延寿作用还不得而知。它可能直接延缓了衰老进程，或阻滞了衰老相关疾病。其中一个假设是主要通过阻止肿瘤的发生。

宠物狗应该采用比实验小鼠更贴近实际的方式开展试验，以检测它是否在人体发挥作用。宠物狗经历很多与他们的主人相同的环境影响，瘰患与他们的主人相似的衰老相关疾病，Kaeberlein说。（他已经计划登记，等到自己的德国牧羊犬足够老后也让它参与此试验。）

其它研究者认为Kaeberlein和Promislow的论证很有道理。“我们正在谈论是否年老的宠物犬能从中受益，它们的确是替代人类的好模型。”缅因州巴港Jackson实验室的生理、遗传学家David Harrison说，他曾使用小鼠研究rapamycin的作用。

Kaeberlein和Promislow已经在华盛顿大学为先期试验募集了US$200,000。但他们需要更多的钱用于后续更大规模的试验：观察给药长达几年后是否能起到延寿作用，还要研究成千的动物以弄明白正常的衰老过程和延寿效应的可能机制。

西雅图会议与会者还在考虑宠物的主人是否能为大规模试验予以基金资助，如果这样，研究人员是否考虑在不损害研究信度的前提下，承诺给予他们的宠物rapamycin，而不是（分到对照组）仅给予安慰剂。通常，实验必须严格根据随机原则为处理组和对照组来分配动物。

 “这是一种很特殊的情况，因为试验动物是人的宠物” Kaeberlein说，“我们在具体如何操作这一研究上尚无定论。”

http://www.nature.com/news/pet-dogs-set-to-test-anti-ageing-drug-1.16237

Pet dogs set to test anti-ageing drug

Trials would study extension of lifespan in domestic setting.

Erika Check Hayden

Yeast, worms and mice: all have lived longer when treated with various chemical compounds in laboratory tests. But many promising leads have failed when tried in humans. This week, researchers are proposing a different approach to animal testing of life-extending drugs: trials in pet dogs. Their target is rapamycin, which is used clinically as part of an anti-rejection drug cocktail after kidney transplants and which has also been shown to extend the lives of mice by 13% in females and 9% in males (D. E. Harrison et al. Nature 460, 392–395; 2009).

The compound’s effect on lifespan has not yet been tested in people — human trials are expensive and it takes a long time to learn whether a drug can extend a human life. Furthermore, rapamycin is no longer patentable, so pharmaceutical companies are unwilling to invest effort in it. The drug can also cause some serious side effects that might rule it out as a pharmaceutical fountain of youth. It has, for example, been linked to an increased risk of diabetes in people who have had kidney transplants (O. Johnston et al. J. Am. Soc. Nephrol. 19, 1411–1418; 2008). But at low doses, researchers suspect that the drug will not be a problem for healthy dogs.

 “Any compound has side effects of some sort; the question is what kind of side effects one can live with,” says Randy Strong, a gerontologist at the Barshop Institute for Longevity and Aging Studies in San Antonio, Texas.

To answer that question, molecular biologists Matthew Kaeberlein and Daniel Promislow at the University of Washington in Seattle propose to give low doses of rapamycin to dogs in a study that would also test whether the drug can extend the animals’ lives. The pair invited experts in canine health and the biology of ageing to a meeting in Seattle on 28–29 October to discuss how to structure such a trial.

The researchers hope to test rapamycin in large dogs that typically live for eight to ten years; they would start giving the drug to animals aged six to nine. A pilot trial would involve about 30 dogs, half of which would receive the drug, and would allow the researchers to dose the dogs for a short time and observe effects on heart function and some other health measures. The trial could be completed in as little as three years, but researchers will know long before that — perhaps in months — whether rapamycin improves cardiac function or other aspects of health.

Rapamycin acts on a protein that is involved in cell growth, but little is known about how it extends life. It might retard the ageing process itself or it might prevent age-related diseases. One hypothesis is that it works primarily by preventing the development of cancers.

Pet dogs should provide a more realistic test than lab mice of how the drug would work in humans. Pets experience some of the same environmental influences and get some of the same age-related diseases as their masters, says Kaeberlein. (He plans to enrol his own German shepherd dog when it is old enough.)

Other researchers say that Kaeberlein and Promislow’s reasoning makes sense. “We’re talking about whether aged pets will benefit, and that’s a good model for a human population,” says physiological geneticist David Harrison of the Jackson Laboratory in Bar Harbor, Maine, who has studied rapamycin in mice.

Kaeberlein and Promislow have collected about US$200,000 in University of Washington institutional funds for the pilot. But they will need much more funding for a larger trial of several hundred dogs to test whether the drug, given over years, can extend lifespan — and to study the normal ageing process in thousands of animals to try and understand the mechanism of any life-extending effects.

Participants at the Seattle meeting are also considering whether pet owners could be asked to help fund a bigger trial and if so, whether researchers could promise donors that their dogs would be treated with rapamycin rather than a placebo without compromising the study. Usually, participants in a gold-standard clinical trial are randomly assigned to a treatment or control group.

“It’s a kind of unique situation because they are people’s pets,” says Kaeberlein. “We haven’t come to any decision on how that’s going to be handled.”

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