IN THE next few weeks, scientists in the US will begin a remarkable medical experiment. They are seeking 100,000 applicants from all walks of life 鈥� young, old, rich, poor, urban, rural, fat, thin, black, white, brown. They will winnow them down to 10,000 and then spend years studying every aspect of their health, including why some of them age better and whether drugs might extend their lives.
During the trial, the subjects will be taken out for walks and have their faeces collected in bags. They will have their tummies tickled, fetch sticks, chase balls, sniff one another鈥檚 butts and urinate against lampposts. Not because those are part of the experiment, but because the subjects are pet dogs.
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The , based at the University of Washington in Seattle, has been years in the making but is finally off the leash. First and foremost, it will tell us a lot about the ageing process in dogs, says project leader Daniel Promislow. But the real goal is to understand more about how we ourselves age, and how we might slow it down or even reverse it. It seems our best shot at defeating human ageing will come from studying not ourselves, but 10,000 of our best friends.
The idea of using animals as proxies to study our own ills is nothing new. The edifice of modern human medicine is largely built on animal experiments, particularly mice altered to get human diseases, which can be used to test treatments. But useful as these are, they can only get us so far. Lab mice aren鈥檛 humans, and the gulf between them and us is almost always too wide, with most experimental drugs falling by the wayside. Experiments on monkeys and chimps can bridge the gap, but are ethically unacceptable.
Enter Canis lupus familiaris. A few years ago, cancer doctors hit on the idea of using domestic dogs as a bridge between mouse studies and human trials, reasoning that owners would be highly motivated to care for their sick dogs and hence 鈥� perhaps 鈥� happy to consent to them being given experimental treatments. They were right: the lymphoma drug and approved by the US Food and Drug Administration in 2013 partly on the basis of those experiments.
The Dog Aging Project takes the idea of using dogs as medical guinea pigs to the next level. As well as testing a specific drug, it will study all aspects of the ageing process.
Dogs, it turns out, are a great model of ageing. 鈥淧et dogs develop essentially all of the same age-related diseases and functional declines that people do,鈥� says Matt Kaeberlein, one of the project鈥檚 lead scientists. They also share our homes, and hence the same environment 鈥� and environment is a key determinant of health. And they have a healthcare system that is second only to ours, with their vets often keeping detailed medical records. Another plus is that owners tend to be diligent about giving their dogs medication so compliance can be better than in a human trial. And, crucially, most dogs only live about 8 to 12 years, so can tell us about the ageing process in a much shorter time than humans.
Once the 10,000 dogs are recruited, they will be followed for the rest of their lives. 鈥淥ur first goal is to understand the biological and environmental factors that determine whether dogs are healthy agers or non-healthy agers,鈥� says Promislow. 鈥淐an we come up with some metrics so a vet can say, 鈥榶our dog is ageing extremely well鈥�, or 鈥榯here are some problems here we need to figure out鈥�?鈥�
As well as regular surveys of the owners and veterinary check-ups, all 10,000 dogs will have their genomes sequenced. 鈥淥ne of the things that makes dogs a terrific model of ageing is that they show tremendous diversity, not just in size, shape, coat colour and behaviour but also in the diseases they get,鈥� says Promislow. 鈥淪ome breeds get heart disease but never get cancer, some get cancer but never get heart disease. There are long-lived breeds and short-lived breeds. All that diversity creates a great opportunity for us.鈥�
About 1000 dogs will also have several other 鈥渙mics鈥� done: the epigenome of modifications to their DNA; the microbiome of the microbes living in them; and the metabolome of molecules that their bodies produce. These are also thought to influence the ageing process, although how they do it is unknown.
But as well as learning about ageing in dogs, the trial will teach us a lot about ourselves. 鈥淭here鈥檚 no question that we will have a direct impact on the health of pet dogs,鈥� says Kaeberlein. 鈥淏ut we anticipate that the ageing process in dogs will share features with the one in humans, so I think a lot of what we learn will be directly applicable to human health.鈥�
鈥淒ogs certainly age more quickly than people,鈥� says Linda Partridge, a director at the Max Planck Institute for Biology of Ageing in Germany, who isn鈥檛 involved in the project. But they age in a similar way to humans, she says, 鈥渁nd are very social, like humans鈥�.
From a human perspective, perhaps the most exciting leg of the project is a small experiment called TRIAD, which will put 500 dogs through a placebo-controlled clinical trial of rapamycin, a drug that is considered one of the best candidates for a general purpose anti-ageing medicine in humans.
Rapamycin was developed to suppress the immune system so people鈥檚 bodies would accept transplants, but at small doses it has repeatedly been shown to delay ageing and promote longevity in lab animals. 鈥淥f the many molecules that extend lifespan in lab organisms, rapamycin is the most reliable and has the largest effect,鈥� says Promislow.
The team will recruit healthy middle-aged dogs aged 7 or over and give half of them small doses of rapamycin three times a week for three years; the rest will be given a placebo. The dogs will then be monitored for up to a decade to see if the drug had any effect on longevity or the onset of age-related diseases. The study has been designed so that, statistically, it should be able to detect any changes to the dogs鈥� lifespan within three years of stopping the treatment.
How much of a lifespan boost the dogs might get is unknown, but if mouse research is anything to go by, then the answer could be a lot. In one , Kaeberlein鈥檚 team gave rapamycin to a group of 20-month-old mice, roughly equivalent to 60-year-old humans. They fed the mice small doses of rapamycin for three months, then took them off the drug and waited for them to die鈥� and waited, and waited. Untreated mice in the study enjoyed a fairly standard murine innings of about 30 months. But the treated ones lived significantly longer, an extra two months on average 鈥� a long time in the life of a mouse. Some lived much longer. The final survivor died more than two years after the start of the experiment, at the ripe old age of 3 years and 8 months 鈥� the equivalent of about 140 in human years. Extrapolated to 7-year-old dogs, that would increase life expectancy by three or four years, says Kaeberlein. For a 50-year-old woman, it adds around two decades.
鈥淭he Dog Aging Project is finally unleashed, and might help defeat human ageing鈥�
What, you might think, are we waiting for? Some people aren鈥檛 waiting and self-medicate with rapamycin. But for it to become a validated longevity drug, it would have to go through clinical trials, which is easier said than done. Imagine trying to repeat the mouse experiment in humans. You would have to recruit a group of 60-year-olds, give half of them rapamycin for nine years and then wait long enough to see if it had any effect. You could be waiting for decades. 鈥淚t鈥檚 not feasible to do a clinical trial in people,鈥� says Kaeberlein. That is where dogs come in. 鈥淓verything happens faster in dogs, so we can learn a lot in a matter of just a few years,鈥� says Promislow.
This won鈥檛 be the first time that dogs have been given rapamycin. The project has already completed a . After 10 weeks on the drug or placebo, the dogs came into the clinic for a physical examination, blood and urine tests and an echocardiogram. The principal goal was to make sure the drug was well-tolerated. 鈥淵ou don鈥檛 want to hurt anyone鈥檚 dog,鈥� says Kaeberlein. 鈥淲e didn鈥檛 see any side effects, which is really important.鈥�
The trial wasn鈥檛 large or long enough to pick up increases in lifespan but it did indicate there may be some health improvements. Dogs given rapamycin had improved function of the left ventricle, the chamber of the heart that pumps blood around the body and which weakens as dogs (and humans) get older. Similar cardiac improvements have been seen in mice given rapamycin. 鈥淚t is a marker that the intervention is working,鈥� says Kaeberlein.
They also saw some other positive, though not statistically significant, changes. Seven out of the 10 dogs on the high dose were reported by their owners to be more energetic and active, and some owners of rapamycin-treated dogs said their pets were more affectionate, which Kaeberlein says may indicate an improvement in cognitive functioning. All of these are consistent with what is known about mice treated with rapamycin: they don鈥檛 just live longer but age more healthily, enjoying more disease-free months as well as more months overall. In gerontology circles, this extension of 鈥渉ealthspan鈥� is seen as more desirable than merely adding extra years.
Based on the success of the first trial, Kaeberlein started a longer one in 2018, with dogs treated for six months and then followed. The trial is due to finish about now. It focused mainly on cardiac health but also measured the dogs鈥� activity levels using special canine 鈥淔itbits鈥�. It also assessed cognitive function to see whether rapamycin can help old dogs learn new tricks. Assuming the results are good, the full-scale trial will follow.
If TRIAD turns out to be barking up the right tree, it would be a step towards getting rapamycin approved as an all-purpose anti-ageing drug in humans 鈥� though whether the dog data would be taken into account by drug regulators isn鈥檛 known, says Kaeberlein. Even if it fails, TRIAD will pave the way for future anti-ageing trials. 鈥淚 view it as a proof of principle for how to test other interventions,鈥� says Kaeberlein, who has three dogs himself but hasn鈥檛 volunteered them for the trial because of conflicts of interest. 鈥淩apamycin is arguably the best we have now and the one to move forward with first, but there are other interventions that could be tested in the future. We鈥檙e going to learn a lot about which measures of ageing in dogs are most useful, and provide measures for other people to test.鈥�
Even if the drug extends dogs鈥� lives, nothing lasts forever. 鈥淥ne thing that keeps me a little bit awake at night is that, because of the way the study is designed, dogs are going to die during it,鈥� says Kaeberlein. In the current trial, they expect about two-thirds of the dogs to die during the three-year follow-up. 鈥淭hat鈥檚 what gives us the statistical power to see any change in lifespan. But I do worry about how we manage owners鈥� expectations and help them understand that, you know, your dog is old and this is not going to ensure anything. This is why we鈥檙e doing the study to find out.鈥�
Other dog ageing projects are already up and running. In Denmark, for example, a team at the University Hospital for Companion Animals in Copenhagen is turning to pet dogs to study age-related cognitive decline. Old dogs can get a form of dementia called canine cognitive dysfunction (CCD), which is similar to Alzheimer鈥檚 disease. 鈥淐CD is a good model of sporadic Alzheimer鈥檚 disease in humans,鈥� says veterinary neurologist Barbara Blicher Thomsen. One goal is to identify brain changes in dogs that could be treated with drugs. 鈥淥ur overall objective is to investigate the disease for the benefit of both the dogs and humans.鈥�
One thing is for sure 鈥� these projects won鈥檛 have any problem recruiting volunteers. 鈥淥wners are very enthusiastic,鈥� says Promislow. 鈥淭hey love their dogs and they鈥檙e excited to understand how they might be able to give them a longer and healthier life. The benefits are not just for the dog but also for the owner, they get more healthy years together.鈥�
If you live in the US and would like to volunteer your dog to take part, please visit
Herding cats
Dogs aren鈥檛 the only pets to be proposed to help the study of ageing: cats have also been put forward. But as might be expected, they aren鈥檛 as amenable as dogs. 鈥淭here are a couple of challenges with cats,鈥� says Daniel Promislow of the Dog Aging Project at the University of Washington in Seattle. 鈥淭hey don鈥檛 show as much diversity as dogs and they tend to be longer-lived so it鈥檚 a harder study 鈥� we鈥檇 have to wait longer to see patterns emerging.鈥�
Nonetheless, a project called , a pet citizen science project led by researchers at the Broad Institute of MIT and Harvard, is recruiting cats for a genetics project that could eventually produce insights into human ageing.
Dog years
It is often assumed that a calendar year is equivalent to seven 鈥渄og years鈥�, so that a dog鈥檚 life expectancy is about a seventh of a human鈥檚. Thisis inaccurate for two reasons. One is that dogs reach sexual maturity much earlier in their lifespan than we do. The other is that different breeds of dog have different life expectancies (see 鈥�Live big, die young鈥�). As a rule, larger breeds die sooner 鈥� a common pattern in animals, though a paradoxical one given that larger species such as humans tend to live longer than smaller ones such as mice. Small dogs live on average for about 15 years but big dogs only 10. Cats typically live for 15 years.
Article amended on 9 January 2020
We corrected the name of the Bernese Mountain Dog.
