E250: 다니엘 프로미스로(Dr. Daniel Promislow) - "노견의 과학"

that as animals get older, they're more likely to die within a year than when they're younger. And that's one way that we define aging. So that work started a long time ago. And then when I started my own lab in the mid-1990s at the University of Georgia, I started working on fruit flies. And I still work on aging and fruit flies. And the common theme that ties together studying mammals in the wild and studying fruit flies, for me anyway, is I'm really interested in variation. Why is it that there's so much variation for anything that you could imagine measuring, including aging? If you think about human populations, there are families where everybody seems to live really long. You have lots of grandparents living into their 90s and even hundreds. And then other families where people aren't so fortunate, and they might have a lot of cancer or a lot of cardiovascular disease. What is it that accounts for all that variation? So I use the fly as a model to study that variation. So really, my whole career has been about variation and aging. And dogs are highly variable in everything that you could imagine. And what got me interested, I've always loved dogs, but really what got me interested in thinking about dogs and aging was a paper that came out in Science. So Science is the premier science journal in this country. And back in 2007, I was thinking about aging and variation. This paper came out and on the front cover of the journal was a picture of two dogs walking side by side, a Great Dane and a Chihuahua. So a little bit different in size. A little bit. So, you know, something like 50-fold difference in size. And inside was a scientific study of size in dogs. It wasn't about aging. It was about size. But what really piqued my interest was what they found. So this is a paper from... First author was a guy named Nathan Sutter. He was working in the lab of Elaine Ostrander. She's a very famous dog geneticist who's now at the National Institutes of Health. And the cool thing was not only that they were able to identify genes that affect size in dogs, but the gene that they found that accounts for more variation than any other gene was a gene called IGF-1 or insulin growth factor 1. So what got me excited about that is that previous studies in mice and fruit flies and even in humans suggest that this gene, insulin growth factor 1 or IGF-1, might have something to do with aging. That when you knock that gene down, when you reduce the expression level of that gene, you tend to get mice that live longer. When you knock that pathway down in flies, you get flies that live longer.

And even in people, there are people who have a mutation in this gene, and they tend to be very short in stature, and they seem to be protected from cancer. So really cool things going on there. Yeah. And then the last thing I'll mention is that there are two forms of this gene. There's the ancestral form that we see in the wolf that was passed down from wolves when dogs were domesticated from wolves, that ancestral version. That's what we see in the giant breed dogs and a lot of the large breed dogs. And then there's a new version of that gene that we don't see in wolves that we see in the toy breeds. And some of the smaller breeds. And then here's the last thing. The smaller breed dogs are the longer-lived dogs. So that led me to wonder. So I saw this paper from the Ostrander group, and I thought, wow, this is really cool. Is the reason that small breed toy breed dogs are long-lived, is that because of this new IGF-1 gene? We don't know the answer, but it led me to wonder whether dogs might be a good species to study aging. That's so interesting. There's so much in there to unpack. I mean, for one, I'd never thought of aging defined the way that you defined it, which, of course, makes total sense, right? But I'd never thought about it that way before. Yeah. So you can just start there. Yeah. Let me just jump in there. So we can think of aging in lots of ways. And when I talk to people who don't work on aging, people in my family or friends, we see aging all around us because of our friends and loved ones and ourselves. As we get older, things change. And we look in the mirror and we look different than we did 20 years ago. There are more formal ways to measure it. And one way is just to measure the probability of mortality. And in almost every species, that risk of dying this year versus next year versus the following year actually goes up exponentially. So what that means is that it doesn't just go up linearly over time like a straight line. That line is going is looking steeper and steeper and steeper. So in humans, the risk of mortality starting from our early 20s or even earlier, risk of mortality doubles every eight years. So it and and so it's like compound interest in the bank. If you if you put a penny in the bank today and it doubles every day, tomorrow you're going to have two cents. And the day after that, you'll have four cents. It's no big deal. But in 10 years, you're going to be like a gajillionaire. Right. So if you think about mortality doubling every eight years, that that's a really dramatic increase. And the same is true for lots of diseases.

So if you look at the risk of cancer for most cancers in humans and also in dogs, they show this doubling time, this exponential increase. Of course, in dogs, it's much faster than in humans, much shorter. Sure. Lifespan. Yeah. Makes total sense. So to kind of pull that into what you're doing now, can you share a little more about the dog aging project in particular, kind of what it is, what the goals are, how this all weaves together? Sure. So let me back up a little bit. Yeah. So I sort of went off on a tangent and answered more than you probably wanted me to do. Hey, it was interesting. Keep going. So one reason to study dogs is that they have this really interesting genetic pattern of size and sizes associated with aging. But there are a whole lot of other things about dogs that make them a perfect organism to study aging. So they're the most variable species on the planet. If you go to the dog park and you look around, size, shape, color, coat pattern, behavior, hugely variable. Well, it turns out they also vary in the spectrum of diseases they get. There are some breeds that are really prone to cancer and other breeds that almost never get cancer. Other breeds that are prone to heart disease, to cardiomyopathy, to heart failure. Others that don't get that. So huge variation in the diseases they get. Also in how long they live from the very shortest lived giant breed dogs to very long lived toy breed dogs. Their genetics is quite similar to us. They share more than 80% of their genes with humans. They live in our environment. So if we can identify environmental risk factors for aging in dogs, they're likely to also be risk factors for us. They have this really sophisticated health care system, second only in sophistication to our own. And then probably the most important thing, which we like to think about a lot at the Dog Aging Project, that motivates us to study aging in dogs is that people love dogs. So what we learn about dogs is good for dogs and good for the owners and also is going to apply for in a lot of ways to understanding aging and human populations. All right. So you mentioned it in there. Go ahead. What is the Dog Aging Project? Ah, so the Dog Aging Project is the largest long-term longitudinal study of aging in companion dogs. It's a huge study whose primary goal is to understand how biology and environment shape healthy aging in dogs and to discover ways to maximize healthy aging in dogs. It's a study of dogs in their homes. So it's not studying dogs in laboratories. These are our own dogs that live with us. And we follow these dogs for their entire lives.

So people will sign up their dogs and we can talk about how that works. And then we collect data from those dogs. And we're already analyzing the data that people have shared with us to begin learning lessons about what is it that makes for healthy aging in dogs. So you mentioned that people can get involved. So go ahead. How do we do that? How do I get my dog involved? It's really easy. And I want to say to your listeners, if you're not yet a member of the Dog Aging Project, you can become a member. All it takes is that you have a dog. If you don't have a dog, you can't sign up your dog. But you could convince your friends to sign up your dog. You take all dogs, all breeds, mixed breed, purebred, male, female, intact, sterilized, large, small, old, young. The only criterion is they have to be, right now anyway, in the 50 U.S. states. We hope to go international, but one step at a time. It's really easy to sign up. You just go to dogagingproject, all one word, .org. So dogagingproject.org. And you'll see a button there to nominate your dog. Click on that. And there are just a few questions. It'll take two minutes to answer these questions about where you live, what your zip code is, and what your dog's name is, and your email address. You have to be able to type your email the same way twice without making a mistake. That's hard. And then we will right away, we'll send you a link to create your own portal, password protected. We won't share your information with anybody. This is all private information. The study is funded by the National Institute of Health. So it's a publicly funded study. We're not a company. We're not selling the data to anybody. And when you create your own portal, then we will ask you to fill out a 10-part survey. That's where we begin to collect all the data. We really start digging down deep. For this audience, you'll be interested that we collect a lot of information about behavior, activity levels, number of hours a day that your dog is active, how intensely it's active, whether it's a slow walker or a fast runner, whether it likes to chase rabbits and squirrels or not, all kinds of behavioral attributes, but also feeding, health, a little bit about your own demography. So lots of information about the dog. And it's that data that allows us to begin asking scientific questions about aging in dogs and what happens as dogs age and what are the potential factors that influence what happens. I should note that just like in human health care, as your listeners know, there are lots of veterinary specialties. So there are veterinary infectious disease specialists.

Those of you who had a puppy that got an infectious disease, which is when most infectious disease happened in the first year of life for dogs, might have seen an infectious disease doctor. You might have had a dog that broke a bone and you saw an orthopedic specialist. So just like in human medicine, there are all these specialties. One of the specialties that isn't in veterinary medicine is geriatrics. And so if you take your dog that might be a Bouvier or a King Charles Spaniel or whatever it is into the vet, there's no specialty that has developed all this information about what happens as a particular dog of a particular size or breed ages naturally. And so partly what we're doing is with your help, if you sign your dog up, learning what happens naturally as bugs age. And that can help veterinarians to know when you bring your dog in, your 8 or 10 or 12 year old geriatric dog, how well it's doing. Super interesting. I think the phrase for this, right, is citizen scientists. Can you just share a little more about kind of that piece of it, like what that term means? I know I said on the website. So can I talk about that a little bit? So we talk about the Dog Aging Project as a citizen science project. We also like to use the term community science. So you don't actually have to be a U.S. citizen to participate in the Dog Aging Project. We use those terms really to point out that this is not just about scientists in lab coats working alone in a laboratory. It's really about a community of people, scientists and non-scientists working together to ask scientific questions. What we want people to realize is that science is actually a social activity that all of us can participate in. So, you know, I love the idea that some of you might sign up your dog and then you might have your five-year-old daughter or your eight-year-old son work with you to fill out the survey. And as they're doing it, they're going to learn about how surveys work. And that's a part of science. So it's an opportunity to teach the community about science, to do science with the community, which is a lot of fun. And then as we start making discoveries, not just to publish them in scientific papers for the scientific community, but to share our discoveries. And when I say our, I really mean the big hour, the discoveries that the scientists on the team and the participants, which currently number more than 30,000, are all making together to share our discoveries with the participants. So it's really a community social activity that everybody can take part in. That's awesome.

I know this isn't the only community science type project I've heard of recently. And so I was kind of curious, is it something that's growing in popularity at the moment? Or is it just something that like kind of I've only just become aware of? And then are there downsides to doing it this way? So first of all, it's definitely growing in popularity. There are some projects that have been around for a long time. There are some projects where being a part of a community science study doesn't require anything other than, for example, letting scientists use the computer time on your desktop computer to help them solve a problem that requires millions of computers. For example, there are researchers at my institution here at the University of Washington that are trying to understand how the proteins in our cells fold. And that turns out to be a really challenging problem because proteins can fold in a virtually infinite number of ways. And so to figure out the best way for a protein to fold requires millions of computers. And so one early version of community science was people sharing their community time. Sorry, their computer time. Something else that's been going on for many, many decades is the Christmas bird count. So those of your listeners who are bird watchers might know that every year at Christmas, people are invited to go out to their neighborhoods and nearby neighborhoods and see how many birds that they can find of which species and they share those data. And we actually have learned a lot about changes in the distribution and numbers of birds from the Christmas bird count, which is a community science project. So there are all kinds of things that people are doing. If your listeners are interested in learning more, if you just look on your favorite search engine and just look up citizen science or community science, you'll find websites where you will be invited to join other sorts of projects as well. So it's definitely a growing movement. And I think especially now when people, lots, so many people in our country have so many questions about science and can they trust what scientists are doing? And this is such a great way to learn how science works to sort of demystify it by being a part of a really fun science project. Yeah. Yeah. So any downsides to kind of using this approach? Oh, sure. All right. There are challenges to using this approach. There are lots of benefits, especially this is the only, so right now we have 30,000 participants. I would love to get to 100,000 participants and maybe even more.

So sign up your dog, tell your friends and relatives to sign up your dogs. There are some downsides. So one thing is that we are, when scientists do experiments in the lab, they design the experiments in a way that they're controlling everything. They know exactly what the temperature is and what the humidity is. And if they're looking at bacteria in a culture, they know exactly what the acidity is and what the salt content is. Exactly. They control everything. And in a community science study, we control nothing. We want everything to be natural. We don't want people to change anything just because we're asking them questions. We want them to do what they normally do. But that makes it very noisy data. And when we ask a question like, how fast does your dog run on a one to five scale? What you think is really fast, someone else may think is not as fast as she used to be. So even though the dog is running at exactly, the two dogs are running exactly the same speed, we'll get two different answers because there are two different perspectives. Now, we're going to try and put activity collars on dogs so we can get actual measures. But those are some challenges. It's really important that the quality of this data depends, really importantly, not just on a one time survey, but on resurveying all those dogs every year for their life. If we just capture one year, that's what we call a cross-sectional study. And if we find that two things are related, we don't know if they're related because one caused the other or the other caused the first thing or because they're both impacted by some other third thing that we didn't measure. And I can give you some examples. If we look longitudinally, year after year, then we can begin to say, oh, look, dogs that were more active when they were young had this thing happen or not happen when they're old. So one of the challenges is to not only recruit tens of thousands of people, but to retain those people year after year and make sure that they appreciate how important this is and that we make it fun for them. So they want to come back every year and do the survey again and again. And I want to stress that everybody can be a part of this. As long as you complete the survey, you are in the Dog Aging Project. There's nothing else that you have to do to be a part of it or stay a part of it. Excellent. All right. So you kind of mentioned, you know, the surveys themselves. What types of questions are we looking at? What types of things are you asking? So there are actually a few different surveys that we give the participants.

The first survey we call the Health and Life Experience Survey or H-L-E-S. That's the survey that they'll see when they create their password protected portal. There are 10 different categories. We ask about the basic information about the dog, the age, the size, the breed, those sorts of things. We ask about the health of the dog and a range of different questions. Skin health, trauma, infectious disease, cancer, and so on. Lots of different health categories. We ask about feeding behavior. We ask about the environment. It's potentially important to know whether the dog spends a lot of time on the grass, whether you have hardwood or carpeting. How you heat the house. If the house has a fireplace, maybe that has an impact on the dog's lung health. We don't know. So collecting all this information will, in the years to come, help us answer those sorts of questions. And then we've also put together special surveys, and we will continue over the life of the study, as we think of other things we want to work on, put together new surveys. So, for example, we've also, there's another survey that people, that everybody was invited to fill out just about cognitive function. We call it the canine social and learned behavior survey. So telling us about how your dog behaves and its social interactions and that kind of thing. So really what we can ask is that the sky's the limit. And then we also collect a lot of biological data. So right now we have funding from the National Institutes of Health to collect genetic data from 10,000 dogs. And we are sharing that data with the owner as soon as we sequence their genome. That's awesome. Now, we hope to get more funding so that we can sequence every dog's genome. And then we also, for a smaller set of dogs, again, limited only by funding, we have them go to the veterinarian and we collect blood samples, urine samples, fecal samples, hair samples. And there we can dig down a little deeper and do the kind of clinical studies that you would have your dog get when he or she goes to the veterinarian. And then more sophisticated things that we can do in our own laboratories. So really collecting tons of different information at different levels, really just depending on the kinds of funding we have. And then finally, we have a clinical study, a clinical trial. So about 1% of our dogs, about 500 dogs, are enrolled in a clinical trial of a drug called rapamycin, which is very commonly used in humans in transplant patients. Turns out that at very low doses in the laboratory, rapamycin makes laboratory animals like mice and worms and flies live healthier longer.

And so we're doing a trial with veterinarians around the country to ask a very low dose rapamycin in dogs might help dogs live healthier longer. Very cool. And that's like a very direct means to the goals that you've set, right? Like the idea that you want to help dogs live longer. There's a very specific piece there that you're testing. That's really kind of neat. Yeah. And something that this audience might be interested in is we did a very small pilot, two pilot studies, actually. And in the first pilot, after we gave dogs rapamycin, and this part of the project is led by my colleague Matt Kaverlein. And I should say that the team that runs the Dog Aging Project is not me. It's about 100 people. It's a huge team of people centered at the University of Washington and Texas A&M and College Station, Texas, but also around the country. It's an awesome team. So it's not only community science. It's also team science. We have every day, all day, there are people on Zoom meetings helping to run the project. So Matt Kaverlein here at the University of Washington leads this study of rapamycin. And in the first trial that he led, after the trial, we asked the participants, is there anything else you'd like to share with us? And half of them were on a placebo and half of them were on rapamycin. They didn't know which was which. And the ones that were on rapamycin, a few of them said, you know, my dog was more active. So we don't know if this will hold up in a larger study, but one of the things that we are deliberately collecting data about is asking the owners to tell us about activity levels to see if rapamycin improves activity levels in these large breed older dogs. Yeah. So these are dogs that are moving into their geriatric years. Mm-hmm. So interesting. Is there anything else that you can share now kind of on what you've learned so far and on takeaways or little nuggets of wisdom that you've gained here? So we're just in the process of analyzing our first set of data. So every year we'll collect these surveys from tens of thousands of participants. Our first set of data were completed at the end of 2020. And it's a huge survey. So that includes 27,000 people and a total of 5,000 questions. Most people don't answer all the questions. So, for example, if your dog has never had cancer, and I hope your listeners have dogs that are cancer-free, then you won't answer any of the questions about cancer. But each person answers, on average, a few hundred questions, 27,000 surveys. So we've been spending the last few months writing papers about this first set of survey data.

We're just beginning to learn about aging in dogs. So one of the things that we're really – several groups on our team are looking at activity levels and aging. I know that will be of interest to this group. There are a couple of studies looking at cognitive function. So what I mentioned earlier in the podcast that different breeds age at different rates or have different lifespans. And that's true for the diseases that they get as well. So the shorter-lived dogs, the giant breeds, which tend to be short-lived, get diseases like cancer much earlier than the toy breeds and the small breeds, many of which do get cancer, but later in life. One of the things that we found that's quite striking is that if we measure cognitive function, how well is your dog functioning cognitively? We see that at a certain point, cognitive function begins to decline, and those of you listening who have had geriatric dogs will have experienced things like maybe your dog gets lost or doesn't recognize you sometimes or starts having accidents in the house. Lots of different things that can happen as dogs move into the geriatric years. One of the striking things is that that pattern of cognitive decline seems to be the same in terms of when it happens for both long-lived and short-lived breeds. So we start seeing that decline really around age 10, 11, both for long-lived dogs and short-lived dogs. So that pretty serious cognitive decline is quite rare in the giant breeds because they don't live long enough to show it. Interesting. That was something that we found. A group on our team did a study in another set of dogs a couple years ago and found that pattern, and we've just shown in the Dog Aging Project dogs the same is true. So while there are some things that happen with age faster in the shorter-lived large breed dogs than in the longer-lived small breed dogs, there are other things like changes in cognitive function that seem independent of whether it's a long-lived or short-lived dog. Hmm. Hmm. Hmm. Super interesting, because I would expect those things to correlate more than it sounds like they actually do, which is really kind of interesting, the way that that works. Yeah. I think, I mean, we're just beginning to learn what does correlate with lifespan and what seems independent of lifespan. That's, I think, something that we'll be able to share with our larger community of participants pretty soon. In the coming year, we'll be publishing papers about that. We also have blog posts on our website. We have a monthly newsletter that goes out to about 90,000 people.

If any of your listeners would like to sign up, please do. So these are the sorts of questions that we're really just beginning to learn about. How cool. So part of the reason that I got to talk to you today is because you're presenting for us for the Lemonade Conference in February that's coming up. Anything else you want to share about your talk, about what you're going to cover? Sure. Well, I will tell you a lot about the details of the study, and I hope that viewers will be encouraged to participate and share the study with their own communities. I will talk a little bit about what we've already discovered about dog activity and age. We see quite clearly in our analyses how age affects activity levels, at least owner-rated activity levels. We've learned that older dogs slow down, and those of us who have dogs know that already. But we can actually quantify how that happens. We can also see how it differs across environments. For example, and maybe this is not so surprising to this community, but dogs that live in rural environments at all ages tend to be more active than dogs in urban and suburban environments. Interesting. Maybe not surprising. Maybe not surprising. One of the things that really surprised us, though, is that dogs whose owners are older tend to be much more active than dogs whose owners are younger. Going into the study, we predicted the opposite. We thought as we age, we often slow down, and so our companions will slow down with us. Turns out it's the opposite, and we don't know why, but one hypothesis is that as we get older, we have more free time. When we're in our 20s and 30s, we're pushing hard to build our career and working long hours. And as we get into our 60s and 70s, we have more flexibility, we move into retirement, and we can spend more time outside with our dogs. That was a real eye-opener for us. That's so interesting. So before I got into all the stuff that I do today, I worked for a pet trade magazine, and there is an organization. I don't know what they call themselves now, but they put out an annual study on who your typical pet owners are, like where there's the most growth in the market, right? And so I would be really curious over the next 10 years if some of that data changes, because I know in their research, they've certainly seen an increase in people roughly my age who are getting pets instead of having kids, right? So you see the number of pet owners growing in that market. So I'd be really curious to see how those two things kind of compare and contrast as things develop. Yeah, that's a really great point. A couple of other things.

So we hope to put activity monitors like Fitbits for dogs, for a thousand of our dogs. We're still trying to figure out which company to work with to put these collars on the dogs. And that, I think, is going to be really valuable, because what we're also learning is that the ways in which people answer the survey questions depends on the people themselves. So older people have more time to be outside with their dogs. Older people also tend to say that their dogs are healthier in terms of their cognitive function. And my guess is that that might actually reflect not the dog, but the perspective of the owner. And we don't know what's going on. One possibility is that older owners have had many more dogs. And so they're comparing their current dog with many other dogs. But these are all questions that we can explore. Yeah. And that reminds me to say to this audience that we are really laying a foundation here. So the Dog Aging Project is not the be-all and end-all. It's the beginning. And the foundation that we're laying, first of all, includes sharing all of our data with the scientific community around the world, so that people who have any question that they could ask with our data can do so. And that's freely accessible. They don't have to pay for access to the data. And the other thing is that we're welcoming people to design future studies to take advantage of the infrastructure, the foundation that we've created, so that they can build on it. And our hope is that the Dog Aging Project will, first of all, last for many, many years as we follow what I hope will be the long lives of all of your dogs, but also that it's just the beginning and it will be a forever study, that 20 years from now, 30 years from now, there will still be a Dog Aging Project, studying the next generation of dogs and learning new lessons from those dogs. Super interesting stuff. So cool. So I've got kind of one last question here to kind of round things out. And it goes nicely with what you were just talking about. If we were to pull, you know, kind of the whole conversation today, which we've been a little wide-ranging in our conversation, but if you were to kind of drill it down to one piece of information you kind of want to leave people with or leave them thinking about, what would that be? So that's a great question. The Dog Aging Project is so many things to so many people and has so many different communities that are a part of it. If I had to distill it down to one thing, I would say that there's no one scientist or one lab or one publication that can tell us the whole story of aging in dogs.

But by working together across this entire country with this huge community of dog lovers, we can begin to learn in the coming years just how to help dogs have the healthiest long lifespan. What a great place to kind of leave things. Thank you so much for coming on the podcast, Daniel. It's been great talking to you. It's been a super interesting conversation. I really enjoyed talking with you, Melissa. This is really fun. And I do want to say if any of your listeners have questions, please feel free to go to our website, dogagingproject.org, and you will find a link there where you can send questions to the team and the right person on the team will get back to you with an answer in no time. Awesome. All right. Thank you again. Thank you to all of our listeners for tuning in. We'll be back next week. Don't miss it. If you haven't already, subscribe to our podcast in iTunes or the podcast app of your choice to have our next episode automatically downloaded to your phone as soon as it becomes available. Today's show is brought to you by the Fenzie Dog Sports Academy. Special thanks to Denise Fenzie for supporting this podcast. Music provided royalty-free by bensound.com. The track featured here is called Buddy. Audio editing provided by Chris Lang. Thanks again for tuning in and happy training.