25 August 2021
In what is the first episode of Let’s Talk Pet Longevity, we are delighted to host Prof. Matt Kaeberlein. Matt is a Professor of Laboratory Medicine and Pathology at the University of Washington School of Medicine. His research focuses on the basic mechanisms of aging in order to facilitate translational interventions that promote healthspan and improve quality of life.
Matt is also a co-director of the Dog Aging Project, in Washington. By enrolling over 32,000 dogs, the goal of the Dog Aging Project is to understand how genes, lifestyle, and environment influence ageing.
Here’s what was said:
(The timestamps relate to when the question in asked in the full video)
00:27 – Andrew: Could you tell us a little bit about the regulatory process that occurs for animals? Like the process with FDA?
Matt Kaeberlein: Sure. I’ll tell you what my experience has been. I will say I’m perhaps not the best person to answer this, when it comes to the process with FDA. So FDA in the United States regulates veterinary medicine and human medicine. And you can absolutely go after an FDA approval for veterinary indication. And that process, and this is my intuition and my little bit of understanding, still pretty complicated, although maybe not quite as complicated as it is for human clinical trials. But it is a real sort of deeply bureaucratic process that you have to go through, if you want to get FDA approval for veterinary medicine.
In our case, because we’re an academic project based out of academic institutions, the regulations that we are subject to, are our institutional animal care processes. To the extent that we collect human data that the IRB, although we’ve been designated as not having IRB approval, at least so far, and then mandated rules. So for the clinical trial in particular all of the procedures for the Dog Aging Project undergo institutional animal care approval at the relevant institutions. For the clinical trial, we also have a data safety monitoring board, just like you would for a human clinical trial. And I will say that we actually, as the Dog Aging Project, have made it part of our culture to go above and beyond when it comes to animal safety and ethics. And in addition to the data safety monitoring board, we also have an animal welfare advisory board, that is not mandated but that we put in place to have extra oversight over everything that happens at the Dog Aging Project.
So those are the kinds of processes that we have put in place for the clinical trial for triad. We are not seeking FDA approval for rapamycin in our study for lifespan. So we have not gone through the steps of trying to get the study approved by FDA, with the goal of then getting a drug approved as an aging drug in dogs. Part of the reason for that, is that rapamycin is already off patent and available as a generic. And that sometimes, it’s not commonly used in veterinary medicine, but it is sometimes used for certain types of cancer and things like that. So this is not from our perspective about trying to get FDA approval.
03:26 – Aaron: So, the most interesting thing about this project for me is the comparison between the castrated and non castrated individuals. Can you talk more about that or your plans for any kind of data you’re taking for that?
Matt Kaeberlein: Sure. Great question. So first of all, I’ll just start by saying that it’s not often appreciated until you think about it, that there are actually four sexes in companion dogs. There are intact male, intact female, sterilised male and sterilised female. So it’s a really interesting question. How does sterilisation affect age-related outcomes and is it different between males and females? So, we definitely capture that information. Absolutely. And we will be able to correlate health outcomes during aging with reproductive status as well as biological sex. So that’s absolutely something we’re looking at.
The one thing I will say is, in the United States, it is relatively uncommon that companion dogs will be intact. Most companion dogs are spayed or neutered. Sometime early in life. So we are relative to the sterilised dogs and were underrepresented for intact dogs. And that’s a group that we are trying to recruit actively forward. But even still with 32,000 dogs in the study, we have several thousand intact dogs. And so we’ll be able to start asking ourselves those kind of questions. I can’t tell you right now what the answer is, because we’re still at the beginning, but I agree that it’s a fascinating question. And absolutely we expect that a spayed status or reproductive status will have an impact at least on the spectrum of diseases and disease risk that goes along with aging. There might be small effects on lifespan just based on what’s in the literature now, but it doesn’t seem to be a major determiner of lifespan at this point. Although we’ll see what happens.
For triad, we made the decision that all the dogs in triad will be sterilised. And the reason for that, is that by that age group the proportion of dogs that are intact so small, that we would have been underpowered to detect a fact associated with reproductive status. So we made the decision that we would take that out because of the potential complications in the analysis and that all of the dogs are sterilised that will be involved in triad.
06:01 – Chris: Hi guys. So my question is a speculative one. And I know how scientists hate speculative questions without a million caveats, but I’ll go for it. So what are two or three things that you believe are inevitable for the future of longevity over the next five to ten years? And what obstacles may prevent these from happening?
Matt Kaeberlein: Good question. So this is a prediction, which I’m terrible at. So I’ll just start by saying I’m wrong more often, than I’m right. But I’ll give it a shot. So I think one thing that we’ll see for sure are registered clinical trials, and this is not really much of a guess because it’s already starting to happen. So registered clinical trials for aging. And my hope is that within the next ten years certainly, we’ll see the first FDA approval for a geroscience intervention. That probably, if it’s in the human space, won’t be for aging as an endpoint. But everybody’s going to know. As these trials get designed in a smart way, I think people are going to know that’s really what’s being measured. Even if that’s not what it causes.
So I think that’ll happen. I certainly hope, and I think certainly with dogs, there’s a good chance that we’ll see the first FDA approval for something to directly target biological aging and where the endpoint might actually be aging or something like that. I actually think that’s going to be a watershed moment in the field once that happens, because then it’s proof of principle. That’s the way I think about a triad. The fact that we’ve got a triad off the ground is proof of principle that you could do a clinical trial for aging in pet dogs. And now other people are doing the something, which is great. And I think that’ll be the same way with the first FDA approval for a drug that targets aging. So I think that’s going to be something that will happen and will be really important. I think we’re already seeing the sort of flourishing small biotech industries coming into the field. There’ve been a couple of false starts. Over the last 20 years where it looked like that was going to happen. And then, some very obvious big failure happened and everybody backed off. I think we’re over that sort of area now. And this is happening. There’s a lot of interest in the biotech world in the biology of aging. The field has matured to the point where there are lots of different strategies that can be taken. So, I think that will continue and I think that’s going to have a big impact on the field. What do I see as the challenges or potential barriers? Still we have a real challenge in the field in convincing serious people who control federal funding. That the field is ready for investment. This is obvious by the fact that geroscience is still funded as less than one half of 1% of the NIH budget in the United States. Despite the fact that biological age is the greatest risk factor for almost all the diseases of NIH, we have not done successful at convincing the policymakers and the serious people who control where federal funding goes. That this field is to the point, mature enough to warrant that kind of investment.
I hope that happened in the next decade, but it’s going to be hard. And we have challenges with that there still are high profile individuals. Some of them are scientists and some of them talk about themselves as scientists who say crazy things that turn off serious policy. So I worry about that and I don’t know how long it’s going to take. It’s great to have a donor drop of $25 million on the field. That’s a drop in the bucket compared to 2.5 billion, which is what the NIH could move into the field like that if we can convince them that we should do that. So that’s what I would like to see to be successful. I would like to see the field will be recognized in terms of resource allocation at the federal government level that it deserves. And I think honestly, you could make a case. And I wrote an open e-mail a couple of weeks ago, that 6.5 billion is actually small compared to what I think the field deserves, in terms of resource allocation. But we’ve got to convince the people. And again, these are serious people and they don’t want to talk about immortality or stuff like that. They want to talk about rigorous real science. I think that’s a challenge that we’ve got and it’s still a bottleneck in the field.
11:12 – Angie: Hi everybody. I’m very happy to be on stage here with you and I think this longevity project is amazing. And I’m happy that I’ve found a video about it. And I have a quick comment on something that you mentioned in so many different amazing discussions. So to talk about biological age, I think I’m in my midlife, but I’m super cool and fit. And when I would do such a test and I’m not 28 years old as I am, that would be a real disappointment for me. And I would do it for the empowerment to say then like ‘oh my god, all these things I’m putting back to tomorrow such a running, I will start doing them because I would like to live as long as I can’. So that’s one of the reasons why I might want to do that. And then my dog is a mixed breed and I just filled out your form. And I wonder what the breed means in your study, what you have observed so far and your decision process? And also a small practical question, I have basically made up the breed of my dog and when I went to the veterinary, she told me it was possibly indeed this breed. And since then, every person on the street who asked before if she was a Shih Tzu, said now ‘Oh my god a Tibetan Terrier’. So I put that one and hope that’s good enough. And that’s maybe a question in which other people are interested in. So, how specific we need to be about the breed of our dog in the form. And then my other question is about how the breed impact the process and what you have observed so far.
Matt Kaeberlein: Yes, great, thank you for that. I’ll just say my sort of comments on the epigenetic practice test. And absolutely, if you want to get it tested, you need to get it tested. And obviously, everything I say comes from my perspective. But certainly, if getting the epigenetic test is going to motivate the people to have healthier lifestyle habits, it’s great. The only point I was making, and I think this kind of ties into your breed question as well… The only point I was making is that right now, those kinds of tests like the epigenetic clock or the breath test that you can get through your doc. There are several tests that you can get that will tell you the breed of your dog. They’re not actionable at this point. There’s no really good sound medical or lifestyle changes that you would make based on those tests. For medical reasons. That’s the only thing I would like to say.
But I think it’s great if it’s a motivating factor. So, for the Dog Aging Project, first of all, thank you for nominating your dog. That’s great. The data seems to be the case that the normalized per body size mixed breed dogs live about a year longer than pure bred dogs. That’s just observational, but that does suggest there are potentially real differences, certainly in longevity and maybe in aging. For the health and life experiences survey, we absolutely recognize that owners do their best. And answering the questions around ‘what breed is your dog’, oftentimes, it’s going to be wrong. So that’s actually an interesting aspect of the health and life experiences survey, as all of that data is owner report. And then we compare that with the medical records. But for things like breed, the medical record is not going to be any more reliable necessarily than what the owner says.
So we recognize that there are a few questions in the survey that help us understand the degree or perceived certainty that the owner has around the breed. But we recognize that it’s not as good as it’s DNA. Does that influence selection into the, what we call, the sample coat? So foundation cohort, precision, try out. The answer is yes, it does, but not in any way that is important. The way it influences selection is that we try not to be overrepresented for any given pure bred breed of dog. So for example, if we didn’t do that would we probably have a ton of Golden Retrievers. So we limit the number of dogs for a common breed. But other than that, it doesn’t really have an impact on which dogs are invited to participate in the sample coat. And there’s no limitations on breed for the pack.
16:11 – Nikhil: Hi, thank you Matt for staying on and taking our questions. Part of my question was to ask how many dogs are involved in this Dog Aging Project, and I think I heard its 32,000 in one of the previous questions. It’s really interesting to think about the amount of data that will be generated over the years of the progression of the project, because my question is more about your opinion on the following two issues when it comes to studying this data, in terms of data analysis. So, in general when we have datasets, we often remove the exceptions and normalize the data. And that helps us understand what exactly happened with these exceptions. What has gone wrong or what has gone correct. In such cases, the definition of exceptions means that there were exceptions and that we do not have a lot of data on exceptions. So how does one accurately assess that this kind of thing is a causation in the case of an exception? That’s the first thing. I’m talking from a big data and analysis on the data that is going to get generated, and the extension of the data, the primary endpoint is of course lifespan and that just tests how long the dog will live but between two age-related disease, in terms of aging, if there isn’t a problem then this means progression of body aging.
Matt Kaeberlein: Yes, both good questions. Both challenging questions. Especially a challenging one to answer in a concise way, but I’ll try. So, I think with the exceptions, this is going to be a bit unsatisfactory. But it really depends on a specific type of exception or extreme individual that you’re talking about. So one way we’re approaching this, I didn’t mention it, but we do have a small cohort of dogs that we call the centenarian dogs. These are dogs that live exceptionally long for their body size. And so, there we’re actively going out and trying to find these exceptional agents, sequence their genome, and ask what’s different about the genetics in our environment.
So, that’s an example where we’re actually doing exactly what you said. We are seeking out the unique individual that might tell us something important about how you achieve exceptional long. In other cases, it really depends. So we talked about how a lot of the data that we collect is owner reported. And there, the exceptions are often going to be ownerless stakes. You don’t want to get bogged down by including that data that is, like if an owner says that their 80 pound dog lived to be 37 years. We can be pretty sure, unless they can provide documentation, that’s a mistake. And so we are less likely to include or more likely, for awhile, those extremes on owner reported data. Unless we can actually adopt documents of those data.
So that’s the way that we’re thinking about that kind of data. Honestly, I’m not a statistician and that’s above my pay grade in terms of when it comes to the actual analysis, how do we handle the details of the data. We’ve got really good statisticians in our team and big data people who know how to do that. Okay, what was the other question? Sorry. My age related, cognitive decline is showing itself. What was your other question?
Nikhil: The other question was how do you assess the effects of rapamycin on health?
Matt Kaeberlein: Yes, that’s a really good question. That’s important in any study of aging, even if you look at the mouse studies in this field, you will see lots of cases where people claim that they have extended health. So first of all, this is my personal pet peeve. I use the word sometimes incorrectly myself.
If anybody tells you that they have shown that intervention X extends health span, they’re wrong. They have not done that, because we do not have a quantitative way to measure health span. Which I think is what you’re getting here. There’s no quantitative measure of health span that is accepted in the field. Everything that has the title ‘X increases health span’ in it, is misleading.
And I will say that, recognizing completely that I published a paper in 2016 that had that phrase, I’ve come to change the way I think about it. But the point is, we don’t have a good way to assess whether the intervention has actually broadly increased health span. I think in people, health span is something where you know that somebody has a good quality of life and good health. But even there, we don’t have a great way to assess what’s that tipping point, where you go from having health span to having your health span ending. Not only that, but at the individual level, you can go below and come back above. You could have good health span. Something happens to you. You’re sick for a while and dropped below this arbitrary threshold. And then you come back up. That happens all the time. So I think these are all conceptual challenges that we face when we’re trying to assess whether an intervention is really broadly impacting biological aging. I don’t have a great answer for you, except to say that the way I approach it is first of all, I think lifespan is the gold standard. That’s true in laboratory studies. And I think it’s going to be true in the real world. That’s one quantitative metric that there’s no ambiguity about, right? Either an intervention makes individuals live longer or it doesn’t have control. So I like lifespan for that reason, but I started to recognize that it doesn’t capture everything that we want to capture when we talk about the aging. And that’s why I try to look as broadly as possible. So I do that in my laboratory studies in my lab. Whether that’s in C. elegans or mice or multiple functional measures of aging. I’m going to come back to that. And molecular measures. And look as broadly as possible. And in triad, that’s why we have multiple second end points. For exactly that reason. That’s why we’re looking at heart function, kidney function, liver function, brain function, activity, and muscle function.
Now, for your specific question, let’s say rapamycin increases heart function, but nothing else. Or increases kidney function, but nothing else. How do we interpret that? I don’t know. I think we’ll get there and then we’ll see what the data looked like. My gut feeling is that rapamycin only impacted one aging related outcome and not the others. At least not multiple of the others. I would interpret that as did it rapidly slow aging in dogs in that context, but I think we got to get there and see what the data looks like. What you can do, is look at multiple functional measurements. And honestly, that’s more or less frailty index. It’s to broadly assess how, as opposed to only looking at one thing.
23:11 – Lena: Great, thank you. Hi Matt. So, in humans it appears that stress and traumas could cause early onset disease. I don’t know when it could happen in dogs, maybe when it was a puppy? That kind of thing.
Matt Kaeberlein: That’s a good question. The answer to your question is kinda related to the studies. We’re doing the best we can and there are some constraints in the population. You’re absolutely right that some dogs will come from a shelter, in middle age, the owners know much about history before that. Other dogs, the owners may have had since it was a puppy. So we’re collecting all of that information, including potential traumatic events. And traumatic events could be obvious, dramatic events like a dog hit by a car. But it could also be, events in the dog’s life. Having to move because, either the family relocated or there was divorce. The dog goes with one owner and not the other. So we’re trying to capture as much of that information as we can. But it’s going to be quarterly at best, and that’s also where we’re at.
I agree with what you were suggesting. Which is that those kinds of life-like experiences are likely to be important for health outcomes and potentially for biological aging. And we’re doing our best to capture that information. But just given the nature of the data set, it’s going to be an imperfect data set for us to actually really tease out a lot of those effects. We will also of course get other information. It could be also considered to stress, but is also likely contributed to health. Such as, dogs who always live in an urban environment versus in a rural environment or suburban environment. What’s a typical day like? Is most of §§the day spent outside or is most of the day spent inside? How many other dogs are there in the house? All of that stuff is information that we collect. Which I hope will, kind of, all go together to paint a picture of the experience that dog has in its environment. And some of that could contribute to trauma and stress.
25:16 – Matt: I have a question about how has it been working with local vets for bio-specimen collection, insurance quality and what have been the challenges? And second question, is there any post-mortem analysis as part of the Dog Aging Project?
Matt Kaeberlein: Yeah, that’s a good question. So I think we’re still a little bit early on to know exactly what the challenges are going to be with the private practice veterinarians. I think it’s going pretty smoothly. So one thing I’ll say is, private practice vets are extremely busy and underpaid individuals. So we’ve done everything we possibly can do to make this as easy for them as it can be to make it as little work as possible. And most private practice veterinarians are very invested in the health of their clients and they are excited to participate in the project. So I think it’s been pretty smooth, honestly. I think the biggest challenges we’ve run into with sample integrity at this point is, I don’t know what’s going on with FedEx and if they’re struggling right now with getting stuff actually delivered overnight. So by the point, the one thing, I think that’s been a challenge with sample integrity. But hopefully that’ll be better. I’m distant on FedEx and as well if anybody’s listening. But the vets have been great.
Sorry, what was the other question? Oh yeah, necropsy or autopsy. So we are in fact asking the owners, when they nominated the dog, if they would be willing, at the end of the dog’s life, to donate the body. And we have actually a biobank at Cornell. So the director of that is part of Marta Castelhano and she’s the director of the Cornell veterinary biobank and also dog aging biobank. She has experience in facilitating donations of bodies at the end of life for dogs and companion animals . And so the plan is that, at least when feasible, we will collect tissues and organs from dogs that have been in the Dog Aging Project or the longitudinal or the triad. For those kinds of end of life studies. They’re particularly important for our studies of dementia, because as you can imagine that Alzheimer’s disease is really a disease diagnosed at death on autopsy. And so being able to actually look at brains from dogs that develop dementia during aging in normal life, will be really important for understanding to what extent does that mirror Alzheimer’s disease or other dementia in people. So, that’s something that we have incorporated and it really, honestly, just be a matter of time to see how that goes.
There are a lot of challenges, as you might imagine that to that process of facility.
Laura Minquini: Thank you, Matt. So that was a question for Matt from another Matt. Thank you so much, Matt, for spending time with us and for kicking off the series with us. I guess you did say that you are looking for funding for the Dog Aging Project. Are you guys thinking also about collecting from private individuals or only looking to ground bigger donors?
Matt Kaeberlein: We are taking donations from anybody who wants to donate. If you go to Dog Aging Project website, of course there’s a donate button. Click on that and people actually should have two options. You can donate to the university of Washington or through Texas A&M, sometimes it goes to one or the other. But it’s all administered through the university and it’s all tax deductible. And we would absolutely be grateful for donations from anybody.
We would like to say a huge thank you to all of the panelists for giving us a portion of their busy schedules, and providing such an enlightening and thoroughly fascinating conversation. Our thanks also goes out to the hosts who cultivated such a fantastic discussion!