Almost three years ago, Dr. Matt Kaeberlein, a Professor of Pathology and an Adjunct Professor of both Genome Sciences and Oral Health Sciences at the University of Washington in Seattle, outlined the nascent Dog Aging Project (DAP) for our readers in an extensive interview. Along with the intrinsic value of helping our beloved pets live longer, DAP also seeks to establish dogs as a highly effective platform for studying aging in humans.
Now, with the foundational phase of the project nearing completion, we have asked Dr. Kaeberlein to give us an update, and he has responded with some exciting news. Our talk with one of the world’s leading authorities on aging also touches on several other hot topics, including rapamycin and geroscience in the age of COVID-19.
We interviewed you about DAP back in 2018. Maybe you can walk us through the progress you have made. Where does it stand now?
Around the same time, we got a large grant from the NIH, about 5 million dollars a year, to build and carry out a longitudinal study of aging in dogs and to fund our rapamycin clinical trial. We refer to the rapamycin trial as TRIAD: Test of Rapamycin In Aging Dogs. There are two big parts to the Dog Aging Project. One is a true observational longitudinal study of aging, and the other is TRIAD, and most of the time so far has been spent building the infrastructure to carry this out. The goal of the longitudinal study initially was to enroll 10,000 dogs, but we have expanded this with a new goal of 100,000 dogs enrolled in what we call the Dog Aging Project Pack. For each dog in the pack, we obtain high-resolution data on the dog’s environment and health history through owner surveys and electronic veterinary medical records. At this point, we are nearing 30,000 dogs enrolled in the Pack.
From the Pack, we are selecting 10,000 dogs to have their genomes sequenced along with owner survey data and veterinary medical records. That is what we call the Foundation group. A thousand dogs are selected for what we call the Precision group, and that’s a systems biology study where, every year, in addition to these dogs’ genome sequencing, we will collect their fecal microbiome, blood metabolome data, blood epigenome data, and comprehensive chemistry from blood, and there are also annual veterinary visits. TRIAD is designed to have 500 dogs come in for the initial visit with the goal that 350 of those dogs will be randomized into the clinical trial, which is half rapamycin, half placebo.
You can imagine that, first, there is a ton of infrastructure on the computing side and the survey instruments that had to be built. Basically, that is 95% built. We have a partnership with the Broad Institute, and all the data that comes into the Dog Aging Project is then eventually sent to its cloud computing Terra platform, where it can be accessed. One of the main features of the Dog Aging Project is that we are an open science project. We want to stimulate discovery outside of our team, and our plan is to release the data that we have collected in annual installments to the scientific community and eventually to the public. Because of COVID, we pushed back all the stuff that requires dogs to come into the veterinary clinic since, like medical human hospitals, veterinarians only wanted to see patients who needed to be there during COVID.
So, like I said, 95% of the project infrastructure is built, but we are not yet having dogs in the clinic. We have focused mostly on collecting data through survey instruments. We have rolled out a large survey that really captures as much information as we can about the dogs, some information about the owners’ demographics, and a lot of information about the environment that each dog lives in along with the dog’s behavior and comprehensive health history. This Health and Life Experiences survey, which we call HLES, has been completed for almost 30,000 dogs. This is now one of the largest citizen science projects in the world.
We are getting our first longitudinal snapshot right now, as the very first dogs to enter the Pack are reaching their one-year anniversary and their owners are being asked to update the HLES with any changes to their dogs’ environment or health status. This will continue for every dog in the Pack once each year for the rest of their lives. This is going to be a super-rich data set, and we’ll be able to see how those dogs are aging, what environmental, dietary, and genetic factors might correlate with health outcomes during aging, and a baseline of what aging looks like in dogs. Nobody has ever done that. One of the things that people don’t really appreciate is that unlike in human medicine, in veterinary medicine, there is no geriatric subspecialty. There are no veterinarian clinicians who are trained specifically to understand what happens during aging in our pets, and so this is an opportunity to actually provide this information to the veterinary community.
The other thing that we have added that wasn’t part of the initial plan, but that I’m super excited about, is a second survey that is specifically dedicated to cognitive function and dementia in dogs. There is a validated survey instrument for diagnosing canine cognitive dysfunction, which is a disease that looks somewhat like Alzheimer’s in dogs. It has some of the same neuropathological hallmarks. We’re hoping that this survey will actually be able to detect changes in cognitive function associated with aging that don’t reach the threshold of dementia. If we’re able to do that, it gives us a really important insight.
I have a grant proposal that, if funded, will allow us to expand our studies of cognitive aging into molecular sorts of questions like amyloid beta. I think that companion dogs potentially offer a super-powerful model of dementia in people. There is a whole collection of cognitive disorders that share some similarities but clinically present very differently. I think that dogs potentially offer an opportunity to understand some of the factors that influence cognitive aging because they do show cognitive changes with age that look very similar to aging in people.
You told us back in 2018 about the rapamycin trial coming up. What is the situation on that front?
I already mentioned that the intention is to select up to 500 dogs from the pack. In order to be eligible for the rapamycin trial, the dogs have to be at least 7 years old and weigh between 40 and 100 pounds. That’s because big dogs age faster than small dogs, and we need to have a middle-aged cohort in order to have the statistical power to detect the changes in lifespan that are our primary endpoint.
Unlike the Foundation or Precision cohorts, where owners can go to their own veterinarians, all the clinical components of TRIAD will be carried out at seven different veterinary teaching hospitals around the United States. Obviously, that means the owners have to be willing to take their dogs to these clinical sites twice a year for the duration of the study, which limits the geography. Then, there’s a training and consent process that the owners go through before we will schedule them for their first appointments at the hospitals. We want to make sure that the owners in TRIAD understand what is involved before we bring them in for their first visit.
We haven’t had any dogs come into the clinic yet because of the pandemic. Our expectation is that we’ll have the first few dogs probably in May, and then we’ll gradually ramp up. Our target is to have a hundred dogs enrolled in the trial by the end of 2021 and the remaining 250 randomized in the first half of 2022. This is what we are powered for: to see a 15% effect on lifespan over three years.
Secondary endpoints include cardiac function, which is one of the reasons we’re working with the hospitals; they all have outstanding cardiology teams. Cognitive function is another secondary endpoint, and we’re very interested in disease incidence, particularly cancer. We predict that rapamycin could reduce cancer incidence in dogs. Activity is a secondary endpoint too.
We’ve decided to go with a one-year treatment followed by two years of follow-up. This is based in part on the human clinical data with rapamycin derivatives. We want to minimize the risk to all the participants. Owners’ fatigue is also a factor: after talking with a lot of people, it became clear to us that asking owners to give a study drug for a randomized, double-blind, placebo-controlled trial to their dogs for three years was asking a lot.
The drug will be given once a week based on the human data from clinical trials with everolimus, which is a rapamycin derivative. It seems that an equivalent total dose given once a week rather than daily has better efficacy with reduced side effects. We are using a form of rapamycin that is coated for enteric release. It’s not the eRapa (encapsulated rapamycin) that’s used in mice, that’s a different formulation, but it is also not exactly the same as generic rapamycin (sirolimus) tablets that organ transplant patients take.
Will you be accounting for differences between male and female dogs?
We don’t know if there are differences in rapamycin efficacy between male and female dogs yet. If you’re familiar with the mouse data, at least at lower doses of rapamycin, female mice tend to show bigger lifespan effects than male mice. That’s not necessarily true for all of the functional measures or what people call healthspan measures. That effect is likely due to the fact that female mice tend to have higher steady-state blood levels than males do. However, I don’t think there’s any evidence to suggest that there are large sex-dependent effects of rapamycin in people, and there’s no data yet in dogs. So, the answer to your question is, we are aware that that could be the situation, but we don’t have any particular reason to think that’s going to happen. We are stratifying by sex. Our goal is to equally enroll male and female dogs and roughly equally distribute them between placebo and treatment groups. That’s the best we can do at this point.
What about breed differences? Do you expect any problems there?
We are not restricting by breed. We were anticipating that we will have roughly half purebred versus mixed breed. We decided not to stratify based on that. We’re going to limit the number of any one breed in the study so that most popular breeds don’t get overrepresented, like golden retrievers.
I’ve said repeatedly that there’s intrinsic value to improving health during aging in our pets, but if we see big effects from rapamycin in dogs, that certainly enhances enthusiasm for continuing to look for similar effects in people. In that regard, the fact that dogs are genetically heterogeneous is important. The question is not whether rapamycin will work in German Shepherds, the question is whether it will work in a heterogeneous population that looks genetically something like the human population. So, we want to capture that genetic diversity, and we will have full genome sequencing on every dog in TRIAD. Unless there are huge genetic signals, I don’t think we have enough dogs to map genetic variants to efficacy in the trial, but there are large genetic interactions, we might be able to identify some of them.
Where do we stand with rapamycin in general? Has it been living up to the expectations?
I think if you look at the preclinical data in mice, rapamycin is head and shoulders above anything else in terms of interventions that have been tested repeatedly, work repeatedly, and appear to broadly delay aging in mice. Compare it to metformin, which doesn’t extend lifespan in mice most of the time, and the health benefits of metformin in mice are pretty much restricted to cancer in certain backgrounds and metabolic outcomes. Metformin is a different beast because there’s a lot of human data that actually supports the idea that metformin might affect aging in people, but I think if you were to pick a drug based only on the mouse data and you were being honest with yourself, rapamycin is the only game in town. There is nothing else in mice that comes anywhere near the data that we’ve got for rapamycin.
Then the question is, does the human data for rapamycin support the idea that it actually has impact on age-related outcomes in humans? I think the fair answer is that nobody has done a great clinical trial with rapamycin. There were two trials with everolimus, which is a derivative of rapamycin. If we accept for the purpose of this conversation that those two drugs are biochemically pretty much identical, the data is pretty good. In the two Phase 2 clinical trials, there was a positive effect on immune function in healthy older people from six weeks of treatment with a rapamycin derivative. They responded better to a flu vaccine and they got less infections. So, that’s at least as good as you could hope for. There have been a couple of small clinical trials for safety showing that at lower doses of rapamycin, there are little to no side effects. There was one very small study looking at skin senescence in people, but we really just don’t have any data to say one way or the other. I think there’s a lot of confusion and misinformation out there when the data comes from people who have had organ transplants, who are taking high doses of the drug along with a bunch of immunosuppressants. You can’t really look at those patients as a reflection of what rapamycin might do at lower doses in healthy individuals.
In the previous interview you gave us, you pointed at insufficient funding as the main problem that hampers progress in the longevity field. Do you think this is still the case, or maybe we’ve already seen some commercialization of the field?
There’s a couple of things to say. One is that I think it’s very exciting that there is a lot of interest and some resources coming into the field on the commercial side, and clearly that momentum is building. I also think it’s important to recognize that if you take Calico out as a hybrid of a company and academia, the total amount of money that’s coming into this field on the for-profit side is a tiny drop in the bucket compared to the annual budget of the NIH or even the NIA. So, I still would argue that the resources that are coming to the field are miniscule compared to what they should be, given where the science is at and the potential benefit for human health.
This needs to change at the federal funding level. I don’t think you’re ever going to see the same kind of impact from private investment. I would love to be proven wrong, and you never know what might happen, but I think that even though more is coming into the field that way, it’s not as impactful as if aging biology went from 0.5% of NIH funding to 5% of NIH funding. That would be a tenfold increase overnight, which is still a small proportion of NIH funding given the impact of this biology on human health. People have this perception that all this money is coming through the commercial side, and while it’s true compared to the past, it’s still not that much in the grand scheme of things.
I’m thinking of what you said about the openness of your project and the wide availability of the results, which is something that commercial enterprises are not really good at. You are saying that there is still not a lot of money on the for-profit side, but could it already be harming cooperation?
It’s possible. It’s hard to know. Because people aren’t sharing, we don’t really know what they’ve got. Calico, again, is an interesting example because they’re kind of in the middle, they published some papers, but they obviously must have a lot of data that they’re not publishing, and so we don’t really know how important or impactful that data would be. Again, though, I would say because 95 to maybe 99 percent of actual research in this field is happening in academia right now, I don’t think it’s a huge barrier to progress.
That’s my personal opinion, and maybe I shouldn’t say this, but I’m going to anyway. I think that most of what’s happening right now in the anti-aging for-profit arena is really not cutting-edge science. There are a lot of people coming up with their own ideas who don’t have sufficient background knowledge or understanding of aging, and so they’re making a lot of maybe newbie mistakes that could be avoided if they didn’t come in thinking they already knew everything. But they do come in thinking they know everything and that they’re going to solve aging, and they just throw a bunch of money at it, and it fails miserably. That’s my impression from a lot of what is happening on the for-profit side.
I think that’s changing. I also think some of the newer companies that have come in recently are a bit more sophisticated; they actually have some people with appropriate background and knowledge to guide them. However, I’m quite skeptical that there is a ton of super-valuable data in the for-profit sector right now.
On the NIH side, the tide is starting to turn as well. Do you feel it?
I do, and I think the tide is turning in a way that I’m personally very pleased about. An RFA (request for applications) came out fairly recently for clinical trials to target the hallmarks of aging, which is great. That clearly shows interest at the NIH in this area, but that RFA was released by the NIA, the National Institute of Aging. If it had come from the Director’s Office, I would be super excited because then it would show me that this has gotten beyond the NIA and permeated the NIH more broadly. Interestingly, in a way, it is already happening. For example, if you look at cancer, the NCI (National Cancer Institute), if you look at diabetes, the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases), they’re now studying aging processes. They’re not calling it biology of aging, but they’re interested in senescence, or in changes in mitochondrial function that go along with age, or age-related inflammation that we’re studying as a hallmark of aging. They’re studying it in the context of their disease, but they’re starting to view these things from the perspective of aging. Honestly, I don’t care if they call it aging, I don’t care if the money flows through the NIA or it continues to go through each individual Institute. I’m pleased by the fact that scientists who haven’t previously focused on aging biology are starting to incorporate it into their research, even if they don’t realize it.
In a paper you co-authored, “Geroscience in the Age of COVID-19”, you argue that “one of the most important lessons to be learned from this pandemic is the need to therapeutically address degenerative aging processes to prevent aging-related ill health as a whole”. Many scientists have called for the same approach, and we ran an editorial about that. Do you think we have been heard?
I don’t know. My intuition is that these changes were already happening. Certainly, the pandemic might accelerate them, and I think that papers and editorials on this topic have helped to make the point that COVID-19 is an age-related disease. Hopefully, this will shift mindsets a little bit towards recognition of how important aging is, specifically in the context of COVID-19 but not exclusively. For example, before COVID-19, we accepted that 250 to 500 thousand people a year worldwide would die from influenza, mostly old people. There’s an important biology for this disease that we have accepted for a long, long time will kill half a million people a year, and we could potentially do something about it. So, we need to continue to get that message out there, and hopefully it will help accelerate this recognition that there is a biology of aging that is malleable, that we know enough to actually have an impact and hopefully protect the most vulnerable people from COVID-19, influenza, and other infectious diseases.
I assume that you are doing research apart from the Dog Aging Project. Would you like to tell us what you are working on?
Sure. My lab has always been focused on conserved mechanisms of aging. We still work in yeast and C. elegans and mice. Our mouse studies are primarily focused on metabolic diseases, mitochondrial diseases. We have a project on a metabolic disease called maple syrup urine disease. We have an obesity project, and then we have normal aging, so we kind of work on a lot, but it’s all from the perspective of understanding how the hallmarks of aging, the molecular mechanisms of aging, impact these various diseases in different mouse models. A lot of what we’re interested in, as you might guess, is mTOR biology, rapamycin, and other mTOR inhibitors.
We published a paper last year on the ability of rapamycin to reverse periodontal disease in mice. We haven’t yet moved this into the clinic, but I’m hopeful because periodontal disease is unique from a clinical trials perspective: it is a very easy endpoint to measure in humans, and it’s very non-invasive. You go to the dentist, and they do a pocket depth measurement and an x-ray. They look at your gingival inflammation, and you can sequence the oral microbiome, and those are the three clinically defining features of periodontal disease. So, it’s actually quite an easy clinical trial to carry out. I’m hopeful that we’ll be able to get a clinical trial going to see whether rapamycin, or a couple of other interventions that we’ve got, can have a clinical impact on periodontal disease in people.
Unfortunately, it is a ridiculous example of how the for-profit system and the regulatory system is broken. There is a very good chance that we will be able to reverse periodontal disease in people. I believe that’s true, and our preclinical data is rock solid for rapamycin and looking pretty good for another intervention, and yet there is very little interest in commercializing that, not because people don’t think it’s going to work, not because rapamycin is off-patent, but because of the way that dental insurance is billed and they don’t think they’ll be able to get reimbursed. It’s not worth the risk of an FDA clinical trial for them.
We have a really nice endpoint where there’s an opportunity to have proof of principle that a geroscience intervention works for an age-related disease in a pretty short period of time. Like I said, there’s rock-solid preclinical data, better than the preclinical data supporting 90% of the biotechs that are out there, but people aren’t interested in commercializing it because of the way that dental insurance is billed. I was sort of surprised that that’s the reality. I haven’t given up on the idea, but it’s a really unfortunate consequence of the way in which we regulate and charge for healthcare in this country.
I feel that we have become accustomed to this US-centric approach, but other countries do health insurance differently. Do you think that those differences in regulation, and maybe in the way societies work in general, can lead to a breakthrough in longevity research coming from, say, China, because they have a huge problem with their one child policy and because they are less scrupulous with regulation, privacy, and human rights?
I think it’s certainly possible, but, obviously, most of the money right now is focused on drug approval in the United States. That’s just the way the system works. So, it’s absolutely possible that a breakthrough may come from a different country, but, unless things change, they’re still going to want to get FDA approval and have to go through that process. I absolutely agree with the premise that there is exciting aging research going on outside of the United States, and it would not surprise me at all if something important on the therapeutic side gets tested and validated first somewhere else before coming into the US FDA approval system. China, sure, but that’s not the only place for this. It’s wherever the science is happening and wherever the infrastructure is in place for for-profit entities to come in.
We thank Dr. Kaeberlein for taking the time to talk to us, and we look forward to seeing the future results and developments of the Dog Aging Project.