As we discussed in a recent article about Prof. George Church’s new startup, endeavors to undo aging aren’t directed exclusively toward human aging; extending the healthy lifespan of our pet dogs and cats is also currently being researched. The Dog Aging Project (DAP) has been around quite a bit longer than Prof. Church’s startup, and today, we have the pleasure to bring you an interview with one of the lead scientists behind it, Dr. Matt Kaeberlein.
In much the same way that other projects are aiming to extend healthy human lifespan, the DAP team intends to do the same, targeting the aging processes directly. Given the rate of progress in geroscience over the past years, Dr. Kaeberlein and his team are optimistic that, in the near future, the interventions that have been shown to slow down aging in mice and rats could do the same in our furry companions.
Besides Dr. Kaeberlein—who is a Professor of Pathology and an Adjunct Professor of both Genome Sciences and Oral Health Sciences at the University of Washington in Seattle—the DAP team is comprised of Dr. Daniel Promislow, Professor of the Departments of Pathology and Biology at the University of Washington; Dr. Kate Crevy, Associate Professor of Small Animal Internal Medicine at Texas A&M University’s College of Veterinary Medicine; Dr. Tammi Kaeberlein, a research scientist at the Department of Pathology at the University of Washington; Dr. Silvan Urfer, a veterinarian and Senior Fellow of Washington University’s Department of Pathology; and Kelly Jin, a doctoral student currently pursuing a Ph.D. in Molecular Medicine and Mechanisms of Disease at the University of Washington.
The team believes that extending our pets’ healthy lifespan will have benefits in both their and our lives, which is perfectly understandable. We all would like to spend a longer time with our loved ones—and these rightfully include our pets—in the prime of their and our health. To this end, DAP intends to run a longitudinal study of aging in pet dogs and is running a rapamycin intervention trial in dogs, phase 1 of which has already been completed. Rapamycin is an mTOR pathway inhibitor, about which you can read a bit more in this older LEAF article.
Dr. Kaeberlein was kind enough to answer our questions about the DAP’s story and work; without further ado, here’s what we talked about.
Could you tell us the story of DAP? How did it all start?
About 5 years ago, I was able to recruit Daniel Promislow to the University of Washington to join the UW Healthy Aging and Longevity Institute. At that time, Daniel had recently obtained a small grant from NIH to develop companion dogs as a model to understand the genetic and environmental determinants of aging. After a series of discussions with Daniel, it occurred to me that we had an opportunity not just to study aging in dogs but to potentially develop interventions to delay or even reverse aspects of aging in dogs from those that had already been shown to increase lifespan and healthspan in laboratory rodent models.
I decided to focus on rapamycin first, because it was (and still is) the most validated and effective pharmacological approach for increasing longevity in mice, and it has the added benefit that it is effective even when initiated in middle age. After spending a couple of months convincing myself that we could safely perform a rapamycin veterinary clinical trial in dogs, I organized a conference in Seattle in 2014, where I pitched the idea. Soon after that, we started getting quite a bit of media attention, and we decided that we should officially form the Dog Aging Project, which, at the time, consisted of myself, Daniel, my wife Tammi, and our lead vet, Kate Creevy. Tammi quickly built the website, and I started putting together funds for our Phase I rapamycin intervention trial.
What can you tell us about trials you’ve already run and their results?
So far, we’ve only completed one trial, a 10-week, randomized, double-blind, placebo-controlled study of rapamycin in pet dogs. The results of that study were as positive as we could have hoped. We saw no evidence for increased side effects in the dogs that received rapamycin and statistically significant improvements in two of the three measures of age-related cardiac function that we looked at.
Are there any trials you’re running right now or are preparing to launch soon?
Yes, the Phase 2 rapamycin intervention trial is currently enrolling dogs. That trial is funded by the Donner Foundation and is a one-year trial to, again, assess effects of rapamycin on cardiac function and to also look at effects on cognitive function and activity.
Depending on the outcome of our submitted NIH grant, we hope to begin officially enrolling dogs into the Longitudinal Study of Aging and Phase 3 of the rapamycin intervention trial toward the end of 2018 or early 2019. We hope to have an official announcement on the outcome of that proposal within the next 3-4 weeks.
Can I volunteer my dog for the program, and how do I do that?
Anyone can nominate their dog to participate in either the Longitudinal Study of Aging or the Rapamycin Intervention Trials through the Dog Aging Project website at www.dogagingproject.com. The Longitudinal Study is currently open to all breeds, ages, and sizes of dogs. The Rapamycin Intervention Trials are restricted to healthy dogs of at least 6 years old and at least 40 lbs in weight.
What are the most promising lines of intervention that you are studying to extend the healthy lifespan of dogs?
Currently, rapamycin is the only intervention we are testing due to budgetary limitations. I have recently begun pitching the idea of a Companion Animal Intervention Testing Program to take the most promising interventions from basic geroscience research and test them in pet dogs as long as that can be done safely. Obvious candidates would include NAD+ precursors, metformin, acarbose, deprenyl, 17α-estradiol, spermidine, and NDGA.
On your website, you say that the possibility to increase the healthy lifespan of our pets by up to five years is within our reach. Could you give us an estimate of how long it’ll take before these therapies might be available for our pets?
I’ll answer that assuming you want to know how long it will take to obtain scientifically rigorous evidence that an intervention is working. There is nothing stopping an owner from giving NAD+ precursors or rapamycin to their pet if that person can identify a vet who will prescribe it.
Based on our power calculations, we anticipate that it will take about 3 years of treatment, beginning in a middle-aged cohort of appropriate size, to detect significant extension of lifespan. Our Phase 3 study plans to enroll dogs over the first year and a half, so the total timeframe is 5 years, start to finish. Other changes, such as improvements in heart function, can be detected much more rapidly.
Those same power calculations and design features are equally applicable to other interventions. When and if we are able to test them will depend on funding.
What about cats; do you think we might do the same for our pet cats as well as dogs?
In general, I expect that any intervention that slows aging in dogs will have a similar effect in cats, although it is the case that certain compounds are toxic in cats and not in dogs and vice versa. I know that rapamycin has been used in cats for other indications, and there’s nothing about the biology of mTOR that makes me think that rapamycin will be less effective in cats than it is in dogs. From a clinical trial perspective, it makes sense to start in dogs for a couple of reasons. First, big dogs age faster than cats, to the outcome is knowable in a shorter time frame. Second, it’s easier for owners to give a pill to their dogs than to their cats.
How expensive do you imagine the first generation of anti-aging therapies for pets will be? Can we expect them to eventually become affordable?
If rapamycin is shown to be effective at slowing aging in dogs, I think it will become quite affordable. The cost of rapamycin currently is largely driven by relatively low demand, but it is off-patent, and generic versions are available. If there is sufficient demand to drive competition, prices will drop substantially. Even at current prices, it would probably cost an owner $50-200/month, depending on the size of dog and dose given, which is affordable to many people. Some other candidates from the list I suggested are even cheaper than rapamycin.
Recently, Prof. George Church co-founded a new start-up, Rejuvenate Bio, which is poised to reverse aging in dogs using gene therapy in the hopes of eventually doing the same in people. What do you think of this approach?
I think the approach is viable in theory and could turn out to be quite powerful in the future, but it has yet to even be proven in a laboratory mouse model of aging. Show me that you can increase the lifespan and healthspan of a mouse by 25% through this approach without significant detrimental effects, and I’ll be more optimistic. Reproduce it in a dozen labs as has been done with rapamycin in mice, and I’ll jump on board the bandwagon.
I don’t know precisely what they are planning, but I do have major concerns about the safety of applying gene therapy to healthy dogs at this stage. In general, I would urge anyone considering performing intervention studies in companion animals to recognize how important it is to ensure that you don’t harm anyone’s pet.
I suspect that they will start with specific diseases of aging, and I’ve read that they are planning to attempt some sort of gene therapy to treat heart disease in Cavalier King Charles Spaniels. Again, I would like to see proof of principle that such a therapy can work in a laboratory model of valvular regurgitation (the primary problem in that breed of dogs) before moving to testing in people’s pets.
It is clear that in the last decade, there has been a real leap in our understanding of what aging is and the processes and potential points of intervention. While we do indeed have lots more work ahead of us before the medical control of aging is plausible, are you optimistic about progress in the field?
Absolutely. I’m more optimistic than I’ve ever been, both because of the scientific advances and because of the growing recognition and respect that geroscience is receiving among the broader scientific community and the biotech/pharmaceutical world. I do have concerns that the field continues to be hindered and progress is delayed by fringe elements who give us a bad reputation among funders and policy makers, but we are gradually overcoming this as real interventions that have been validated in preclinical studies begin to make their way to the clinic.
What are some of the key studies that convinced you that doing something about aging was plausible?
I never really doubted it once I became knowledgeable about the field. It seems obvious that longevity is quite malleable – all you have to do is look across the animal kingdom to see that. We’ve known for many years that single-gene mutations can alter aging rates in every laboratory species that we’ve examined, and it’s increasingly becoming clear that it’s not that hard to find them. So, aging is malleable at the species level as well. The big unknown in my mind is how well laboratory interventions will translate into the real world. I think that this is where companion animals can help immensely, since a true longevity clinical trial in people is simply not feasible.
If I have to point to one study though, it is the ITP study showing that rapamycin treatment increases lifespan in mice when started in middle age. Before this, everyone was testing interventions beginning in young age, which is obviously not translationally viable. Now, we know of several interventions that appear to have effects in middle age in mice (NAD+ precursors, senolytics, “young blood”, etc.) and that all of these interventions probably not only slow aging but actually rejuvenate function in at least some organs and tissues in aged animals. In the case of rapamycin at least, there is now initial evidence that mTOR inhibition can rejuvenate immune function in healthy elderly people as well. I would be surprised if other effects of rapamycin in mice don’t translate just as well.
Currently, one of the most highly regarded theories of aging is the 2013 Hallmarks of Aging, which describes the various aging processes with particular emphasis on humans. How relevant to humans is your research in dogs; do they share the same aging processes?
Everything we know indicates that dogs age very much like people, only 7-10 times faster. Dogs get all of the same diseases of aging that people do, although not necessarily at the same frequency. Vascular disease, for example, is a bigger killer in people than in dogs.
Do you think that your work may prove useful to scientists working on therapies against human aging?
For the longitudinal study of aging, undoubtedly. Any environmental or genetic factor that we can correlate to healthy aging in dogs will be a high-priority candidate for validation in humans.
If we are successful at showing that rapamycin (or another intervention) can increase healthy longevity in dogs, this will demonstrate that the intervention works in a large mammal that shares the human environment. It’s an important next step toward human application. Perhaps equally important is that this should be quite helpful in terms of convincing the FDA and other regulatory bodies that aging is a viable endpoint for treatment. Keep in mind that the FDA also regulates veterinary medicine. While it’s not feasible to do a lifespan study in healthy elderly people, it is completely feasible to do several of them in healthy elderly dogs, so a true clinical trial with longevity and/or healthspan as the endpoint is doable.
In addition, if we are able to convince owners that it is possible to slow aging in their pets, this should accelerate acceptance of and support for geroscience among the general public.
Clearly, the DAP team thinks that we can at the very least slow down aging; do you think we might be able to reverse its effects, potentially postponing “the unpleasantries of extended life”, as Prof. Jay Olshansky once put it, indefinitely?
It’s clear that most of the interventions I’ve mentioned above can restore function to at least a subset of aged organs and tissues. I don’t know if this is really “reversing aging” as a whole, but it is at least functionally rejuvenating some aspects of aging.
Whether this can be done indefinitely is pure speculation at this point. Is it possible? Probably. Is it likely in the near future? I’m doubtful, but I’ve been wrong before and I wouldn’t mind being wrong now. My personal opinion is that it’s irresponsible and damaging to the field for people to talk about immortality being a reality in X number of years from now. These people simply don’t understand the complexity of biological aging if they think they can put a number on how long it will take to achieve immortality when the best we’ve been able to do in a rodent is a 50% extension of lifespan. That’s not much better than Clive McCay managed in 1935.
Some researchers suggest that aging is a disease or, more specifically, a co-morbid syndrome; would you agree with this or not, and why?
Frankly, I think it’s a semantic argument that some people in the field spend way too much time arguing about. Despite what some people think, it doesn’t matter from a regulatory perspective, since aging could be an indication if you had sufficient quantitative endpoints to prove efficacy of an intervention.
I think the more fundamental question here is whether aging is actually a molecular process that can be targeted or a collection of unrelated ways that different organs and tissues break over time to cause different diseases of aging. To me, the answer is obvious. You can’t explain the unrelated processes model given that we know about single gene mutations that not only extend lifespan but also delay most (if not all) of the functional declines of aging.
I think what we still don’t quite have a handle on is whether aging at some level can be boiled down to one molecular process/pathway or if it will turn out to be a collection of processes (i.e. the current Hallmarks framework). In any case, there are key nodes in the network that you can hit, such as mTOR, that appear to affect all of the Hallmarks simultaneously, so, at some level, there is a unifying mechanism.
The idea of human life extension is often met with fierce, irrational opposition. In your experience, do people react in a similar way to canine life extension, or are they more supportive of your work?
I’ve never really experienced fierce opposition to the idea of increasing healthy longevity in pets. Some people do express concern that there are already many pets in need of homes and wonder if this might make it harder to find good homes for those pets. The point I make in the context of targeting aging, for both dogs and people, is that this is really no different in principle than what we already do. If your dog or your spouse has cancer, your goal is to treat the cancer to keep them alive longer. We are just trying to do it in a more efficient and humane way by preventing our dogs and our loved ones from getting sick in the first place. When explained that way, most people get it.
In the past few years, senolytics have made the headlines more than once as the first bona fide rejuvenation therapies that might become clinically available for people. Are you optimistic about senolytics as a potential way to address aging in both dogs and humans?
Definitely. I think there are still some concerns about safety with the current generation of senolytics, but I expect that this will be improved upon. I do wonder if they will be any more effective than rapamycin, however. So far, there’s not much evidence that I’m aware of to suggest that will be the case. The excitement may have gotten a bit ahead of the data in that regard. It will be important to test combination treatments of senolytics and mTOR inhibition in mouse models to address this question.
What do you think is the greatest bottleneck to progress in aging research?
Funding and perception, and these two are related. There is insufficient funding for scientific research in general and insufficient funding for geroscience in particular. That has been the biggest bottleneck to research progress. The field has also suffered from a reputation problem for many years as not being particularly rigorous, and this has hurt the flow of research dollars into the field. This has been changing but is still a problem.
Do you have a take-home message for our readers?
I think we know enough about the biology of aging to increase healthy longevity in pet dogs by 3-5 years today. Almost certainly, one or more of the interventions we could test today would be successful. I know that we all want progress in translational geroscience to be as rapid as possible, and I believe that rigorously demonstrating that we can increase healthspan and lifespan in pet dogs will be a huge step toward gaining the support and credibility that the field needs. Plus, I want my dogs to live longer ☺.
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.