Modern Methods in Aging Research: From Laboratory Mice to Companion Dogs

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• Model Organisms in Aging Research
• Laboratory Mice as the Gold Standard
• Companion Dogs as a Powerful Model
• The Dog Aging Project Infrastructure
• Diet and Nutrition in Aging Dogs
• Feeding Frequency and Health Outcomes
• Full Transcript

Model Organisms in Aging Research

Dr. Matt Kaeberlein, MD, PhD, provides a high-level overview of the methods used in modern aging research. The field relies heavily on a core group of model organisms often called the "Security Council of Biology." Dr. Matt Kaeberlein, MD, explains that about 90% of preclinical work is done in budding yeast, nematode worms (C. elegans), fruit flies, and laboratory mice. These models offer different advantages, such as the incredibly short three-week lifespan of C. elegans, which allows for thousands of experiments.

Laboratory Mice as the Gold Standard

Dr. Matt Kaeberlein, MD, PhD, identifies laboratory mice as the current gold standard for preclinical aging studies. This is largely due to their extensive use over several decades. A significant development has been the commercial availability of aged rodents. Researchers can now purchase aged mice instead of maintaining colonies for years. This change has greatly expanded the capacity for conducting lifespan and healthspan studies in mice. However, Dr. Matt Kaeberlein, MD, notes this may come at the expense of exploring aging in other valuable model systems.

Companion Dogs as a Powerful Model

Dr. Matt Kaeberlein, MD, PhD, expresses particular excitement about studying aging in companion dogs. Pet dogs age about seven times faster than humans, allowing studies to be completed in a reasonable timeframe. Crucially, dogs share the human environment, experiencing similar environmental variations. This is a major advantage over laboratory mice raised in controlled, pathogen-free facilities. Dr. Kaeberlein believes this makes dogs a powerful model for understanding how environment impacts biological aging.

The Dog Aging Project Infrastructure

A key initiative discussed by Dr. Kaeberlein is the Dog Aging Project. This longitudinal study aims to build the infrastructure for using companion dogs in aging research. The project has enrolled approximately 34,000 dogs into its foundational component. Owners complete an extensive health and life experiences survey for their pets. This comprehensive data collection captures health history, home environment, and food consumption patterns. The goal is to understand the genetic and environmental determinants of healthy aging in dogs.

Diet and Nutrition in Aging Dogs

During his conversation with Dr. Anton Titov, MD, Dr. Kaeberlein addresses the role of diet in canine aging. He clarifies that while dog diets in the Western world are not identical to human diets, there is significant variation. Dogs are fed different formulations, including kibble, wet food, prescription diets, and raw food diets. This diversity, though not as broad as human food variety, offers a chance to study diet's impact. It represents a step up from the highly refined and controlled diets given to laboratory rodents.

Feeding Frequency and Health Outcomes

Dr. Matt Kaeberlein, MD, PhD, shares compelling data from the Dog Aging Project on feeding frequency. Analysis of the large cohort revealed a striking correlation. Dogs fed only once a day showed lower frequencies of diagnosis for ten categories of age-related diseases. For six of those categories, the effects were large and statistically significant. Dr. Kaeberlein cautions that this shows correlation, not necessarily causation. However, it powerfully illustrates how studying companion dogs can generate important hypotheses about nutrition and aging.

Full Transcript

Dr. Anton Titov, MD: But if we step back a little bit and perhaps address the methods of modern aging research, because there are several model organisms, as they say, the Security Council of Biology. How is modern aging research being done? Perhaps you can give a high-level overview.

Dr. Matt Kaeberlein, MD: I would say laboratory mice are still probably the gold standard for preclinical studies. That's in part because that's the model organism that has been used most extensively over the last several decades, and the availability of laboratory mice.

One of the really important changes over the last five or ten years has been the commercial availability of aged rodents for experimental studies. It used to be hard to do aging studies, lifespan and healthspan in mice, because you had to start three years ago to get your mice old enough to do the experiments. Now you can just buy aged mice from Jackson Laboratory, so that has had a big impact on facilitating an expansion of aging studies in preclinical models.

Another consequence of that, though, is that even more people are using mice, perhaps at the expense of exploring aging in other model systems.

The classic animal models for aging research are budding yeast, the nematode worm C. elegans, fruit flies, and mice. I would still say 90% of the preclinical work in the field is done in those models. Killifish is emerging as a really interesting new vertebrate model, but it's still a relatively small number of animals using killifish.

There are some of these other more esoteric animal models like the naked mole-rat that a couple of people have been studying for many years. But again, that's a real minority of the field, studying aging in these very long-lived animal models, because it's hard to do experiments in an animal model that lives 30 years.

That's the brilliance of something like C. elegans, that ages and dies in three weeks. You can do thousands of experiments in a reasonable amount of time. You just can't do that even in mice, and certainly not in a naked mole-rat that lives 30 or 40 years. So it's a balancing act.

The other animal model that might be worth mentioning is the marmoset, which is a non-human primate. There are a few labs studying aging in the marmoset. One of the advantages of the marmoset over larger non-human primates is that they have a lifespan in the range of 10 to 20 years.

One of the disadvantages of the marmoset is we don't know what its lifespan in captivity is. I think that's been a challenge for some of the people working with the marmosets is they thought that the marmosets were only going to live ten years, but it turns out they probably live longer than that in captivity. So we'll see whether the marmoset emerges as a useful non-human primate model.

And then, of course, the animal that I am particularly interested in and excited about understanding the biology of aging is the companion dog or the pet dog. Pet dogs are really interesting animals in which to study biological aging for a variety of reasons.

Two of the big ones are they age rapidly. Everybody's familiar with the idea that one human year is about seven dog years. All that means is dogs age about seven times faster than people do. That, of course, is not a true biological equivalence, but it's pretty close.

So that means you can do studies to try to understand what are the most important genetic and environmental determinants of healthy aging in pet dogs in a reasonable timeframe.

Another feature of dogs, though, that I think is really important to appreciate is they share the human environment. We've already talked a little bit about how most of the studies in mice are done in very well controlled pathogen-free facilities, not much variation in environment.

Dogs experience almost all of the environmental variation that people do. So from the perspective of trying to understand the role of environmental variation in biological aging, I think companion dogs are a particularly powerful animal in which to study that.

Then maybe most importantly, people love their dogs. I'm a dog person. I love my dog. And so I think if we're able to both understand the aging process in dogs and potentially modify that process to give pet dogs extra years of healthy lifespan, that has a significant intrinsic value in and of itself, for the quality of life both for the dog and for the human.

For those reasons, I kind of feel like companion dogs provide a lot of value for the field in terms of understanding the biology of aging. We're actively trying to build the infrastructure that will allow the field to be able to use the companion dog to study the biology of aging.

Dr. Anton Titov, MD: So this is, yeah, dogs are very interesting. But considering the importance of diet in disease in humans in every interaction, it seems like the companion dogs diet, at least in the Western world, is quite well controlled, standardized and optimized. And human food is not advised for dogs. Obviously, in other parts of the world, it's significantly different. How do you see that comparison? That sort of diet factor being removed from the environment essentially?

Dr. Matt Kaeberlein, MD: Yeah, it's a good question. So a couple of things, I would say, I think you're right, at least in the Western world, most companion dogs don't eat a diet that is comparable to the human diet, at least in terms of the specific composition of the foods consumed. There are, of course, many, maybe most companion dogs do get some human food from time to time.

But the other point I would make is, you said that the diet is well controlled and optimized in companion dogs, and I would say that's not the case. There are various diets that people will give to their pets. Even just from the major brands of dog food, there are dozens of different formulations, lamb and rice, chicken, beef kibble, wet food, prescription diets, fish oils.

So there's a lot of variation actually in the diet that companion dogs are given, including a lot of people now that feed their dogs a raw food diet. So they don't eat the same diversity of foods that people do, but there is a maybe comparable diversity of foods that companion dogs eat.

I think we can certainly if you can get a large enough population of companion dogs and understand what diet those dogs are receiving, there's the potential actually to do some correlative sorts of analyses to try to understand does composition of the diet have an impact on health outcomes during aging?

In that way, I don't think anyone would argue dogs are a perfect model for human aging. The only perfect model for human aging is going to be humans. But in that way, I think still it's a step up from the laboratory rodents, which are almost exclusively fed a very refined diet with a very controlled amount of diet suitable for the study.

So I think companion dogs can capture dietary diversity to a pretty good extent, which may give us some insights into the role of diet in healthy aging.

And I think the other thing you can look at for companion dogs is how much are they eating? So caloric intake? And how frequently are they eating? How often are the dogs fed?

We analyzed feeding frequency with health outcomes during aging recently as part of the Dog Aging Project. One component of the Dog Aging Project is a longitudinal study of aging, where we now have enrolled about 34,000 dogs into the Dog Aging Project Pack, which is the sort of foundational component of the longitudinal study.

For dogs to be enrolled in the Pack, the owners complete a fairly extensive survey that captures their health history, their home environment, food consumption patterns, things like that. So a comprehensive health and life experiences survey.

One of the questions on that survey is how frequently do you feed your dog? Not surprisingly, some people feed their dogs ad libitum, so the dog always has access to food. Some people feed their dogs three times a day, some people two times a day, some people one time a day.

The most common feeding frequency for pet dogs, at least in the United States, appears to be twice a day. I think it was more than maybe half of the owners in our cohort fed their dogs twice a day, but a significant fraction fed their dogs once a day.

We just asked a very simple question, which is, if you look at the dogs fed once a day, and you look at the dogs fed more than once a day, you just put them into those two buckets. And then you ask, what is the frequency of diagnosing a given age-related disease in those two groups?

What was pretty striking was that in the dogs that are fed once a day, they had lower frequencies of diagnoses for I think ten different categories of age-related functional or disease outcomes. And in six of those categories, the effects were big and statistically significant.

So it's a strong signal that I think is suggestive. You can certainly say there's a correlation between many age-related health outcomes and feeding frequency in dogs. It doesn't prove causality, and you can think of some potential explanations like maybe dogs fed once a day are less likely to be obese, that could be underlying this.

But I think it illustrates the power of having a large number of companion dogs, where you've got data on something very simple like feeding frequency and disease diagnoses. So you can start to ask these big picture questions, which then are hypothesis-generating, and potentially allow you to ask more mechanistic questions in the future.

So again, that was sort of a long-winded answer to your question, but I think that dogs can tell us something about the impact of diet nutrition on aging.