Great Danes to Grandads: Comparative Cancer and Aging Research

Please join us in welcoming Dr. Nicole Ehrhart, VMD, MS, ACVS, Director at the Columbine Health Systems Center for Healthy Aging and Professor in Clinical Sciences at the College of Veterinary Medicine & Biomedical Sciences at Colorado State University.

She is an innovative orthopedic researcher, engaged in translational aging, bone, and muscle regeneration studies to benefit both human and canine patients.

How did your interest in cancer begin?

When I was still a resident, I met a little girl named Jenny at a camp for children with cancer. She recently had an amputation. We were researching limb salvage in dogs, and I wondered, “How can we do this in dogs and yet, still be amputating in children?”

Amputation was very common in the 90s, and it led me to discover an interest in getting bone, muscle, and other tissues to regenerate. There’s a knife-edge to walk between regenerating bone/tissue safely while avoiding causing cancer again by restarting cell growth.

You published a recent article looking at secondary amputation in dogs with osteosarcoma. What did you find, especially in terms of additional survival time?

Similarly to humans, if you can resect a recurrence successfully, you can generally prolong life!

The answers to many challenges are often found between disciplines.

Can you tell us more about your aging research? Is cancer involved?

While learning about how our bodies only have limited regenerative capacity, I began thinking about aging. Aging is basically a build-up of small issues with our bodies over time, and our lack of regenerative capacity is crucially associated with aging.

When you think about it from a cellular level, if you were able to affect aging, instead of playing ‘whack-a-mole’ with a bunch of different diseases, you could make a big difference at a higher level.

The cellular hallmarks of aging and the cellular hallmarks of cancer are quite similar. There are 7 out of 9 major characteristics shared by aging and cancer. Age is, of course, the biggest risk factor for cancer.

Now we have to think, “Is aging a modifiable process? Are processes like cellular senescence (both an anti-cancer process in younger people and a cause of cancer in older people) reversible? What if, instead of treating cancer, we treated senescence? What if we used scencescent cell inhibitors?”

In lower organisms, they actually reverse aging!

Many models (from naked mole rats to progeria) show aging is reversible.

In pretty much any other animal, aging happens in similar ways to all of them at the same time. In humans, we see two distinct groups of old people that diverge. By around age 80, some of them are out playing golf and physically fit, and some are in assisted living. It’s been found that the fit and active older people actually have biologically younger cells. Unfortunately, it’s impossible for us to find out when these populations diverge.

Some dogs age much more rapidly than others, too (i.e. Great Danes vs Jack Russells). While we can’t know when elderly human populations diverge, we do know when dogs start to do this! Based on body size, we can predict how fast dogs are going to age. It’s a model we don’t have really in any other animal.

Do you see more cancer researchers joining together with their colleagues in the aging field? If not, why do you think that is?

It seems to be catching on! At Flint Animal Cancer Center, Dr.Rod Page has been working on exploring cancer and aging. As people begin to look across disciplines, we see the proverbial  floodgates opening and collaboration explodes into being - and that’s what’s happening now.

Seeing how aging is related to cancer, are cases of cancer in young dogs considered outliers? Should we still be focusing on aging in these young dogs?

There’s not a single factor that goes into why someone might develop cancer at a young age. Often, it’s just a “bad genetic hand.” Sometimes, you can trace it to familial genetics. Sometimes, it’s truly just bad luck.

What are you currently working on?

There are two major themes with a paired biobank between humans and dogs. This involves the Colorado Longitudinal Study, surveying a million Coloradoans for medical info to be stored in a biobank. A cohort is being created among those surveyed who also own dogs, and their dogs are also having their medical information stored in a biobank.

The hope is to show on a very specific basis that dogs indeed are “sentinels” of human aging. Especially as these dogs, who are living in the same household as their owners, are going to be exposed to the same environmental drivers that influence longevity, it’s hoped that it’ll be possible to find common biomarkers between humans and dogs which influence aging.

Based on the biobank, we are hoping to develop intervention trials to influence cellular aging.

What are you working on that you are most excited about?

What excites me is the concept that we can actually live healthier longer, and the concept that we can

This isn’t really about prolonging life or lifespan. It’s about prolonging healthspan. I think we all want to see this with our animal companions and loved ones.

Think about the great minds out there who begin to lose their ability to think clearly due to Alzheimers and neurodegenerative diseases. If we could delay that and keep them as contributors to society, think of how much more we could learn!

On the veterinary side, if we can have animals without being burdened with disease, such as arthritis, this would be such a win!

Q&A

You mention age 120 for humans. Is there an upper age limit for dogs?

We have an expiration date. There is a point after which we cannot continue to live in a healthy way. What happens over time is the ability to repair the micro damages that happen as we age -- we can intercede in that and rejuvenate our regenerative capacity, longer than we can do it currently. I believe we can do it in dogs.

We die of chronic diseases, earlier than our expiration date would normally be. If we can delay the onset, we can increase longevity. The number of healthy years we can live has not changed. We need to figure out how to work in a complex system of how we age.
What have you learned from your research that has most surprised you?

In some sense, this became an opportunity. As I was going to the biology of aging conferences, I was surprised by how little people were educated on the companion dog as a potential model. We’ve been so immersed in it for 20-30 years. I’ve grown up in this world. The aging world is behind. The biggest thing is the Dog Aging Project. They’re setting the stage to educate people in the realm of how important this is. It’s a longitudinal study of how dogs age and the environmental drivers in aging, seeing how it will translate to centennials. We can build on this with intervention trials, how longevity changes over time, how it influences diseases we see in dogs and people.

It surprised me how little people understood about it on the aging research side.

Momentum builds. We can continue to build on this knowledge base and launch it into the aging world.

Is there any research looking at aging in cats? Is there an advantage to using a different species as a model?

The cat is a great model. We’re limited where they do not have divergent aging pathways based on body size. With dogs, we see it diverging, similar to people.

Cats are useful in particular areas, such as periodontal disease. It changes with age as can be used as a model for people with age modifying drugs.

Again, what makes dogs special is the divergent aging pathways based on body size and the opportunity to intercede with different therapeutics at known intervals from the beginning of that divergence to the end phenotype that we see. It helps us find which points are the most effective.

The education and thought processes that veterinarians go through is unbelievably precious in tackling real world problems that don’t always relate to veterinary medicine. For young veterinarians who look to other fields, how has your veterinary background influenced your work?

As the director for the Center for Healthy Aging, I’m always looking for new clinical trials. The entire research enterprise at CSU shut down with COVID. The only thing that continued was work considered as essential. I had a conversation with a virologist colleague about testing and diagnosis. As veterinarians, thinking about herd health, we would do surveillance work to figure out asymptomatic carriers. To respond to the public health crisis, we thought about doing surveillance with the most vulnerable populations: workers at senior care center facilities.

We learned that 15% of them were positive. They had no idea. When we found those people and asked them to self-isolate for two weeks, it helped mitigate the situation. This project got a lot of attention from the CDC and national press, and now I am working on COVID testing.

The main point of this story is that how we think is very different and unique.

The perspective of a veterinarian has helped us gain a lot of insight. It’s been interesting and we have learned a lot. I’m most proud of being a veterinarian. Don’t ever underestimate how much you can recreate yourself in this career.

Can you speak to the difference between dogs and other mammals where large size is associated with longer lifespan?

There are a number of different mechanisms where other animal species in which  large body size is associated with longevity. These larger species have “longevity genetics’ built in. This is paradoxically true in dogs. Dogs are the same species, though.

There’s a concept that within a species, we have long-lived individuals and short lived individuals. The ability to compare within a species is where we have an opportunity we find the key mechanisms and key-modifiable processes. It is fascinating to take this to the rest of the animal kingdom.

In humans, males and females age differently and have different average life spans (women live longer). Is there anything we can learn from this about anti-aging in dogs/animals?

The gender differences in average lifespan are really interesting. It’s interesting to think about the incidence and prevalence of chronic diseases, like heart disease. It is much lower in women in their 50s or once they go through menopause.

What is the primary mechanism that protects women? It’s not just estrogen. What are the downstream effects?

What can we learn about this in dogs? The sex hormone influence is absent in dogs because they are spayed and neutered and do not have exposure to sex hormones throughout their entire life. Is there something deeper? I don’t know a ton about that, but there is a ton of interesting sex hormone information.

What concerns, if any, are there about reverse aging promoting carcinogenesis?

This is a tangled ball of yarn to unravel. There is a lot of optimistic, early data. When looking at slowing aging, you are actually preventing cancer. Think about senescent cells. Initially, they are good. Up until our peak reproductive age, we need senescent cells.

If you do senolytics in young, juvenile mice that are still growing, they have a high incidence of cancer because one of their defenses is taken away to prevent cancer from developing. We don't want to take senolytic drugs too early because it takes away from its benefit.

There is a dark side to this same point to senescence. When we get into that SAS phenotype,, we hit a certain minimum amount of cells in our body that accumulates, we get zombie cells that can create a pro-inflammatory response. This is a cancer promoter. Then we think about what is a good time to go in to wipe out those cells? Or we can do this intermittently?

This is the concern about senolytics. When looking at other factors of aging, we can examine things like telomeres. Do we want to lengthen them? When is it okay?

There is a lot to think about for continued research and comparative medicine to see when they will make a difference.