Kate Creevy 300
Texas A&M University College of Veterinary Medicine & Biomedical Sciences photo
Dr. Kate Creevy, chief veterinary officer for the Dog Aging Project, with her dog Poet (left) and a pal Sophie. Creevy hopes the project will provide veterinarians with tools for supporting healthy aging in dogs.
Dogs make great pets, and pet dogs make great research subjects. That's not exactly a truism, but it will be if the Dog Aging Project achieves its goals.
The study, based at Texas A&M University College of Veterinary Medicine & Biomedical Sciences and the University of Washington, aims to identify the biological and environmental factors contributing to healthy aging in dogs, and potentially generate insights applicable to human medicine. If all goes as planned, researchers will follow 10,000 pet dogs as they live their normal lives for 10 or more years, making it likely the largest ever canine study.
The project launches a major public enrollment push for pet owners this fall.
The Dog Aging Project comprises four major research components:
- providing clinical definitions of and metrics for aging in dogs
- analyzing genes associated with aging in dogs
- identifying molecular biological predictors of disease and longevity in dogs
- studying how dogs might be impacted by rapamycin, a drug shown to increase lifespan and mitigate aging in mice.
Pet dogs are interesting to researchers because they have a lot in common with humans. They get many of the same age-related diseases as we do, such as cancer; and receive similar treatments, and live in our environments with us. Researchers also posit that studying aging in dogs will be more time efficient than in humans because dogs age seven to 10 times faster.
These are the key reasons the National Institute on Aging (NIA), part of the National Institutes of Health, provided a $15 million, five-year grant for the Dog Aging Project in 2018, said Daniel Promislow, co-director of the project. "NIA has clearly bought into the idea that large-scale veterinary research is great," said Promislow, who is a professor of pathology in the UW School of Medicine and a professor of biology at UW. "My hope is that other institutes will buy into this as well, and we will help lay the groundwork for veterinary researchers to increase the scale of the work they can get funded from NIH, and so really change the way veterinarians think about what is possible."
In addition to Promislow, whose background is in evolutionary genetics and fruit fly biology, the interdisciplinary team includes veterinarians, epidemiologists, biostatisticians with expertise in human studies, sociologists, demographers and a medical ethicist. The project co-director Matt Kaeberlein also is a professor of pathology at UW School of Medicine and specializes in yeast, nematodes and mice.
New tools for veterinarians
Canine aging hasn't really been a defined thing in veterinary medicine, said Dr. Kate Creevy, the Dog Aging Project's chief veterinary officer. That's why a core goal of the project is to provide "a clinical picture" of aging.
"When we see a dog, we'll say, 'Wow, that dogs looks really good for his age,' or 'That dog doesn't look so good for her age,' but we can't easily put that into any kind of objective description," said Creevy, an associate professor of small animal medicine at Texas A&M.
Unlike in humans, there are no defined metrics to determine if a dog is aging well. There are no chair-stand or grip-strength tests for dogs, nor are there age-based normal ranges for chemistry measurements, Creevy said.
The Dog Aging Project aims to change that. It is geared as much to providing tools for veterinarians as it is to extracting lessons for application in humans, according to Kaeberlein. "I'm driven as much or more by what this will mean for veterinary medicine and canine health," he said.
Why do small dogs live longer?
Participating in the Dog Aging Project
Promislow started studying aging in mammals 30 years ago as a graduate student. He shifted his focus to fruit flies in the mid-1990s but remained interested in mammalian aging. One question that has animated his research is: If across mammals, large species such as whales and elephants are generally longer-lived than small species such as mice and voles, why among dogs are large breeds generally shorter-lived than small breeds?
Promislow's thinking on this question got a nudge in 2007, when a research team led by Dr. Elaine Ostrander at the National Human Genome Research Institute came out with a paper on the genetics of size in dogs. It made the cover of Science magazine. Researchers discovered that a single gene, insulin-like growth factor 1 (IGF1), explained about half of the size variation among all dog breeds. All giant breed dogs and many large breed dogs possess an IGF1 gene in which one or both of the two alleles that make up the gene is traced to wolves. In all toy breeds and many small breeds, the IGF1 gene does not have that wolf ancestral allele but a novel allele instead.
The study intrigued Promislow because IGF1 has also been shown to be an important, if not fully understood, regulator in the aging process. That connection drove him to investigate further. Through colleagues with links to veterinary medicine, he learned about the Veterinary Medical Databases, a collection of seven million abstracts of teaching hospital records going back to 1964. To help in his review of records for 80,000 dogs, he put out feelers for an interested veterinarian at the veterinary teaching hospital at the University of Georgia, where he was at the time. Creevy, then an early-career internist with time on her hands, was recommended for the project. They've been working together ever since.
"We never answered that question [about size and aging in dogs] but people started getting excited that we were working on aging in dogs," Promislow said. He was encouraged to pursue the work by researchers at NIA, which funded his first dog-related work in 2013. He used the $143,000 grant to create a Canine Longevity Consortium, a network of researchers and clinicians with the expertise to design and implement a Canine Longitudinal Aging Study, the precursor to the Dog Aging Project.
Dogs helping humans
The study follows in the footsteps of multigenerational human aging studies, such as the Framingham Heart Study (1948), the Baltimore Longitudinal Study of Aging (1958) and the Women's Health Initiative (1993).
For the majority of the terms of the human studies, Creevy said, researchers did not have access to scientific tools and insights that are available today. The Dog Aging Project will deploy high-throughput DNA sequencing from the outset, as well as diagnostics focused on analyzing biological systems. These include:
- the epigenome: the structure of DNA, not its code, which determines which genes are more likely to be transcribed
- the metabolome: the collection of the body's small molecules, the "building blocks" of the body's structures and processes
- the microbiome: the collection of microorganisms in or on the animal, including those living in the gut, mouth or skin.
And because dogs age faster than we do, "it's possible to determine the value of some of these assays [investigational approaches] more quickly and more cheaply," Creevy said.
"We hope we can apply those very modern, cutting-edge diagnostics to the dog project in a way that makes it more feasible to say which ones should be applied to the long-term studies of human aging," Creevy said. In some cases, insights about what tests work well in the study of dogs might allow human-focused researchers to use the finite resources of banked tissue samples from longevity studies more efficiently and effectively.
The Dog Aging Project will collect cells and sequence DNA from cheek swabs taken from all 10,000 participating dogs. The data will be integrated with health and behavioral measures as the basis for comprehensive genome-wide association studies among all the dogs to "try to identify populations of genes associated with healthier or less healthful aging," Creevy said.
This work builds on the efforts of Dr. Elinor Karlsson, who has sequenced and analyzed the genes of pet dogs from all over the country through a citizen-science project originally called Darwin's Dog (now Darwin's Ark). "She helped researchers develop a deeper understanding of what parts of the genetic analysis are breed-specific, and which are not," Creevy said.
Karlsson is one of more than 50 collaborators from 15 institutions on the Dog Aging Project. A genetics researcher at the Broad Institute of Massachusetts Institute of Technology and Harvard University and an assistant professor of bioinformatics and integrative biology at the University of Massachusetts Medical School, Karlsson had been studying dog genetics for many years. She has a special interest in the genetic basis of dog behavior, disorders such as obsessive compulsive disorder, and diseases such as cancer.
Frustrated when working with small sample sizes, from which it's hard to identify genetic changes, Karlsson in 2015 created Darwin's Dogs to tap the enormous population of pet dogs in the U.S. The project invites dog owners to provide information about their dogs in surveys and submit cheek swabs for genetic testing.
Karlsson offers up a potentially new framework for veterinarians thinking about research on aging. She said that many practitioners don't think about healthy dogs. "They deal with sick animals," she said. "Aging happens in all the dogs that survived everything else." The question she'd like to answer is: What's protecting this dog?
Extending dogs' 'healthspan'
The majority of the dogs in the project will be followed as they live their normal lives. But one subset of 500 middle-aged dogs will be included in a double-blinded, placebo-controlled trial of rapamycin for three years and then followed for an additional two years or until they die.
FDA-approved rapamycin has been used in human medicine to prevent organ-transplant rejection and to treat some rare forms of cancer. Treatment with rapamycin has been shown by Kaeberlein, Promislow and others to extend life in yeast, nematodes, fruit flies and mice. Furthermore, in mice, that longer life appears to be healthier. Older mice on rapamycin are more metabolically active, exhibit greater mobility and improved cardiac function, and perform better on cognitive tests as compared with a control group, Creevy said.
The Dog Aging Project's rapamycin trial will test the effects of the drug on subjects' cognitive function, heart function, immunity and cancer incidence. Participating dogs will be given heart ultrasounds and have their blood pressure monitored at one of seven veterinary school teaching hospitals. They are: Texas A&M University, Colorado State University, North Carolina State University, Iowa State University, Washington State University, Oregon State University and the University of Georgia.
Data for all
The Dog Aging Project is not the first large, longitudinal study of dogs in the U.S. The Golden Retriever Lifetime Study (GRLS), for example, funded by the Morris Animal Foundation, has followed more than 3,000 pet dogs since 2012 to learn about the nutritional, environmental, lifestyle and genetic factors for cancer and other diseases.
There is a lot of overlap between the two studies. For example, Dr. Rod Page, the chief scientific officer for GRLS, serves on the scientific advisory board of the Dog Aging Project. Promislow serves on the steering committee of GRLS.
"I think of the GRLS as the giant on whose shoulders we are standing," Promislow said.
Because the Dog Aging Project is funded by the NIH, the data will be broadly available.
"We are committed to sharing it with not just other researchers but finding a way to share it with the general public," Creevy said. "To the extent permitted by privacy concerns and an embargo period that will make sure that we support our own trainees and our own post-docs, all of the data will be made publicly available."
Organizers plan to build two data-access platforms, one for researchers and another for the public. The latter platform will be a "curated" database that provides some demographic information about the dogs and big-picture outcomes. Organizers envision the platform being used for research fodder by, for example, students from elementary school to community college, especially those who don't have access to laboratory facilities.
"That's one of my favorite things about the project, to be perfectly honest," Creevy said. "As a teacher, the ability to give kids their own science to do, not cookie-cutter science, not repeating somebody else's work, but their own science, their own raw data; that, to me, is so exciting."