Researchers at the University of California (UC) San Diego School of Medicine have mapped methylation changes in the genomes of Labrador retriever dogs to create an “epigenetic clock” that effectively throws out of the window the old maxim that multiplying your dog’s age by seven gives you their age in “human years.” The researchers compared the methylation changes that occur in the genomes of dogs and humans throughout their lifespans, to identify conserved age-related changes—predominately impacting on developmental gene networks—which allowed them to generate a formula that can more accurately compare the ages of humans and dogs. In fact, the results indicated that the two species don’t age at the same rate over their lifespans, so the comparison isn’t completely linear, as the 1:7 years rule-of-thumb would have suggested. More importantly, the team said methylation-based formula is the first to be transferrable across species. As well as providing a potentially useful tool for veterinarians, the epigenetic clock could also help scientists evaluate anti-aging strategies.
“There are a lot of anti-aging products out there these days—with wildly varying degrees of scientific support,” said senior author Trey Ideker, PhD, professor at UC San Diego School of Medicine and Moores Cancer Center. “But how do you know if a product will truly extend your life without waiting 40 years or so? What if you could instead measure your age-associated methylation patterns before, during, and after the intervention to see if it’s doing anything?” Ideker led the study with first author Tina Wang, PhD, previously a graduate student in Ideker’s lab. The team reported on their research in Cell Systems, in a paper titled, “Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome.”
The old adage that each year in a dog’s life equates to seven human years reflects what the researchers termed “our deep intuition” that development and aging are conserved processes that occur at different rates in different species. “All mammals, whether dog, human, or any other creature, pass through similar life stages of embryogenesis, birth, infancy, youth, adolescence, maturity, and senesce” they wrote. “Yet, the extent to which this conserved physiology reflects the underlying conserved genomic events is unclear.”
Over the last decade or so studies have found that a key molecular alteration during aging is remodeling of the DNA methylome, essentially the pattern of epigenetic modifications in which methyl groups are attached to some cytosine-guanine dinucleotides (methyl-CpGs). “The methylation states of tens of thousands of CpGs have been found to change predictably over time, enabling the construction of mathematical models, known as ‘‘epigenetic clocks,’’ that use these shifting patterns to accurately measure the age of an individual,” the investigators continued.
Epigenetic changes effectively provide scientists with clues to a genome’s age, Ideker said—much like wrinkles on a person’s face provide clues to their age. Epigenetic clocks for humans have previously been published by Ideker and others but they may only be accurate for the specific individuals on whom the formulas were developed. They may not translate to other people, let alone other species. So it’s not been clear if major epigenetic changes that occur with age involve the same or different (or even random) CpG sites in different species.
Ideker said it was Wang who first brought the dog idea to him. “We always look at humans, but humans are kind of boring,” he said. “So she convinced me we should study dog aging in a comparative way.” Dogs provide a unique opportunity to compare and contrast methylation changes across species, the scientists pointed out. While there may be more than 450 different breeds, most are derived from small numbers, and there is strong phenotypic and genetic homogeneity within breeds. Given how closely they live with us, perhaps more than any other animal, a dog’s environmental and chemical exposures are also very similar to humans, and they receive nearly the same levels of health care. It’s also important that we better understand their aging process, Ideker said, as veterinarians frequently use the old 1:7 years ratio to determine a dog’s age and use that information to guide diagnostic and treatment decisions. And epigenetic clocks have already been demonstrated in dogs, “… establishing them as a system for studies of age-related epigenetic modeling,” the scientists stated.
For their studies, Ideker and Wang collaborated with dog genetics experts Danika Bannasch, DVM, PhD, professor of population health and reproduction at UC Davis School of Veterinary Medicine, and Elaine Ostrander, PhD, chief of the Cancer Genetics and Comparative Genomics Branch at the National Human Genome Research Institute, part of the National Institutes of Health. Bannasch provided blood samples from 105 Labrador retrievers. As the first to sequence the dog genome, Ostrander provided valuable input on dog genome analysis.
The researchers analyzed and compared conserved patterns of methylation changes at different developmental and aging timepoints between species. They found that “… the canine epigenome progresses through a series of conserved biological states that align with major physiological changes in humans, occurring in the same sequence but at different chronological timepoints during each species’ lifespan.”
What emerged from the study is a graph that can be used to match up the age of your dog with the comparable human age. Importantly, the results have shown that this comparison is not a linear 1:7 ratio over time. Especially when dogs are young, they age rapidly compared with humans. So, a one-year-old dog is similar to a 30-year-old human. A four-year-old dog is similar to a 52-year-old human. Then by seven years old, dog aging slows. “This makes sense when you think about it—after all, a nine-month-old dog can have puppies, so we already knew that the 1:7 ratio wasn’t an accurate measure of age,” Ideker said.
Although there has been increased interest in epigenetic clocks because they can effectively translate an individual’s methylome to an accurate prediction of age, this approach has typically been applied to study methylome data in one species only, the team pointed out. Their results, extended to mice, indicate that the methylation states of sets of genes can be used to construct a conserved model of age that can be transferred between species. “Analysis of this data shows that multiple mammalian species experience conserved methylation changes during aging, and that the scope of these changes is methylome-wide,” they wrote. However, “… the trajectory of changes followed by one species as it ages is not necessarily the same as that followed by another … our study has demonstrated that the methylome can be used to quantitatively translate the age-related physiology experienced by one organism (i.e., a model species like dog) to the age at which physiology in a second organism is most similar (i.e., a second model or humans).”
The researchers do acknowledge certain limitations of their study. The epigenetic clock was developed using a single breed of dog, but some dog breeds are known to live longer than others. More research will, therefore, be needed, but since it has proven accurate for humans and mice as well as Labrador retrievers, Ideker predicts that the clock will apply to all dog breeds. In their report, the researchers concluded that the ability to use the methylome for cross-species translation of age and physiological state of aging may provide “… a compelling tool in the quest to understand aging and identify interventions for maximizing healthy lifespan.”
Next, the investigators plan to test other dog breeds, determine if the results hold up using saliva samples, and test mouse models to see what happens to their epigenetic markers when you try to prolong their lives with a variety of interventions.
Meanwhile, Ideker, like many other dog owners, is looking at his own canine companion a little differently now. “I have a six-year-old dog—she still runs with me, but I’m now realizing that she’s not as ‘young’ as I thought she was.”