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Sunday, February 5, 2023

Longevity in Dog Years

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Celine Halioua and Wolfie

Epigenetic aging biomarkers in dogs could help your furry friends live longer, healthier lives.

By Robin Donovan

“I would do anything for my little pom poms to live longer,” tweeted Yasmeen Roumie in late March. She’d just registered two keen-eyed Pomeranians for the X-Thousand Dogs study, an epigenetic research project that could spark the development of new age-fighting pharmaceuticals for dogs. Scientists at Loyal, a San Francisco startup focused on extending your pup’s lifespan, recruited more than 2,000 dogs to build an epigenetic profile to identify biomarkers associated with aging.

Soon after the call for participants, Loyal CEO Celine Halioua was retweeting photos of dog owners ready to swab their pups and mail in samples. From misty-eyed seniors to scruffy mutts, each pup received a packaged treat along with the test kit.

The kits are designed to identify biomarkers known as methylation sites in the doggie DNA. These are places in the genome where a type of non-genetic or “epigenetic” chemical change takes place.

Halioua hopes that her team can correlate changes to specific methylation sites with factors like a dog’s age, its environment, and its overall health — and ultimately quantify the aging process. It would be a step toward predicting and extending a dog’s lifespan and quality of life that could lead to lifespan-extending medications for dogs and humans, too.

“Absolutely, if we live our dreams, you and your dog will both get to take an aging drug,” Halioua says.

Gene editing, popularized by CRISPR in recent years, holds promise for helping humans and other organisms stave off illnesses and improve their health. But the complexities of the human genome mean it’s still difficult to map the precise genes responsible for various traits. Predicting the outcomes of genetic changes is even more difficult. Epigenetics skirt these complexities by altering gene regulation rather than the DNA itself. The genetic code itself stays the same, but the body “reads” it differently.

Biologists are turning to DNA methylation as the epigenetic key to understanding aging. The classic epigenetic change to DNA is when clusters of hydrocarbons, known as methyl groups, attach to DNA at various sites. This can dial gene expression up or down, depending on which sites they attach to, and builds something of a genetic map, in which genes are read a bit more here, a bit less there, when methylation rates at these sites shift as the years go by.

“With age, environmental factors, or just biological randomness, we’re seeing the activation or deactivation via the methylation or the demethylation of certain sites that are now correlated with dogs who, later on, end up developing or not developing cancer,” Halioua says.

As organisms age, “across the genome, the trend is decreasing methylation, and that’s why it’s correlated with increased likelihood of cancer,” says Jerry Wilkinson, an evolutionary biologist at the University of Maryland who has researched DNA methylation in bats. “You’re losing control of the genes that are normally under control.” That means a less precise roadmap for genetic function, and cells that can mutate abnormally as disorganization increases.

Matching methylation rates at these sites to aging is still hit or miss, but there’s one promising outcome for dogs with uncertain histories. DNA methylation “can be a very, very accurate way of estimating the age of an animal using a relatively small number of sites,” says Wilkinson. Studies have already shown that particular patterns of methylation at specific sites can be used to estimate age in dogs.

Matt Kaeberlein, co-director of the Dog Aging Project, an interdisciplinary research initiative, and a scientific advisor for Loyal, agrees that estimating chronological age is realistic, and it could be useful to satisfy the curiosity of dog owners who adopt older pets. But he says the bigger question is whether epigenetics is truly the best way to predict the rate of aging, sometimes termed biological age. In other words, can they measure healthspan as well as lifespan?

If epigenetic clocks can be shifted, some scientists speculate that we could reprogram them to reverse aging.

“Nobody has shown in a person or a dog or even in mice that you can take a one-time measurement and, based on that, predict what happens to that individual in the future,” he says. Still, Kaeberlein believes that within the next few years, we’ll know if DNA methylation sites can be used as a proxy for biological age. He speculates that the FDA might take another 10 years or more before accepting these markers as testable, surrogate endpoints for drugs designed to combat aging — if they accept them at all. But if that happens, biomarkers based on DNA methylation sites stand to revolutionize the testing of potential anti-aging drugs because they will give researchers a way to more immediately gauge their effectiveness. Otherwise testing anti-aging drugs could literally take lifetimes. The possibilities, if yet unproven, offer some hopeful visions of a modern-day fountain of youth for dogs and their owners.

“What people are more excited about these days is maybe reversing the patterns back to a pattern that looks like a younger chronological age,” Kaeberlein says. If epigenetic clocks can be shifted, some scientists speculate that we could reprogram them to reverse aging.

For now, Halioua says, she’s noticed her white husky, Wolfie, is ambling around the house a bit slower than she used to. Wolfie is maybe 7–9 years old. The average lifespan for a husky, currently, is 12–15 years. “I really do hope, selfishly, that the team gets the whole aging saliva swab algorithm sorted because that’d be very helpful for me,” Halioua says.

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