Rapamycin: A real fountain of youth?
Throughout the ages, man has been fascinated with the idea of cheating time, slowing the clock and edging ever more closely toward immortality. Ponce de Leon sought out the Fountain of Youth in what is now Florida. While munching on pop corn at the movies, we watched Indiana Jones find the Holy Grail in the form of a battered cup in Turkey. If you’ve been following the news lately, you might have come across a new narrative—that a team of researchers at the University of Washington are hoping to unlock the secret to eternal dog life using rapamycin, a compound discovered under the mysterious looming totems of Easter Island.
But Dr. Matt Kaeberlein, an expert on the biology of aging and one of the heads of the Dog Aging Project, really hopes you don’t look at it quite like that. Science, after all, isn’t usually that melodramatic.
A brief history of rapamycin
Rapamycin had its humble beginnings as an antifungal metabolite isolated from the bacterium Streptomyces hygroscopicus, an organism found on the island of Rapa Nui, also known as Easter Island. After a brief period of investigation as an antifungal medication, rapamycin truly came into its own when it was found that the compound had strong immunosuppressive properties. In 1999, the drug was granted FDA approval and entered service as a treatment for transplant rejection.
The immune system, as all people in the medical field are well aware, is complex and multifaceted. Drugs that affect one immune function in one area may have different effects up or downstream; such is the case with rapamycin. In 2006, a study published in Genes and Development showed a dose-responsive increased lifespan in yeast organisms, an effect repeated on advanced age mice in 2009, adding an average of 9 to 14 percent to their maximum lifespan.
Encouraged by these promising early results and motivated by his own two dogs, Kaeberlein and his colleague Dr. Daniel Promislow decided to launch the Dog Aging Project to see if the same effects extended to canines. And that’s when things got interesting.
The dawn of the Dog Aging Project
The Dog Aging Project has two components: a large-scale, longitudinal study of aging in pet dogs, and a rapamycin intervention trial. Although the media attention has been focused on the rapamycin component of the project, Kaeberlein is equally excited about the longitudinal study of aging. While similar studies have taken place in the human population, the canine’s shorter lifespan means more information can be obtained in a shorter period, with the potential to benefit both people and dogs.
In this respect it bears some similarities to the Morris Animal Foundation’s Golden Retriever Lifetime Study, and Kaeberlein notes the researchers at that group have been generous in offering advice while structuring this project. In other respects, this study will be breaking new ground. Dogs of all breeds and ages will be enrolled, with the goal of identifying environmental as well as genetic factors that contribute to longevity and the onset of age-related disease.
The second arm of the project is the rapamycin intervention trial, which just wrapped up its first 10-week phase in middle-aged dogs. Of the initial 40 dogs, some were eliminated because of subclinical cardiac disease, resulting in 24 dogs that completed the full 10 weeks. “The goal of the first phase was proof of principle—that we could handle dosing appropriately,” says Kaeberlein. “We saw improvements in left ventricular function in mice, and we saw some in dogs as well. That was encouraging.”
The second phase intends to enroll a larger group of middle-aged healthy dogs into a long-term, low-dose rapamycin regimen. Kaeberlein is measuring four age-related parameters as indicators of health: immunity, cancer incidence, heart function and cognitive function. While aging is a complicated process and rapamycin’s exact mechanisms are not fully understood, we do know that rapamycin targets a protein known as mTOR, which plays a large role in multiple pathways on a cellular level.
A 2013 study published in Cell found nine hallmarks of aging that occur as organisms age. “There are three or four hallmarks that mTOR seems to effect,” says Kaeberlein. “We know that rapamycin is hitting on a few of those. It improves mitochondrial function.” But the real goal, says Kaeberlein, “is to maximize the healthy years of life.”
“We’re not trying to help people live forever ...”
As one might expect with such compelling headlines as “Meet the senior dogs trying the latest anti-aging pill,” the response to the Dog Aging Project was immediate. “It was a little surprising when we first started planning this thing,” says Kaeberlein with a laugh. “We had a very small meeting in Seattle, and within a week we had an article in the Seattle Times, and another in Britain.”
It is both a blessing and a curse, as Kaeberlein found out, when the topic at hand is aging. In a soundbite-ready world of cryogenics, where aging is viewed as either an enemy to be conquered by science or an inevitable consequence of life to be embraced as-is, Kaeberlein treads the middle ground.
“I think there’s a lot of fear out there about the unknown,” Kaeberlein says. “There’s this gut reaction that aging isn’t something we should mess around with.” Even the phrase “anti-aging” is loaded. “There is this association between anti-aging and some fringe elements,” he says, which is why he prefers to think of his work as preventive medicine.
Instead of looking at his research as trying to add years, he emphasizes that his work aims to improve health. Whether a doctor is researching cognitive decline or aging, he says, “the goal is the same. The goal of trying to treat Alzheimer’s disease is the same (as mine)—to help people live healthier, longer lives. I think people want biomedical research to try and help accomplish that goal.
“It’s a matter of explaining it to people in a way they’ll understand,” he continues. “We’re not trying to help people live forever. One of the things that people don’t necessarily realize—the medical community has done a good job of keeping people alive longer, but it’s a little unclear as to whether people are healthier longer. Quantity of life has improved, but has quality of life?”
The goal in this case is not to help an 80-year-old live to 120, but rather to help that same 80-year-old spend a greater portion of his lifespan in good health. If he ends up getting a few more years out of it, that’s an added bonus. To Kaeberlein, the benefit to dogs is an excellent endpoint in and of itself, but it’s also only the beginning. If his research can help reduce the amount of time a senior dog spends suffering from age-related dementia or cancer or heart disease, by expanding his healthy lifespan by 20 to 30 percent, who knows how that might apply to people?
Some of the misconceptions Kaeberlein faces are long-rooted, but he’s optimistic people will be able to differentiate what he’s doing from some of the less evidence-based “anti-aging” products out there in the world. “It is frustrating, but I recognize this has been going on forever. People will always try to sell people on miracle cures,” he says. “The bigger challenge is that so much of the (research) funding has gone to these disease-specific projects. It’s only been in the last five to 10 years that we have potential translational approaches. There’s a momentum shift that is occurring.”
In the canine world, it already has. After a piece about the Dog Aging Research Project ran in the New York Times in May, a good number of letters to the editor said they would not want to take a drug such as rapamycin, even if it adds years to their life. But, they added, they’d gladly give it to their dog.