Carissa Harrison had grown concerned. First, she realized the hair around her English bulldog’s mouth had turned an ominous gray. Then she noticed the lazy way in which he had begun to rouse himself in the morning. Normally active, Mac had also turned into a bit of a couch potato during the day: He showed less interest in playing, and he panted volubly while hefting himself off the floor. Harrison’s beloved meatball of a puppy had become elderly. How much more time, she began to wonder, could he have left?
With this in mind, Harrison found herself one sunny morning in Seattle seated in the waiting room of VCA Veterinary Specialty Center of Seattle, a veterinary emergency room and hospital. On one side of the room, a man in a rumpled black T-shirt, shorts, and tube socks sits murmuring quietly to himself. On the other, a woman in a floral muumuu whispers into the ear of a Chihuahua-Pomeranian mix: “Poor baby. Do you need to go potty?” But the man sitting directly next to her is cheerful. He shows her a cellphone picture of a German shepherd and a keeshond in dog-size football jerseys and little hats.
“These are my dogs in their Seahawks gear,” he says.
“Oh my gosh—that looks like Mac’s jersey!” Harrison says. “But when I try to put anything on his head, he tries to eat it.”
The man with the phone is not just a fellow dog lover. His name is Matt Kaeberlein, and he is working to make animals—and one day possibly humans—live longer. A biologist at the University of Washington, Kaeberlein has launched a trial to test a drug that he has reason to believe could dramatically affect how we age.
Kaeberlein has launched a trial to test a drug that he has reason to believe could dramatically affect how we age.
In an examination room in the back of the ER, Mac is at this very moment reclining on a metal table as a veterinarian shaves his tawny, brown chest in preparation for an echocardiogram. A clean bill of heart health would help qualify Mac for the study of a drug called rapamycin, which has already been shown to increase the life span of mice. If it works on Mac and other dogs, pet owners the world over would be ecstatic. Humans would have reason to hope for a longer, healthier life as well.
Later that day, I sat across from Kaeberlein in his cramped University of Washington office. At 45 years old, he has the kind of boyish appearance that would make him a decent poster child for his wonder drug. He has a wiry runner’s build and brown hair that’s trimmed to reveal a wide, unlined brow, and he moves with the energy of a hyper teenager, leaning backward and forward in his chair while he talks, absently twisting and untwisting a piece of paper. When I ask how he became an anti-aging researcher, he corrects me. “I don’t have a problem with the term ‘anti-aging,’ but a lot of people in the field do,” he says. “It’s got a connotation of ‘snake-oil salesman.'”
Kaeberlein readily acknowledges this skepticism was earned through a long history of fantastical, exaggerated claims from people claiming they could restore youth—whether carnival hucksters hawking useless potions or TV marketers with “miracle” creams. And for half of his life, Kaeberlein, like the rest of us, assumed that aging was something inevitable. You get older, your parts gradually wear out until they don’t work anymore, and then, well…that’s all she wrote.
“Like a car breaking down,” he says.
It wasn’t until Kaeberlein was in graduate school that he reconsidered this assumption. He had just completed his first semester in a biology program at MIT when he sat in a classroom listening to a researcher named Leonard Guarente summarize his work.
By studying aging in primitive organisms, Guarente argued, you could learn a lot about the way that human cells aged. You might, he suggested, even be able to hack into the system and delay the process. Guarente experimented on single-celled yeast with a mutation analogous to one found in humans with Werner Syndrome, a disease that dramatically accelerates aging. Guarente found that as cells age, stray pieces of ribosomal DNA accumulate as a byproduct of normal cellular processes, like stray shavings on a factory floor. (Ribosome is the cellular structure that makes all our proteins.) Eventually this cellular debris forms structures known as rDNA circles. When present in sufficient quantities, they cause the cell to stop dividing and die. Guarente began looking for genetic mutations in the pathway that creates this junk, in hopes of finding one that protects against rDNA circles and thus slows aging.
Before then, Kaeberlein says, “it had never occurred to me that aging and longevity was something that was under genetic control. This was the moment I realized that it’s not something that just happens.”
Kaeberlein had not yet chosen his focus of study, and so he began exploring how he might work in Guarente’s lab. Aging, Kaeberlein reasoned, was one of the most complicated things that you can research because it’s affected by a wide array of factors, both genetic and environmental. Guarente’s rDNA circles were just one cause of aging. But there had to be others, and he wanted to look for them.
When Kaeberlein arrived at the University of Washington as a postdoctoral candidate in 2003, he launched a scientific fishing expedition. There are more than 4,000 “nonessential genes” in the Baker’s yeast genome—that is, genes that can be deleted without killing the organism—and researchers had created strains that were missing each one of them. Kaeberlein and his colleague Brian Kennedy decided they would raise these strains one by one to look for mutations that dramatically increased longevity. By the time they had cultivated 560 different strains, they had found 13 that produced a 30 percent increase in life span.
When Kaeberlein and Kennedy looked up the 13 missing genes in a reference database, seven pointed to the same signaling pathway, called the TOR pathway. A lot had been written about the TOR pathway in relation to other conditions, including cancer. “We weren’t sure what to make of that because yeast are single cell—they don’t get cancer,” Kaeberlein says.
With further digging, it began to make sense. The TOR pathway, Kaeberlein learned, was named after the compound that led to its discovery: TOR stands for “target of rapamycin.” Biologists hunting natural medicines discovered rapamycin in soil samples collected on Easter Island in the 1970s. Pharmacologists then demonstrated that the compound, which is produced by bacteria, seemed to dramatically slow the growth of some kinds of cells placed next to it in a petri dish. It did so by acting like a volume switch on the TOR pathway, turning it down. Rapamycin was so effective, in fact, that doctors now use it as an immunosuppressant for transplant patients and to slow certain forms of cancer.
Biologists hunting natural medicines discovered rapamycin in soil samples collected on Easter Island in the 1970s.
Studies suggested that one role of the TOR pathway was to control the rate of cell division, and that it was highly sensitive to the level of nutrients around the cell. When there was plenty of food, cellular signaling agents combined to turn the TOR pathway up—increasing the rate of cell division. In times of deprivation, the signaling agents turned the pathway down, since the conditions were unfavorable to sustaining many cells at the same time.
Kaeberlein realized that finding might explain another area of longevity research. Scientists have known since at least the 1930s that some organisms live longer when their food supply is reduced. Calorie restriction seems to induce a state designed to help them survive lean years, by slowing reproduction and pouring more energy into systems that recycle cellular garbage and protect the health of existing cells. Maybe calorie restriction, he thought, turns down the TOR pathway too.
Kaeberlein and his colleagues kept investigating the roles that genetics and interventions like calorie restriction play in aging. He also started examining how yeast responded to rapamycin, and found that the more he applied, the longer the organisms lived. Meanwhile, other researchers—including a consortium funded by the National Institute on Aging—began to study the compound too. In 2009, research conducted at the University of Texas showed that rapamycin could extend the lives of mice equivalent to age 60 in humans by between 9 and 14 percent. Further studies found that rapamycin had the same effect on middle-age mice and that higher doses have greater benefits. Rapamycin also seemed to have positive effects on age-related diseases such as cancer and Alzheimer’s in mice.
Then in 2014, Novartis announced it had conducted a study on elderly humans, using a compound derived from rapamycin. Since aging-related conditions progress far slower in humans than in mice, the drug company looked at immune response, which becomes less robust with age. After a course of treatment, the subjects’ immune response to a flu vaccine was enhanced by 20 percent. It was the first evidence that compounds like rapamycin might slow aging in humans too.
The concept of dog years, which keeps Carissa Harrison awake at night, is also what makes Mac an ideal subject for Kaeberlein. In just three years, Mac will have aged from the human equivalent of about 49 to 70. That’s a lot faster than waiting 21 years to see how rapamycin would affect humans.
Kaeberlein also suspected his fellow pet owners might appreciate the opportunity. In fact, he has barely had to promote the study to enroll subjects—he simply mentioned it in passing to a reporter, and that reporter wrote a story that went viral. Soon he was besieged by phone calls and emails from more than 1,500 dog owners, some from as far away as Great Britain and Japan. One man who lived in the Midwest informed Kaeberlein he was ready to sell his house and move to Seattle if he could enroll his dog. (Kaeberlein advised him to wait until a nationwide study came to him.) Harrison was watching the local news one morning when she heard about it. She decided then and there to try to enroll Mac. “Every dog owner dreams of the chance for their best friend to live longer,” she says.
Soon he was besieged by phone calls and emails from more than 1,500 dog owners, some from as far away as Great Britain and Japan.
For the trial, Kaeberlein needs about 30 dogs at least 6 years of age and 40 pounds, with no significant preexisting health problems. They have to pass a physical, a routine blood panel, and demonstrate normal heart function to qualify. Roughly half will take rapamycin for 10 weeks while the other half takes a placebo. To gauge the positive impacts of the drug regimen, Kaeberlein is looking at a few measures, including cardiac function. As dogs (and humans) grow older, the efficiency with which the heart pumps blood deteriorates. Mouse studies have found that improved cardiac function is one of the first signs that rapamycin has begun to work.
He’s also looking for side effects. In humans, rapamycin has been known to cause mouth sores, a spike in triglycerides, and slow wound healing; in mice, some evidence suggests it increases the risk of cataracts. Of the 25 dogs enrolled so far, Kaeberlein has yet to see any significant side effects; meanwhile the data on cardiac function, he says, is encouraging. Next Kaeberlein hopes to win approval for a much larger, three-to-five-year trial involving hundreds of dogs. It would be statistically significant and examine many more metrics, such as cancer rates, cognitive function, immune function, kidney function, and mobility.
Back in the waiting room of the clinic, a nurse wearing a white jacket emerges with Mac. He is panting loudly and dripping saliva.
“Hey, bud!” Harrison says, jumping up. “Look at you!”
“Everything went well,” says the nurse. “Heartwise, everything looks good.”
Mac is one step closer to qualifying for the trial, and Harrison is ebullient. Kaeberlein just smiles quietly. Each additional subject also brings him one step closer to dispelling the long shadow of snake-oil salesmen and proving that aging really is something within our control.
“My hope is that once we have a body of evidence clearly showing that rapamycin delays aging in dogs, it will be something that is available to any pet owner who wants it,” Kaeberlein says. “And I would certainly like to see this translated to humans.”
But rapamycin, in his opinion, is just a start—Kaeberlein is convinced there are other life-extending compounds to be discovered, and that they could be even more powerful. “I believe we can slow aging and have a significant impact on health and longevity, both in dogs and in people—and by significantly, I mean maybe a 50 percent increase,” he says. “When we will get there depends on where money is spent on research. But I am certain that, biologically, it’s possible.”