Kaeberlein is also leading a trial of rapamycin, an immunosuppressant approved by the U.S. Food and Drug Administration for organ transplant patients, in 580 dogs. Dozens of studies have shown it extends the lives of mice and other model organisms.
Some scientists consider rapamycin one of the most promising candidates for a human longevity drug. More than a few people take it off-label for that purpose. Kaeberlein has put out the word that he’d like them to send him information on their health. He also pops a low-dose rapamycin pill weekly, in intermittent 10-week-cycles, and is beginning to monitor the effects on his blood biomarkers and epigenome.
The drug triggers some of the same molecular and metabolic action as extreme calorie restriction, which has consistently extended life span in laboratory studies. Kaeberlein believes rapamycin may also regulate inflammation, an important factor in age-related disease.
But self-experimentation and crowd-sourced anecdotes won’t prove anything, and rapamycin is off-patent, so the pharmaceutical industry has little incentive to fund a large clinical trial. “There is no money to be made, or at least not as much money as if it was a new drug,” Kaeberlein says.
His double-blind, placebo-controlled dog study is enrolling healthy seven-year-olds, so a significant gain in life-extension would become apparent in three years. Depending on his findings, they could shake loose money for clinical trials or consign rapamycin to the long list of drugs that initially raised hopes for a longevity breakthrough but fizzled.
Andrei Gudkov believes there are too many variables in pet households to provide clean scientific data. So he and his colleagues in the Vaika study recruited 102 former sled dogs, ages eight to 11, from across the U.S. to live out their golden years in a Cornell College of Veterinary Medicine kennel under tightly controlled conditions, with ample space to run and play.
The scientists scrupulously monitor the changes of later life—the dogs do treadmill tests, cognitive tasks, and problem-solving activities such as figuring out how to get around a fence. The scientists also have tested two drugs for their anti-ageing potential: lamivudine, an FDA-approved treatment for HIV and hepatitis B, and entolimod. A recombinant protein developed to counter the effects of radiation poisoning, entolimod is also being evaluated at the Mayo Clinic as an immune-system booster in people 65 and older.
Meanwhile, a San Francisco startup with the canine-reverent name of Loyal is testing a dissolvable implant that releases a drug aimed at slowing ageing in large breeds, which grow old faster and die younger than small ones. Also in the pipeline: a tasty pill for older dogs of all but the tiniest toy breeds, code-named LOY-002. Like rapamycin, it emulates the biological effects of calorie restriction.
“While we are building these dog longevity drugs and giving something that pet parents, at least from the emails I get, really, really want, we’re also learning something about how to help people live longer, healthier lives,” says Celine Halioua, Loyal’s founder and CEO. “Honestly, the most important thing that Loyal can do is prove that ageing should be a drug class … that there’s a way to develop a drug for this mechanism.”
The DNA cure
Ace’s mother, Gabby, developed mitral valve disease before he did. The leaky valve causes blood to flow back into the upper left chamber of the heart instead of moving to the lower chamber. At 12, Gabby was part of the first pack of dogs to receive the gene therapy that Ace would later get. Their treatment grew out of experiments led by Noah Davidson, then a postdoctoral researcher in the lab of Harvard biologist George Church.
Davidson knew that gene expression—the process by which information stored in DNA is translated into molecules that control how cells function—can go awry as we grow older. He believed that properly regulating gene expression, which means switching on some genes and turning off others, was the key to slowing ageing and eliminating many diseases that come with it.
He and his colleagues zeroed in on three genes known to promote healthy ageing and longer life in genetically engineered mice. He theorised that an extra copy of any of these genes, or maybe all of them, would have broad health benefits in normal mice. The team created a therapy from each gene and tested them all in mice, one therapy at a time and in two- and three-gene cocktails. In a 2019 paper in PNAS, the scientists reported that a single dose of a two-gene combo mitigated four age-related ailments: type 2 diabetes, obesity, heart failure, and kidney failure.
Rejuvenate Bio, co-founded by Church, Davidson and Daniel Oliver, quickly jumped to tests on dogs. The study, focused on evaluating the therapy’s safety, isn’t limited to Cavalier King Charles Spaniels. But a passionate, well-organised community of owners of the breed, most of whom will have a dog with mitral valve disease, spread word of the trial. “This is a very big deal in the Cavalier world,” Stephanie Abraham says.
In early 2020, Abraham drove Gabby to the Cummings School of Veterinary Medicine at Tufts University, in Massachusetts, an hour from their home. The dog received an intravenous infusion in her hind leg. For all the eye-popping science and painstaking research that went into creating the therapy, the IV drip took less than 15 minutes. “There was no pain or crying,” Abraham says. Ace breezed through the infusion two years later.
Rejuvenate Bio has not announced the results, but it has partnered with an animal health company and plans to seek FDA approval for the canine gene therapy. The startup also plans to recode the gene cocktail for human use and test it for two ailments: arrhythmogenic right ventricular cardiomyopathy, which breaks down part of the heart’s muscular wall and increases the risk of irregular heartbeat and sudden death; and familial partial lipodystrophy, a disorder of abnormal fat storage that leads to diabetes, an enlarged liver, and other health problems in adulthood.
Gabby and Ace have had no discernible complications or side effects from the therapy, and Abraham is encouraged by blood tests for a hormone that indicates how well the heart is pumping blood and can flag incipient heart failure. Gabby’s levels have improved; Ace’s are stable. The scamp shows no sign of keeping his paws off the post.
For information on the Dog Ageing Project and the rapamycin trial, please go to the website.You can nominate your canine companion to participate. The project is recruiting dogs in all shapes, sizes, and breeds.