Scientists who study aging are currently riveted by a group of 20 dogs in Seattle. The dogs, all house pets older than six years old, are early test subjects in a trial of a drug called rapamycin. The way the drug works is not completely understood, but it’s been used for years to prevent rejection of transplanted organs, and in laboratory studies, it’s lengthened the life spans of diverse species: worms, fruit flies, and mice. If it works in dogs, healthy human volunteers will be the next guinea pigs.
In fact, rapamycin is one of several anti-aging drugs that may end up in human trials in the coming years as researchers improve their understanding of the mechanisms of aging.
There are already some known side effects: at high doses, rapamycin can raise blood sugar and thereby increase the risk of diabetes. It causes mouth lesions known as canker sores. Researchers originally worried that because it works as part of an immune-suppressive cocktail for organ transplants, it would raise the risk of infection. But then a study last year in Science Translational Medicine showed that a derivative of the drug seemed to enhance human immunity following a flu shot.
Scientists aren’t sure why rapamycin suppresses the immune system in some contexts and boosts it in others. But they are starting to grasp how it might slow the aging process.
Over time cells are degraded by several factors, including damaged DNA, misfolded proteins, and excessive inflammation. This degeneration can’t be stopped altogether, but researchers have found a surprising number of ways to slow it down in yeast cells and other living things. The common thread seems to be calorie restriction. If you cut down the food supply enough, a series of biochemical changes switch the body into a kind of lower gear so it can hunker down for survival.
Rapamycin and other drugs that appear to slow aging in animals work by triggering this same biochemical pathway. The idea, says Harvard Medical School researcher David Sinclair, is to trick the body into acting as if it’s running out of energy and putting more effort into long-term survival.
S. Jay Olshansky, a professor of public health at the University of Illinois, is an outspoken critic of untested products sold to the public by what he calls the “anti-aging industry.” But he says he’s optimistic about the current work on rapamycin and another drug, a diabetes treatment called metformin. He refers to the leaders of these projects as “real scientists.”
It’s worth noting, though, that even the work of real scientists has led to disappointment. In the early 2000s, Sinclair identified a family of enzymes called sirtuins that became more active when animals were induced to live longer through near-starvation diets. Another group found sirtuins could also be activated by a red wine ingredient called resveratrol.
Red wine, or even resveratrol pills, looked like a much more palatable anti-aging strategy than starvation. Based on his research, Sinclair cofounded a company called Sirtris Pharmaceuticals, which was bought for $720 million by GlaxoSmithKline in 2008. But nobody was ever able to show a connection between resveratrol and human life span (see “The Argument over Aging” and “The Anti-Aging Pill”). Glaxo shut down Sirtris in 2013.
Rapamycin, originally isolated from soil bacteria on Easter Island and named after the island’s native name, Rapa Nui, is one of five drugs that have extended the lives of mice in studies. But it probably will be a lot easier to achieve life extension in mice than in people. Steven Austad, a researcher at the University of Alabama-Birmingham, has studied dozens of species to understand why some whales can live up to 200 years but lab mice are lucky to get to two. Small mammals tend to have shorter life spans than large ones, and it may turn out that mice have more room for improvement, as evolution optimized them for reproduction, while we’re already somewhat better equipped for long-term survival, Austad says.
Still, he and a number of others in the field are optimistic about rapamycin because it extended mouse life spans between 9 percent and 14 percent, and it worked whether mice began getting the drug during middle age or very late in their short lives. Moreover, it prevented cardiovascular damage and memory loss. That suggests that it might lengthen the period in which people are healthy and functional rather than drawing out a period of decline.
The only other substance that has recently generated as much excitement among aging researchers is the diabetes drug metformin. It’s had only modest effects in mice but has already shown promise in humans. According to a 2014 study that followed 7,800 diabetics, those on the drug not only lived longer than other people with diabetes, they lived slightly longer than nondiabetic control subjects. Researchers believe that it’s less likely than rapamycin to have problematic side effects but also less likely to show dramatic results.
Even if these drugs do show signs of working in people, there would still be many details to work out, including what dose to give and how old the subjects should be. But perhaps in three or four years those dogs in Seattle will offer clues.
The study includes only larger dogs, since they age faster than small dogs for reasons that are not completely understood, says University of Washington biologist Matt Kaeberlein, who is heading the study. The researchers plan to eventually follow 32 dogs in an initial phase, after which they’ll examine the data. One quarter of the dogs will get a placebo, not because dogs are subject to the placebo effect but to prevent bias in the owners who will be reporting regularly on their dogs’ health. So far the owners have reported no notable side effects, Kaeberlein says. “The last thing we want to do,” he says, “is harm people’s pets.”