Can Rapamycin Extend Human Life?
How a bacterial metabolite that’s become an immunosuppressant has earned attention for its potential in the aging field.
Rapa Nui, also known as Easter Island, is a tiny plot of land — just 60 square miles in total —in one of the most remote areas of the southeastern Pacific Ocean, thousands of miles away in any direction from any other landmass. You probably recognize Rapa Nui as the site of the majestic thousand-year-old stone Moai sculptures, which make the island a UNESCO World Heritage site. But what you might not realize is that Rapa Nui is also a famous landmark for the science of aging.
In 1972, a team of Canadian scientists removed a soil sample from underneath one of the famous statues. They were there studying the health of the community on the island, and had noticed that people didn’t pick up tetanus via their feet as expected, and they thought something must be going on in the soil to protect them. For a few years, that soil sample sat useless in a pharmaceutical company’s lab in Montreal. Finally, the company scientists found something remarkable after a last round of tests: a bacterial metabolite that worked as an immunosuppressant. The scientists also found it had the curious ability to stop cancer cells from dividing, spurring furious interest in it and how it worked. They named it rapamycin, after its site of discovery.
It wasn’t until 1999 that rapamycin was first brought to market, as a drug known as sirolimus or Rapamune that tamped down the immune systems of transplant patients to prevent rejection of new organs. Derivatives of rapamycin have also gone on to become cancer drugs, such as temsirolimus, used for the treatment of kidney cancer in 2007. But today rapamycin has earned attention for something different: its potential as an alleged “anti-aging” drug.
What Links Rapamycin To Aging?
By the early 1990s, scientists had identified rapamycin’s mechanism: It blocks the activity of a protein complex in cells that is responsible for regulating cell growth and proliferation. The protein complex, which is named mTOR (for mammalian target of rapamycin), functions as the command center for nutrient signaling, so the cell can sense the levels of amino acids, glucose, insulin, leptin and oxygen in its surrounding environment. This tells the cell whether or not the cell should grow, multiply, or in the absence of nutrients, slow its growth or even die-off.
When rapamycin blocks mTOR, it essentially inhibits cell growth. This is why it works as an immunosuppressant, stopping the proliferation of immune cells, and also why its derivatives can help stop cancer cells from growing. This function, the slowing of cell growth is very similar to what happens to cells during calorie restriction, or CR. Scientists studying aging have had their eyes on CR for decades because it’s known to reliably extend lifespan in preclinical studies in monkeys, rodents, worms, and flies, and improve health markers in shorter-term studies in humans.
So naturally, this led scientists to wonder: Would rapamycin extend lifespan the way calorie restriction does? Scientists then began looking at what happened to lifespan if they modified the genes of worms and flies to block mTOR, and found that doing so extended the lifespan of the organisms. Researchers already had a drug that could block mTOR, so the obvious next step was to study whether rapamycin extended lifespan also.
In 2009, the first result of that work was published in the journal Nature: After feeding rapamycin to older mice, researchers found that it extended female rats’ lifespan by 14%, and 9% for males. Then, for a 2014 study researchers tinkered with the delivery and dosage methods, and found that the drug extended the median lifespan 23% in male mice and 26% in female mice. Perhaps most exciting, 2017 research looked at the effects of rapamycin on a group of 24 middle-aged companion dogs. Although the short-term study didn’t determine whether the drug could in fact extend the lives of the animals, the researchers found significant improvement in the canines’ cardiac function after just 10 weeks — with no side effects.
That leaves only the big question: Does it work in humans? To know for sure whether an intervention slows human aging, people would need to be studied throughout their entire lives, so the best evidence right now are a few shorter-term studies. One 2014 study found that elderly volunteers who had been given low doses of an mTOR inhibitor similar to rapamycin had better immune response to the flu vaccine. Beyond the immediate benefits of being less likely to get influenza, the study authors say this is also a sign that the drug is acting on the underlying immune system breakdown that makes older people more likely to succumb to infections, like influenza and pneumonia.
More recently, a 2018 study found that a 6-week course of an mTOR inhibitor led to a significant reduction in the rate of infections for a full year after the dosing. This may be because in smaller doses, rather than fully blocking immune cell proliferation, rapamycin just “turns it down” to youthful levels.
Don’t Experiment Now — Wait For The Next Step
All of this has led to rabid interest in rapamycin and mTOR inhibitors in the past few years — and not just from scientists. With the influence of biohackers and Silicon Valley techies, rapamycin and mTOR has made it onto Internet message boards, where intrepid Guinea pigs report their experiences with DIY rapamycin supplementation after buying it illegally from lab suppliers. It has even led some doctors to begin prescribing rapamycin off-label as an anti-aging drug.
But before you get to Googling “where can I buy rapamycin,” you should know there are major possible side effects of taking rapamycin over the long-term. In some people, rapamycin and like-drugs become quickly toxic, leading to painful mouth sores. Other research has warned that long-term use of the drug may lead to type 2 diabetes. As of now, there are too many unanswered questions about dosing and long-term use in humans to safely take it. In fact, it is one of the few drugs with risks big enough for the FDA to have approved it with a “black box” warning because of its effects on the immune system, which could lead to increased risk of infections, pneumonia and even cancers.
This is why the next step for rapamycin and its analog mTOR inhibitors would need to be the development of rapamycin-like compounds that still imodify mTOR, with fewer negative effects on the immune system. Like all things that sound too good to be true, more research is necessary to unearth what rapamycin could do for the health and aging field.