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Rapamycin: An Accidental Discovery
An accidental discovery in 1965 on a tiny island in the middle of the Pacific Ocean shook the medical community. This finding could be the most significant advance in anti-aging in the last century.
In the 1960’s, Canadian scientists employed by Wyeth Pharmaceuticals roamed the isolated islands of the Pacific to find evidence of bacteria with anti-fungal activity. In 1965 they got to a tiny island in the middle of the Pacific Ocean. This island was called Easter Island and is located 2,300 miles west of Chile.
Scientists were curious as to why the inhabitants of this island were free of tetanus, a frequently fatal bacterial disease found in the tropics. They gathered soil samples and took it back to the lab in Montreal for study. They found that the bacteria on this island had developed a potent mechanism for warfare against yeast. The bacteria targeted a protein complex which was the command and control center of the yeast cell.
At first, researchers looked into Rapamycin to cure fungal infections. Then they found the protein complex that Rapamycin targeted was the command and control center of every cell in every living organism including humans.
This was a major discovery. Scientists named this drug Rapamycin after the indigenous name of Easter Island, Rapa Nui. The protein complex that Rapamycin targets became known as Mammalian Target of Rapamycin (mTOR).
Fun fact: Bacteria and yeast have been fighting each other for millions of years. The antibiotic penicillin was another accidental discovery by Alexander Fleming, and he found that the yeast made a molecule that killed bacteria. This was yeast’s weapon against bacteria, and it is the same fungus that grows on stale bread.
How does Rapamycin work?
The mTOR pathway signals for growth and reproduction in cells in response to the environment. It essentially controls the speed at which cells divide and an organism grows.
So in essence, mTOR looks at the environment and makes a decision: is this a good time to grow and reproduce because nutrients are plentiful, or is this a good time to hunker down and survive because conditions are not favorable such as a drought or famine.
Scientists found that at lower doses of Rapamycin they could slow down cell growth, at higher doses they could completely stop it. That led scientists to target of the types of cells that divide rapidly, immune cells or cancer cells.
Rapamycin could be used to suppress the immune system. But how could that be any good?
It’s good in the cases of organ transplants, and it tells the body to suppress the automatic response to fight off foreign tissue thereby allowing for a successful transplant. The FDA approved Rapamycin in 1999 for kidney transplants.
Scientists found that it was an important regulator of aging in yeast [1]. Additional studies with Rapamycin showed significant increases in lifespan in flies, worms and mice. [2] [3] [4]. In fact, scientists were able to tweak the dosages of Rapamycin to increase median lifespan 23% in male mice and 26% in female mice. These findings shook the medical community, prompting further investigation into the drug.
Scientists later found that by targeting the mTOR pathway, Rapamycin works similar to caloric restriction.
We have known since the 1930’s that Caloric Restriction is extremely effective for anti-aging and a longer lifespan. Caloric restriction achieves that outcome by inhibiting the mTOR pathway. Scientists found that Rapamycin targets the mTOR pathway similar to caloric restriction.
This led to an important conclusion. By taking Rapamycin, you could get all the positive anti-aging benefits of caloric restriction without starving yourself all the time.
Rapamycin and mTOR: What’s the Catch?
As with most complex systems, the devil is in the details.
Even though Rapamycin has shown to do wonders with increasing longevity in lab animals, those results have not been shown in humans because the dosage amounts are very different. For kidney transplants, most immune activity needs to be stopped to not reject the new organ, and that requires a high dose of the drug. This led to several side effects such as mouth sores, increased risk of infection, diabetes-like syndrome and reduced ability to stabilize sugar levels.
Because all the lab tests were done on animals using a very small dosage of Rapamycin, many scientists believe a smaller dosage would demonstrate the same benefits in humans as in the animal testing.
Let’s dig a little deeper to examine the details of mTOR. mTOR is found in two protein complexes: mTORC1 and mTORC2. When mTORC1 is blocked the result is increased lifespan and a delay in age-related diseases (improvement in immune, heart, memory, and other functions). When mTORC2 is blocked the result is a reduced ability to process sugar and reduced immune system function. [5]
Another factor to consider is that mTORC1 is very sensitive to Rapamycin and slows down activity quickly in the presence of the drug, while mTORC2 activity is only affected when Rapamycin is chronically present in the body for a longer period of time.
Due to the factors above, many scientists believe that best use of Rapamycin would be to inhibit mTORC1 while not affecting mTORC2. They believe they found a way to make this work by administering Rapamycin intermittently in small doses, instead of every day. This dosage has been proven in animal studies to have great effect.
Before Humans, Rapamycin Trials in Dogs
While Rapamycin has shown great benefits in yeast, worms, flies, and mice, it has not been formally tested at the proposed dose in humans. Due to its side effects Rapamycin has not been cleared for anti-aging human studies yet, but some in the medical community are hoping to begin work on trials soon.
In the meantime, a Rapamycin study in dogs is giving many people hope.
Dr. Matt Kaeberlein is leading the initiative to conduct Rapamycin studies in dogs. He is one of the primary scientists behind the Dog Aging Project, and the goal of that project is to conduct Rapamycin studies in middle-aged dogs. Veterinarians will administer low doses of Rapamycin to middle-aged dogs to determine the effects of the drug on anti-aging, sugar processing, and cognitive abilities.
There are a few reasons for starting trials with dogs. The first reason is dogs live a shorter time compared to humans, and scientists will have documented results in a decade.
The second reason is that dogs live in an environment very similar to humans. All past studies on animals have been done in the lab. Dogs are very different in this regard. Some dogs even sleep in their owner’s beds and eat some of the same food as the owner. This is a really good test for the benefits of Rapamycin while taking into account diversity of our environment.
The third reason is improving the health and quality of life for the dogs, and gain public support for anti-aging medicine.
Early Human Trials
Novartis did one study involving the inhibition of mTOR on the immune system in the elderly, with the result that Rapamycin boosted immune response considerably [6].
Novartis then sold the research to a biotechnology startup called resTORbio which is focused on the development of drugs for anti-aging diseases by targeting the mTORC1 protein complex.
Human studies are in the early stages and will take decades to perform.
What’s Next for the Anti-Aging Promise of Rapamycin
While we’ve heard of doctors and veterinarians are already prescribing the medication for its anti-aging properties, it takes time to measure anti-aging effects, and we will not have a measurable set of human data for 10 years at the very least.
We urge our readers to be cautious. Within the next few years, we are hopeful in the promise of Rapamycin as a miracle compound which will prevent the diseases of aging and turn back the clock of time to transform you into a more youthful you.
Just think of the curious case of Benjamin Button. Or not.
References:
[1] https://www.ncbi.nlm.nih.gov/pubmed/16418483
[2] https://www.ncbi.nlm.nih.gov/pubmed/20074526
[3] https://www.ncbi.nlm.nih.gov/pubmed/22560223
[4] https://www.ncbi.nlm.nih.gov/pubmed/20947565
[5] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12405
