Summary: Intermittent rapamycin therapy lengthens the lifespan of mice and seems to eliminate side effects in humans. Have geroscientists figured out how to administer the anti-aging drug rapamycin in a way that sidesteps its side effects? [This article first appeared on LongevityFacts. Follow us on Reddit | Google+ | Facebook. Author: Brady Hartman]
The FDA-approved drug rapamycin extends the lifespan of mice by about 25%. Rapamycin therapy is currently in human clinical trials and may be one of the first anti-aging medications to be approved.
Discovered as a bacteria in the soil on Rapa Nui (Easter Island), the drug rapamycin is a leading candidate for the first lifespan-extension drug. Since 1999, rapamycin has been approved by the U.S. Food and Drug Administration (FDA) as an anti-rejection drug for transplant patients. As well, physicians prescribe rapamycin in some cancer chemotherapy treatments. Lifespan-extension researchers, called geroscientists are working to realize the drug’s potential to increase the number of healthy years in humans.
Rapamycin comes from bacteria first discovered in the soil of Easter Island. It is currently FDA-approved for use in organ transplant patients, and in the treatment of a few types of cancer. Anti-aging researchers, called geroscientists, hail rapamycin as the compound with the highest lifespan-extending potential.
Daily Rapamycin Therapy
Because daily rapamycin therapy suppresses the immune system, doctors prescribe the drug to transplant patients to stop them from rejecting their organs. Rapamycin has been shown to be useful not only as an immune system suppressant in organ transplant but as a cancer fighter and maybe even an immune system booster. In the 2016 Annual Report by the American Federation for Aging Research (AFAR), Steven N. Austad, Ph.D., a leading researcher in lifespan extension explains the promise of rapamycin as a lifespan-extending compound, when he says
“There have been probably a dozen studies in mice that all show that rapamycin extends life, even when administered at fairly advanced ages—the human equivalent of 70 years,” adding. “That has been the most remarkable finding because we always assumed that if people were going to affect their later-life health and longevity, they would probably have to start doing something in their 30s or 40s. I think what the rapamycin research suggests is that interventions in the aging process could start quite late in life, but still have a dramatic effect.”
Dr. Austad is referring to the widely-publicized Harrison study published in 2009 in which rapamycin extended the lifespan of mice by about 25%. Rapamycin therapy had these positive effects even when fed to the mice beginning at early-old age (20 months), suggesting that an intervention started later in life may still be able to increase lifespan.
The finding that daily rapamycin therapy extended the lifespan of mice gave rise to the notion that specific compounds can lengthen our lives. The success of rapamycin helped pave the way for trials of other lifespan-extending drugs such as the Taming Aging with Metformin (TAME) Trial, which will test the generic type 2 diabetes drug on people aged 65-79 over just six years.
In the past, one of the most significant obstacles facing researchers considering testing medicines that influence fundamental aging mechanisms was the assumption that the tests would take 50 or 60 years to get results. According to Dr. Austad, the ability of rapamycin therapy to extend the healthspan and lifespan of mice—even older mice,
“started us thinking differently,” adding, “We realized we could give these drugs that target fundamental aging processes to older people and expect to get quite a substantial effect.”
Rapamycin Therapy on Dogs
Rapamycin is now being tested in the Dog Aging Project —led by Matt Kaeberlein, Ph.D., and Daniel Promislow, Ph.D., at the University of Washington—to see if it achieves similar lifespan-extending results in canines as those obtained in mice.
How Rapamycin Therapy Works
All animals, including humans, have longevity pathways that control the rate of aging. Rapamycin therapy targets one of those key longevity pathways. In fact, researchers have identified three longevity pathways so far insulin/IGF-1, sirtuins, and mTOR.
The mTOR pathway—an abbreviation of the mammalian target of rapamycin—plays a role in the aging of many organisms. This pathway controls the cell’s rate of protein synthesis, an essential part of cellular function. Scientists have found that inhibiting the mTOR pathway in mice leads to increased longevity and improved health. Rapamycin therapy works by inhibiting the mTOR pathway.
Side Effects of Daily Rapamycin Therapy
When taken daily, rapamycin causes side effects, the most serious of which include an increased risk of infection due to immune suppression, elevated blood sugar, and an increased risk of type 2 diabetes. Some of the side effects of daily rapamycin therapy are extremely serious, occasionally causing death due to infections. The complete list of side effects reported by daily rapamycin users includes high cholesterol, high triglycerides, glucose intolerance, insulin resistance, new-onset diabetes, anemia, thrombocytopenia, gastrointestinal disorders, sinusitis, respiratory and urinary infections, testicular dysfunction, and skin problems.
Daily vs. Intermittent Rapamycin Therapy
Rapamycin therapy is promising. However, researchers still need to determine the dosage that provides health benefits while eliminating harmful side effects. Scientists think they have already found the answer because rapamycin behaves differently when taken daily, as opposed to intermittently.
When taken daily, rapamycin suppresses the immune system. Immune suppression is the desired effect for transplant patients, but dangerous for the vulnerable elderly.
On the flip side, when rapamycin is taken intermittently – such as once a week – one study showed that the drug has minimal side effects in humans and still preserves its lifespan-extending powers in lab animals.
Intermittent Rapamycin Therapy Greatly Lessens Side Effects
In a study, Novartis researcher Joan Mannick gave rapamycin both intermittently and daily to participants aged 65 and older. While those receiving the drug daily experienced the usual side effects, those on the intermittent rapamycin therapy enjoyed a 20 percent boost in their immune systems, with minimal side effects.
Commenting on the significance of the Mannick study, Dr. Austad gives his opinion in the AFAR annual report, saying,
“Now, whether that dose [intermittent rapamycin therapy] is going to be a dose that also affects healthspan, we don’t know.”
Dr. Austad is only partially correct. While short-term intermittent rapamycin therapy boosted the immune systems of the Seniors, no one has tested the health effects of intermittent rapamycin therapy in humans. However, researchers have tested intermittent rapamycin therapy on mice – and it worked nearly as well as daily rapamycin therapy in extending the lifespan of the rodents.
Intermittent Rapamycin Therapy Extends Mouse Lifespan
In 2016, Sebastian I. Arriola Apelo and Dudley W. Lamming – two researchers from the Department of Medicine, at the University of Wisconsin-Madison, conducted a trial of intermittent rapamycin therapy on mice. At the end of the experiment, the researchers found that intermittent rapamycin therapy extended mouse lifespan nearly as well as daily dosing. In the press release accompanying the report, the authors said,
“we found that intermittent administration of rapamycin starting at 20 months of age [middle-age for a mouse] significantly extends lifespan, to a similar degree as previously reported for every day treatment.”
Intermittent Rapamycin Therapy Reduces Diabetes in Mice
Early in 2016, Apelo published a report which showed that intermittent rapamycin therapy in mice significantly reduced the diabetes-promoting side-effect of the drug.
While no long-term studies of a similar therapy have been performed in humans, the Apelo report suggests that intermittent rapamycin therapy may also reduce the diabetes side effect in humans. However, no one can be sure until clinical trials are conducted.
Another Way to Counter Rapamycin’s Side Effects
One scientist has come up with another way to sidestep rapamycin’s side effects.
In October of 2016, in an article published in Frontiers in Pharmacology, researcher Pei Shi Ong suggested that the side effects of rapamycin could be reduced by combining the drug with other agents that reduce the risk of type 2 diabetes. Ong suggested the compounds resveratrol and metformin as the two best drugs to take the sting out of rapamycin therapy. For evidence backing his strategy, Ong pointed to a study in which combining resveratrol with rapamycin was shown to prevent the onset of diabetes in mice.
Human Testing of Rapamycin Therapy
A clinical trial of rapamycin at the University of Texas at San Antonio (UT-SA) has already been underway since August of 2016.
The trial is being led leading researcher Dean Kellogg, MD Ph.D. and aims to test rapamycin’s lifespan-extension benefits on a small group of healthy seniors. A celebrity in the anti-aging field, Dr. Kellogg’s research is focused on the lifespan-extending effects of rapamycin therapy and translating the results for humans.
While this is a good start, the trial will last only eight weeks, far too short to test the drug’s anti-aging benefits and side effects.
One U.S. doctor is not waiting for the results of clinical trials and is already prescribing rapamycin therapy for anti-aging purposes. Dr.Green – the rapamycin doctor is prescribing the drug to healthy senior adults as part of a cocktail of anti-aging drugs.
Rapamycin’s Future Looks Bright
Pharmaceutical scientists continue to work on rapamycin to tweak the dosage and improve its safety. Dr. Austad says drugs that target fundamental aging processes, such as rapamycin and metformin are extremely promising. As Austad says in the AFAR annual report, these lifespan-extending medications
“are lining up like airplanes waiting to take off, and metformin is just the first one. I do think that rapamycin would be a logical next step. If the dog trial shows a great deal of promise, a human trial designed much in the spirit of the TAME Trial would be next.” Adding “I think what the rapamycin research suggests is that interventions in the aging process could start quite late in life, but still have a dramatic effect.”
Bottom Line on Intermittent Rapamycin Therapy
Intermittent rapamycin therapy has been shown to be superior to daily treatment in mice. Intermittent therapy with the drug lengthens the lifespan of mice while reducing the onset of diabetes. Moreover, intermittent rapamycin dosing has been shown to improve the immune system of humans in clinical trials, with few detectable side effects. Intermittent rapamycin therapy has yet to be tested in long-term human clinical trials to prove its safety and efficacy. A clinical trial of rapamycin therapy is underway at UT-SA. However, the trial is far too short to test the compound’s anti-aging benefits and side effects. Rather than continuing to experiment with the drug in animals, the time is nigh to begin long-term trials of intermittent rapamycin therapy with human subjects.
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Ong, Pei Shi et al. “Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives.” Frontiers in Pharmacology 7 (2016): 395. PMC. Web. 30 June 2017. Link.
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