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Rapamycin is a macrolide, a class of antibiotic that includes erythromycin, roxithromycin, azithromycin, and clarithromycin. Rapamycin exhibits potent antitumor and immunosuppressive activity.
Where is rapamycin found?
Rapamycin was first discovered in 1972 in the soil of Easter Island produced by a bacterium called Streptomyces hygroscopicus. It takes its name from Rapa Nui, the indigenous name for the island. It is known clinically as sirolimus or Rapamune.
What is rapamycin used for?
Rapamycin has been used for many years as an immunosuppressant drug to prevent organ transplant rejection. It is also used to coat coronary stents and to treat the rare lung disease lymphangioleiomyomatosis.
However, in the early 2000s, researchers discovered its potential to increase lifespan. In low doses, rapamycin reliably increases the lifespan of worms, yeast, flies, and mice.
Rapamycin increases lifespan
In one study, researchers gave a group of 20-month-old mice rapamycin. For mice, this age is roughly equivalent to that of 60-year-old humans. They gave the mice small doses of the drug for a three-month period, then they halted treatment and simply observed them until they died naturally.
Normally, these mice would have died of age-related diseases around the 30-month mark; however, the treated mice lived an extra 2 months on average. One plucky mouse managed to live 3 years and 8 months, which would be like a human living to 140 years old!
There are many other examples of increased lifespan resulting from rapamycin in multiple species.
How does rapamycin work?
It was originally thought that rapamycin was able to increase lifespan by mimicking the effects of caloric restriction. Caloric restriction is another reliable method through which researchers can increase the lifespan of many species.
Caloric restriction is known to target the mammalian target of rapamycin (mTOR) pathway, and the same is true for rapamycin. It is an important signaling molecule involved in our nutrient-sensing pathways.
Essentially, a lack of nutrients turns mTOR off and triggers cells to activate austerity measures focused on cell survival and stress resilience rather than growth. This allows us and other species to survive periods of famine.
This is why some researchers believed for years that rapamycin was simply a caloric restriction mimetic. However, recent research casts that into doubt and suggests that it does not use the same pathways as caloric restriction to achieve increases in lifespan.
That said, there are also many studies linking mTOR signaling with lifespan, caloric restriction, and rapamycin. So, it is likely that its influence on the mTOR pathway may contribute to increasing lifespan, it is just not doing it the same way that caloric restriction is.
But if it’s not a caloric restriction mimetic, how is rapamycin increasing lifespan?
Rapamycin and autophagy
Despite it not being a direct caloric restriction mimetic, rapamycin does trigger autophagy just the same, and this is likely one of the reasons it extends lifespan.
Autophagy is the ultimate recycling system of the cell. The word comes from ancient Greek and means “eating of self”. In times of nutrient scarcity, it is one of the pro-survival austerity measures that cells take.
Autophagy breaks down and removes unnecessary or dysfunctional cellular components to conserve energy and keep the cell alive. While it might sound harmful, it appears that autophagy has longevity-promoting effects.
This is likely the case as approaches known to increase lifespan, such as caloric restriction and rapamycin, see their longevity effects reduced when autophagy is blocked.
Rapamycin is a well-known and potent inducer of autophagy in a wide range of cells from yeast to mammals. Because of this, it is highly likely that rapamycin uses autophagy as one way of increasing lifespan.
But, autophagy is not the only potential reason why it increases lifespan, as new research suggests.
Rapamycin improves DNA storage
Recently, researchers have shown in fruit flies and mice that rapamycin improves the way DNA is stored inside cells to support gut health and longevity.
Our DNA is stored inside the cell nucleus and must be tightly wound to fit inside. A family of proteins called histones wind the DNA tightly, allowing it to squeeze into the tiny nucleus. Once packed inside, it can form chromosomes and our cells can function.
Unfortunately, as we age, the number of histones begins to decrease, which means our DNA becomes less tightly packed. This then leads to more genes being expressed, some of which are associated with aging processes, which is bad news.
Thankfully, researchers discovered that exposure to rapamycin increases the number of histones and so reverses that age-related loss. It also does this via the mTOR pathway, making it a previously unknown link between this metabolic pathway and the stability of our DNA.
Perhaps the most intriguing part of this discovery was that this only happened in gut cells called enterocytes. The data shows there is a direct link between mTOR, histones, and gut health. It also suggests that this link is a regulator of health and lifespan.
Rapamycin and diabetes risk
While rapamycin’s inhibition of the mTOR pathway via mTORC1 mediates the above positive benefits, it also inhibits mTORC2, which can result in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin.
Some studies suggest that rapamycin treatment may also increase the risk of type 2 diabetes.
Low Dose rapamycin for longevity
Researchers are currently experimenting with ways to make rapamycin safer in the context of longevity, including, low doses, periodic dosing frequency and using similar compounds called rapalogs, which only target mTORC1 and thus separate the beneficial effects from the negative ones.
That said, it cannot be stressed enough: rapamycin, at this point, is an unknown in the context of human longevity. More research is needed to ascertain if it slows down human aging as it does in animals. While some longevity enthusiasts are experimenting with low dose rapamycin, the data from large-scale human anti-aging trials is yet to be published.
Here at Lifespan.io we have crowdfunded research to support human trials of rapamycin for longevity as part of the PEARL project. The goal of the project is to ascertain the impact of rapamycin on human aging, should there be any.
Rapamycin side effects
Rapamycin is a controlled drug rather than a dietary supplement but it has a good safety profile when used appropriately. There are a number of potential side effects, ranging from mild to serious and possibly life-threatening especially at higher doses. Rapamycin should be taken with caution and with the guidance of a medical professional.
Some of the more common side effects include lowered potassium levels in the blood, anemia, decreased blood platelets, increased blood pressure, decreased kidney function, increased triglyceride levels, constipation, joint and muscle pain, dizziness, fever, headache, nausea, diarrhea, and abdominal pain.
Rarer side effects include lung toxicity and increased mortality due to an increased risk of infections in transplant patients, and, according to the FDA prescribing information, it may increase the risk of contracting skin cancers from exposure to sunlight or UV radiation.
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The Rapamycin Story
Ross Pelton discusses the lifespan-enhancing effects of a drug in clinical trials called rapamycin and alternative ways of attaining its benefits today.
Scientifically reviewed by: Dr. Gary Gonzalez, MD, in April 2022. Written by: Ross Pelton.
As progress in longevity science continues to accelerate, researchers are investigating three innovative strategies that can delay aging, reduce disease, and increase lifespan.
Rapamycin, mTOR, and autophagy are at the forefront of the life extension revolution. In this interview, Life Extension discusses these advances with pharmacist Ross Pelton, author of the book, Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome.
LE: Ross, there’s been a lot of “buzz” lately about rapamycin, an FDA-approved drug used to prevent organ transplant rejection and treat certain cancers. Why are people so excited?
Pelton: What has fascinated the scientific community is rapamycin’s ability to increase median life expectancy in animal models by up to 60%. The hope is that humans may gain significant improvements in health and increases in lifespan by taking rapamycin.
In addition, a clinical trial in elderly adults 65 years and older revealed that once-weekly dosing of everolimus (a rapamycin derivative with properties virtually the same as rapamycin) strengthened their immune system, evaluated by their enhanced response to influenza vaccine of about 20%. This study is important because the immune system in all elderly people has declined significantly compared to the immune function of healthy adults in their 20s and 30s. The ability of rapamycin-like drugs to enhance the immune system in elderly adults is a major outcome.
LE: You said rapamycin can increase life expectancy by up to 60% in animals. Can you discuss that in more detail?
Pelton: When rapamycin therapy was initiated in middle-aged mice, median increases in life expectancy of up to 60% were observed. When rapamycin therapy was initiated in elderly male and female mice that were roughly the equivalent of 60-year-old humans, female mice achieved a 14% increase in lifespan and males achieved a 9% increase in lifespan. This may equate to an increase of more than seven years of human life.
LE: How does rapamycin work?
Pelton: Over the past 25 years, research into rapamycin’s mechanism of action has resulted in the discovery of a new understanding of cellular biology and the aging process. This research has revealed that mTOR and autophagy regulate the health and aging process of all living organisms.
Rapamycin inhibits mTOR and enables the process of autophagy to be activated, which restores youthful metabolic functions. Research reveals that rapamycin delays the onset of many age-related diseases that apply to human health.
In my mind, the mTOR/autophagy story is even more important than rapamycin. The understanding of mTOR and autophagy is revealing how we can delay the onset of age-related diseases and achieve significant increases in lifespan and healthspan.
LE: Can you explain what mTOR is for our readers?
Pelton: When calories are available to a cell, the protein mTOR sends signals that activate cellular metabolism, telling the cell to use the available calories to build new proteins, new enzymes, fat stores, and other cellular components. When mTOR is activated, it initiates anabolic (building) processes of cell growth and proliferation.
LE: And what is autophagy?
Pelton: Autophagy is the process in which damaged proteins, excess fat, and other worn cellular components are broken down for reuse or elimination. Autophagy has been referred to as the cellular housekeeping process or cellular trash removal. The problem is that chronically activated mTOR (caused by relentless calorie ingestion) precludes healthy autophagy.
LE: Is that a serious problem?
Pelton: Very. Throughout 99.9% of mankind’s evolution, people did not eat three meals per day. However, these days, refrigeration and the widespread availability of processed and packaged foods have resulted in food being easily available all the time. Modern humans spend far more time eating compared to our ancient ancestors.
This results in constant over-activation of mTOR and insufficient functioning of autophagy. This imbalance is a major contributing factor underlying today’s epidemic of health problems, such as cancer, obesity, and type II diabetes. I’ve chosen to call this condition “mTOR Syndrome”.
LE: How can people correct this imbalance? With intermittent fasting?
Pelton: Even aggressive fasting does not always induce meaningful reductions in body fat. Many individuals need additional support with compounds that induce beneficial autophagy. Rapamycin is a leading candidate. By inhibiting mTOR, rapamycin mimics calorie restriction and fasting.
LE: Does that mean rapamycin can help with weight loss?
Pelton: Yes. Research indicates that rapamycin may reduce fat mass and body weight as seen in cell and animal studies. And favorable findings from pilot studies in older people have prompted formal clinical trials to evaluate the anti-aging effects of rapamycin, including the ability to improve cardiac function and reduce visceral adiposity.
At this point, clinical trials have not yet been completed to determine how effective rapamycin might be as a drug to induce weight loss in humans. However, I will share my personal experience. In six months of taking rapamycin, I lost 15 pounds and noticed a substantial reduction in the “love handles” around my waist.
LE: What dose is optimal for weight loss?
Pelton: There may be up to 1,000 mTOR sites within each cell. When rapamycin is taken, it enters cells and binds to some of the mTOR sites, which results in partial inhibition of mTOR. The degree of mTOR inhibition is dose dependent. This is a critically important point. Some people may need to take higher doses of rapamycin to optimize the effect on mTOR and autophagy. One clinical trial is studying 5 mg and 10 mg weekly doses of rapamycin and using imaging scans before and after to measure how much visceral fat may be reduced.
LE: What is the most common dose being used by those seeking rapamycin’s potential longevity benefits?
Pelton: Pioneering physicians are discovering that taking 5-6 mg of rapamycin just once weekly partially inhibits mTOR. This enables autophagy to be expressed on a periodic basis, which provides a wide range of health benefits. When mTOR and autophagy are optimally balanced, every cell in the body can experience detoxification, renewal, and revitalization. Everything begins to work better.
Taking rapamycin for life extension is a very new field of science, so studies to determine the best dosage and frequency have not been conducted. Many life extension enthusiasts are self-experimenting by taking 5-6 mg once weekly. Eventually, lab tests to determine plasma levels of rapamycin will be readily available, which will help determine the best dose and frequency of taking rapamycin for each individual.
LE: At what age do you recommend people start taking rapamycin?
Pelton: This is a personal decision for everyone. However, I can offer some guidelines. mTOR is a master regulator of the growth activities in cells. Childhood, adolescence, and even young adulthood are periods of rapid growth. Hence, it would be inappropriate to have young people taking rapamycin. Although there is no agreed-upon age for people to start taking rapamycin, I don’t think people younger than 30 should.
LE: Can elderly people take rapamycin safely?
Pelton: Yes, but as the study of mice showed, the increase in life expectancy was greater when rapamycin was initiated in middle-aged mice. While we eagerly await results from ongoing human rapamycin studies, delays in suppressing excess mTOR and inducing autophagy may diminish the longevity-enhancing benefits.
LE: You mentioned that you take rapamycin. When did you start?
Pelton: I started taking 6 mg of rapamycin once weekly in June 2021. I had blood drawn for routine lab work in November 2021 and discovered that I was anemic. My red blood cell count, hemoglobin, and iron levels were below normal and my lymphocyte count was slightly low, which is an indicator of immune status. Based on my lab values, I reduced my rapamycin intake to 6 mg every other week. I rechecked my labs a month later and everything had returned to normal.
Why was 6 mg of rapamycin too high a dose for me? In addition to rapamycin, I engage in intermittent fasting most days, I exercise regularly, I take metformin twice daily and I take Life Extension® Senolytic Activator®. Based on the multiple components of my life-extension program, I discovered that taking 6 mg of rapamycin every other week is the best dose for me.
LE: Are there natural ways that people can inhibit mTOR and increase the expression of autophagy?
Pelton: Yes, there are. Remember, autophagy is activated when calories are unavailable. Intermittent fasting and time-restricted eating refer to eating protocols in which all your daily food is consumed within a shorter period of time. One of the most popular versions is the 16:8 protocol, in which all your food is consumed within an eight-hour period, say from noon to 8 p.m. This leaves 16 hours (from 8 p.m. until noon the following day) of fasting, which enables autophagy to be activated.
LE: Do you go into greater detail about all this in your new book?
Pelton: Yes. I want to emphasize that decades of research on rapamycin’s mechanisms of action have resulted in a revolutionary new understanding of cellular metabolism, health, and the aging process.
My book, Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome, reviews the history and scientific studies that explain rapamycin’s ability to improve health and delay the onset of age-related diseases. It also discusses alternatives to rapamycin for those who cannot find a physician willing to write them a prescription for rapamycin, and for people who want to wait for the results of clinical trials before initiating this medication.
My book also provides practical guidance on how to improve the mTOR/autophagy ratio, which holds the promise of increasing both healthspan and lifespan.
LE: Is there any new research that documents rapamycin’s effectiveness as a life extension drug?
Pelton: Yes, I want to report the exciting results from a study conducted by Dr. Vera Gorbunova, who is Co-Director of the Rochester Aging Research Center. Long-lived animals are known to have genes in common that negatively and positively affect lifespan. Dr. Gorbunova examined 10 prominent life extension therapies in mice and assessed how each intervention affected the genes associated with maximum lifespan. The interventions evaluated were rapamycin, 17-alpha-estradiol, pituitary-specific positive transcription Factor 1 (PiT1), growth hormone, rilmenidine, ascorbyl-palmitate, acarbose, calorie restriction, methionine restriciton and protandim.
RAPAMYCIN WINS: Rapamycin had the greatest effect in reducing the activity of genes that have a negative effect on maximum lifespan AND, rapamycin also had the greatest effect at promoting the activity of genes that have a positive effect on maximum lifespan. This study provides powerful confirmation that rapamycin is a life extension drug that is ushering in a revolution in life extension and healthy aging.
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Note 2: The origin story of rapamycin: systemic bias in biomedical research and cold war politics