Rapamycin: A Quantum Leap in Life Extension


by Ross Pelton

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Rapamycin is an FDA-approved drug that is ushering in a new era of life extension. However, to be clear, rapamycin is not approved by the FDA as a life extension drug. In September 1999, rapamycin received FDA approval as an immunosuppressant drug to prevent organ transplant rejection.1 Unfortunately, rapamycin’s ability to suppress the immune system has given it a ‘reputation’ that has inhibited its acceptance by mainstream physicians as a life extension drug.

Treatment with rapamycin has resulted in significant increases in lifespan in animal models, including yeast, worms, fruit flies, and mice.2  Animals get many of the same diseases that humans develop. Results from animal studies reveal that rapamycin slows down the onset of many age-related diseases. In addition to improving animals’ health, treatment with rapamycin has produced life extensions ranging from 25-60%.3

Rapamycin is not approved as a life extension drug. However, many life extension enthusiasts have begun taking rapamycin based on the improvements in health and lifespan in animal trials and initial human studies. My new book titled Rapamycin, mTOR, Autophagy and Treating mTOR Syndrome reviews the history and scientific studies that explain why rapamycin is so effective at delaying the onset of age-related diseases and increasing both healthspan and lifespan. My book can be ordered from www.LifeExtension.com/rapa.


Discovery of Rapamycin

Rapamycin is a compound that is produced by a strain of bacteria named Streptomyces hygroscopicus. This bacterium was discovered from a soil sample taken during a scientific expedition to Easter Island in 1964.4 The purpose of that expedition was to search for new compounds that might express antifungal and/or antibiotic properties. Rapamycin expressed strong antifungal activity. However, efforts to develop rapamycin as an antifungal drug were discontinued when it was discovered to have potent immunosuppressive activity.

Rapamycin also exhibited anti-proliferative properties, which prompted scientists to send samples of rapamycin to the National Cancer Institute (NCI). Tests conducted there revealed two remarkable findings. The first revelation was that rapamycin suppressed growth in a variety of solid tumors.

The second finding was the discovery that rapamycin appeared to be a totally new type of anticancer drug because it functioned by inhibiting cancer growth (cytostatic) rather than by killing cancer cells (cytotoxic). Cytotoxic chemotherapy drugs cause a wide range of side effects because they damage other rapidly dividing cells in the body.  Rapamycin’s activity against solid tumors plus its cytostatic mechanism of action motivated the NCI to elevate rapamycin to “priority drug” status in order to accelerate additional research.5


Rapamycin’s Mechanism of Action

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 two mechanisms named mTOR and autophagy, which are found inside every cell, are critical regulators of cellular metabolism.

mTOR and autophagy are counterbalancing mechanisms that regulate the health and aging process of all living organisms. In my mind, the mTOR/autophagy story is even more important than the story about rapamycin. The discovery and understanding of mTOR and autophagy are revealing how we can delay the onset of age-related diseases and achieve significant increases in lifespan and healthspan.

When rapamycin crosses a cellular membrane and enters a cell, it binds with an enzyme that was named mTOR, which stands for the mechanistic target of rapamycin (mTOR).mTOR is a key regulator of cellular metabolism that has stimulated a great deal of scientific interest.

Now, 25 years after its discovery, over 12,000 papers have been published on mTOR. When nutrients are available to a cell, mTOR sends cellular signals that activate cellular metabolism, telling the cell to use the available nutrients to build new proteins, new enzymes, and other cellular components. mTOR activates cellular anabolic (building) processes of growth and proliferation.

Counterbalancing mTOR is the cellular process known as autophagy. In 2016, Japanese scientist Yoshinori Ohsumi was awarded the Nobel Prize in physiology and medicine for discovering the mechanism of autophagy.6 PubMed now contains over 30,000 citations with the term autophagy in the title, which gives an indication of the scientific interest in this topic.  

Autophagy has been referred to as the cellular housekeeping process or cellular trash removal. Over time, various cellular components become damaged, break down, and become dysfunctional. If these waste products continue to accumulate, cellular functions would decline, and the cell(s) would eventually die.7 When autophagy is activated, damaged and dysfunctional cellular components are broken down for reuse and recycling or for removal. Autophagy can also be thought of as cellular detoxification.

Animals get many of the same age-related diseases that humans get. Rapamycin gained prominence as a life extension drug based on its ability to treat a variety of age-related diseases and increase the lifespan in numerous species of animals. However, human trials were lacking because ethical issues, costs, and time constraints make it virtually impossible to conduct life extension trials in humans.


Breakthrough: Rapamycin’s Use in Humans

‘Twas the night before Christmas…on Dec. 24, 2014, a groundbreaking study titled “mTOR inhibition improves immune function in the elderly”8 was published that ushered in the era of rapamycin use in humans. The study was conducted by Joan Mannick, MD, who was a senior scientist at Novartis. In addition to being a human clinical trial, Mannick’s study is important because it sheds light on why and how rapamycin can be used safely and effectively in humans to slow down the onset of age-related diseases and increase lifespan and healthspan.

In this trial, elderly adults were treated with RAD001, which is a synthetic version of rapamycin (a rapalog) whose effects are virtually the same as rapamycin. Dr. Mannick’s wanted to evaluate the effects of mTOR inhibition on human aging-related conditions and she chose the immune system, which normally declines with age, as the target for her study.

In this six-week placebo-controlled trial, 218 volunteers who were 65 years of age or older were divided into four groups. The doses administered were 0.5 mg daily, 5.0 mg once weekly, 20 mg once weekly, or placebo. Following six weeks of therapy, there was a two-week drug-free interval followed by administration of the seasonal flu vaccine.

The hemagglutination inhibition (HI) assay, which measures the concentration of antibodies to the hemagglutinin protein of the influenza virus, was used to measure the subject’s response to the influenza vaccine. The HI titer correlates with protection against influenza illness.9

The results from the Mannick study reported significant increases in antibody titer at all three doses of everolimus (RAD001) for at least one of the three influenza strains they looked at. At the 0.5 mg daily and 5 mg/weekly dosing, two of the strains were statistically significant and the third was trending in the positive direction.  At the 20 mg/week dose the data are less convincing as antibody titers were slightly reduced for two of the strains. Also, individuals taking 20 mg dose experienced a higher incidence of adverse effects, which suggests that the 20 mg dose is probably too high. 

The immune system of the elderly adults who received a 5 mg dose of RAD001 once weekly exhibited a 20% enhanced response to the influenza vaccine with virtually no side effects. The results of this clinical trial suggested that the ability of rapamycin or similar rapalogs to enhance immune function in elderly adults might be able to delay the onset of age-related diseases in humans.10

Joan Mannick’s study helps us understand that rapamycin’s initial classification as an immunosuppressant drug was incorrect. Rapamycin is not an immunosuppression it is an immunomodulator.  


The mTOR/Autophagy Ratio

Life…it’s all about balance. This is especially true regarding the mTOR/autophagy ratio. Extreme suppression of mTOR (hypo-functioning) results in suppression of the immune system. This is what happens when rapamycin is administered daily to prevent organ rejection following organ transplant surgeries.

When mTOR is hyper-functioning, the immune system gets exhausted, which also results in immunosuppression. I believe most people alive today suffer from an under-functioning immune system, which is due to the over-activation of mTOR. I call this condition mTOR Syndrome.


Dysregulated mTOR/Autophagy Ratio

The majority of Americans are not well. We are literally experiencing an epidemic of epidemics. We have an epidemic of cancer, heart disease, diabetes, obesity, osteoporosis, Alzheimer’s disease, ADD/ADHD, autism, opioid addiction, to name a few. The over-expression of mTOR (mTOR Syndrome) is increasingly being recognized as a fundamental mechanism that is present in many of our common diseases such as cancer,11 diabetes,12 cardiovascular disease,13 and Alzheimer’s disease.14

I believe most people living today are suffering to some degree from mTOR Syndrome. Understanding why the mTOR/autophagy ratio has become so universally unbalanced will help explain our epidemic of chronic degenerative diseases and also explain why rapamycin appears to be effective (in animal studies) in the treatment of such a wide range of diseases.

Within the past 300 years, humans have managed to get the mTOR/autophagy ratio severely out of balance. Two categories of technological advancement have played a large role in the development of mTOR Syndrome.

The first technological advancement was the invention and development of refrigeration, which greatly improved the ability to store and preserve foods and make them easily available. Artificial refrigeration began in the mid-1750s. The first home refrigerators were invented in 1913. Fast forward to today and the refrigerator has become the most popular home appliance. According to government data, nearly 100% of American households have a refrigerator and approximately 25% of homes have two (or more) fridges and/or freezers.15

The second technological advancement that played a major role in dysregulating the mTOR/autophagy balance was the rapid development of the industries of food processing and packaging. The rapid development of refrigeration, food processing, and the widespread production and distribution of convenience foods means that food is now easily available ALL the time for most people. As a result, modern humans spend much more time eating every day compared to our ancestors.

Throughout 99.9% of mankind’s evolution, people had to hunt or forage for their food. Consequently, our ancient ancestors did not eat three meals per day. I estimate that our ancestors often only ate one meal a day. This means they spent about four hours digesting their meal and 20 hours without food intake (fasting). There were also probably periods when people went one or two days without eating. Compared to modern humans, our prehistoric ancestors spent much less time eating and during hundreds of thousands of years of evolution, mTOR and autophagy were in balance.

Since mTOR initiates anabolic processes when nutrients are available, the easy access to food 24/7 has resulted in mTOR being constantly overexpressed coupled with a serious under-expression of autophagy. This results in what I’ve chosen to call mTOR Syndrome.


Partial Inhibition of mTOR

It has been estimated that there may be up to one thousand mTOR sites within cells. 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. If the rapamycin dose is too large, or if it is given too frequently, suppression of the immune system develops. However, episodic dosing once weekly or every other week partially inhibits mTOR, which results in a wide range of health benefits.


Benefits of Taking Rapamycin

Rapamycin is not a ‘miracle drug’; it is not going to ‘fix’ everything. However, rapamycin will enable most people to gain significant improvements in their health. By inhibiting mTOR and activating autophagy, all cells in the body begin to detoxify more effectively and undergo revitalization and renewal. Results from animal models suggest that rapamycin will help improve symptoms for virtually all chronic degenerative diseases. This includes metabolic syndrome and type 2 diabetes, neurological diseases such as Parkinson’s disease and multiple sclerosis, inflammatory conditions like rheumatoid arthritis and systemic lupus erythematosus, macular degeneration, glaucoma, obesity, hearing loss, periodontal disease, cognitive decline, and Alzheimer’s disease. 


Dose Recommendations

Rapamycin’s use in humans is so new that studies to determine the optimal dose and frequency have not yet been conducted. I believe that biochemical individuality will play a big role. We will probably learn that the optimal dose will be different for different people. For now, 5 mg once weekly seems to be the dose that most people take, based on the results of the Joan Mannick human clinical trial.

Because mTOR is the master regulator of the growth activities in cells, rapamycin should not be given to children, adolescents, and young adults because these are periods of rapid growth. Although there is no agreed-upon age for people to start taking rapamycin, I don’t think people younger than thirty should be taking it.

Results from animal studies suggest that rapamycin can even benefit the elderly. When rapamycin therapy was initiated in elderly (600-day old) male and female mice (roughly the equivalent of 60-year-old humans), female mice achieved a 14% increase in lifespan while males achieved a 9% increase in lifespan.16 This equates to an increase in more than seven years of human life. The expectation (hope) is that even elderly humans may gain significant improvements in health and increases in lifespan by taking rapamycin.

Rapamycin is the name of the compound that is naturally produced by the soil bacteria Streptomyces hygroscopicus. Pfizer is the drug company that holds the patent on rapamycin under the brand name Rapamune. The generic name for Rapamune/rapamycin is sirolimus.


Obstacles to Taking Rapamycin

Rapamycin is a prescription drug. However, most physicians will initially not be aware of it, and many physicians who have heard of it only know of it as an immunosuppressant agent or a cancer chemotherapy drug. Thus, physicians will need to be educated about the safety and potential benefits of rapamycin with episodic dosing to achieve partial inhibition of mTOR. This was one of my goals in writing my new book Rapamycin, mTOR, Autophagy, and Treating mTOR Syndrome. Also, many physicians now work in group practices that have “standard of practice” guidelines that limit what medications can be prescribed.

The cost could be another obstacle as even the generic version, sirolimus, is relatively expensive. The wholesale price to pharmacies for a bottle of 100 2-mg sirolimus tablets is over $3,000. Some people report being able to have their prescription covered by their insurance. I personally take 6 mg of rapamycin/sirolimus weekly (3 of the 2 mg tablets), and I get my monthly prescription of 12 tablets for a $20 copay.


Natural Methods to Inhibit mTOR and Activate Autophagy

Exercise at moderate- to high-intensity levels is known to inhibit mTOR and activate autophagy.17 This has been documented in animal and human clinical trials.18

Intermittent fasting and/or time-restricted eating are dietary trends that have recently increased in popularity. These programs recommend consuming all your daily food/caloric intake within a shorter time period. The 16:8 protocol is the most popular regime where food is consumed within an eight-hour period, which leaves 16 hours without food, or fasting.


Rapamycin: Risks and Side Effects

There is a long list of potentialside effects, but they are associated with daily and/or high dose administration. Rapamycin is very safe when taken intermittently (e.g. once a week) as opposed to daily. Potential side effects include stomatitis and mycositis (ulceration of the mucous membranes of the mouth and the digestive tract), low platelet count, low iron levels and anemia, and leukopenia (low white blood cell count). But, these side effects seldom occur when rapamycin is taken intermittently.

In a recent placebo-controlled trial, healthy elderly volunteers (70-95 years old) took either 1 mg of rapamycin or a placebo daily. At the end of the eight-week trial, no significant side effects occurred.19

Donate to the Townsend Letter

I am a strong advocate of laboratory testing. I recommend getting lab tests before starting rapamycin and then rechecking your labs on a periodic basis. This enables you to track your progress and determine which dose and frequency work best for you.

I recommend the following lab tests: CBC with Differential, Comprehensive metabolic panel, coronary risk panel, and iron total iron-binding capacity (TIBC). These tests enable you to track your hemoglobin, white and red blood cell count, iron levels, triglycerides, blood sugar, and blood insulin levels.

Rapamycin has been an FDA-approved drug for decades (taken daily) to prevent organ transplant rejection. However, newer research is revealing that when rapamycin is taken at lower doses (once weekly rather than daily), autophagy is activated, which results in significant health benefits. In fact, rapamycin is ushering in a new era of life extension.

Although long-term human clinical trials have not yet been conducted, results from studies on various species of animals consistently reveal that rapamycin therapy slows down the onset of a wide range of age-related diseases. Two trials to look for: The TRIAD Trial and the PEARL Trial.

The TRIAD Trial. The TRIAD trial, which is part of the larger Dog Aging Project, is a double-blind, placebo-controlled clinical trial of the drug rapamycin. Dogs get many of the same age-related diseases that humans get, such as cancer, arthritis, and heart disease. The goal of the Test of Rapamycin in Aging Dogs (TRIAD) trial is to confirm, in a double-blind, placebo-controlled clinical trial, that treatment with rapamycin improves health and slows down the onset of age-related diseases.

The PEARL Trial. PEARL stands for the Participatory Evaluation of Aging with Rapamycin for Longevity. AgelessRx, in affiliation with the University of California, has succeeded in raising $183,000 in crowdfunding donations, which will enable the launch of this double-blind, randomized, placebo-controlled human clinical trial to evaluate the safety and effectiveness of rapamycin in healthy adults for longevity. The PEARL trial is also revolutionary because it is the first nationwide telemedicine trial and the first large-scale human intervention trial on longevity.

My new book titled Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome can be ordered at www.LifeExtension.com/rapa.


References

1. Augustine JJ, et al. Use of Sirolimus in solid organ transplantation. Drugs. 2007:67(3):369-91.

2. Lamming DW. Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond. Cold Springs Harb Perspect Med. 2016 May;6950; a025924.

3. Selvarani R, et al. Effect of rapamycin on aging and age-related diseases-past and future. GeroScience. 2021 Jun;43(3):1135-1158.

4. Tector A. The delightful revolution: Canada’s medical expedition to Easter Island, 1964-65. British Journal of Canadian Studies. 2014 Sep;27(2):181-194.

5. Mondesire WH, et al. Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells. Clinical Cancer Research. 2004 Oct 15;10(20:7031-42.

6. Press Release: 2016 Nobel Prize in Physiology or Medicine.  https://www.nobelprize.org/prizes/medicine/2016/press-release/

7. Stroikin Y, et al. Testing the “garbage” accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy. Biogerontology. 2005 Jan;6:39-47.

8. Mannick JB, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179.

9. Pedersen JC. Hemagglutination-Inhibition Assay for Influenza Virus Subtype Identification and the detection and Quantitatin of Serum Antibodies to Influenza Virus.  In: Spackman E. (eds) Animal Influenza Virus. Methods in Molecular Biology (Methods and Protocols), vol 1161. Humana Press, New York, NY.

10. Mannick J, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179.

11. Zou Z, et al. mTOR signaling pathway and mTOR inhibitors in Cancer: progress and challenges. Cell Biosci. 2020 Mar 10;10:31.

12. Lin Y, et al. Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications. Curr Drug Targets. 2022 Jan 11.

13. Chong ZZ, et al. Cardiovascular disease and mTOR signaling. Trends Cardiovasc Med. 2011 Jul;21(5):151-5.

14. Cal Z, et al. Activation of mTOR: a culpert of Alzheimer’s disease? Neuropsychiatr Dis Treat. 2015 Apr 9;11:1015-30.

15. Long H. 23% of American homes have 2 (or more) fridges. CNN/Business. May 27, 2016. https://money.cnn.com/2016/05/27/news/economy/23-percent-of-american-homes-have-2-fridges/index.html#:~:text=Almost%20100%25%20of%20homes%20have,two%20(or%20more)%20fridges.

16. Harrison DE, at el. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 8 Jul 2009;460: 392-395.

17. Escobar KA, et al. Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. Aging Cell. 2019 Feb;18(1):e12876.

18. Dethlefsen MM, et al. Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise. Experimental Gerontology. 2018;111:141-153.

19. Kraig E, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018 May;105:53–69.