Rapamycin: Benefits, side effects, research and dosage

For centuries, man has always been fascinated by the idea of immortality. Dreaming of immortality has driven many men and women to search for the ultimate elixir to the fountain of youth. 

In recent years, the discovery of a substance that prolongs life at least three times in mutant mice has excited the scientific community [1]. Initial results have shown that this substance, called rapamycin, also prevents age-related conditions in dogs, rodents, humans and nonhuman primates. 

Today, rapamycin and its analog called everolimus has been approved for human use in the US through the regulatory board, FDA. A study [2] has shown that it can be used safely to slow down all age-related diseases and aging, touting rapamycin as an antiaging drug. 

What is rapamycin? 

Life expectancy has steadily increased in the UK, the US and the majority of countries across the world. The increase in life expectancy has also brought fresh challenges as many individuals in their 60s, 70s and 80s battle long-term conditions. The increased incidence of the age-related disease has pushed healthcare practitioners and researchers to delay the progression of these diseases to help promote quality of life. 

Although lifespan has increased, it is argued that healthspan has not kept up with the additional years added to human life. This means that many individuals who are now living longer also must deal with the development of long-term conditions as they age. 

As individuals age, more are likely to experience long-term conditions such as dementia, type 2 diabetes, and other long-term conditions. 

One of the potential medications that can delay aging and long-term conditions includes rapamycin. This drug was initially approved as an anti-cancer and immunosuppressant for patients who underwent transplant surgery. Later, it was discovered that at high doses, it had been shown to rejuvenate immunity instead of suppressing it [3]. The drug acts as an immunostimulatory, improving cancer patients’ immunity. In addition, older adult patients taking high doses of the drug reported improved immunity [4]. 

Photograph: Danijela Maksimovic/Shutterstock

What is the mechanism of action of rapamycin? 

Initial research [5] has shown that as an immunosuppressant, rapamycin blocks cell growth and multiplication. This makes rapamycin effective in preventing the spread of cancer cells. Rapamycin keeps the body from rejecting the donor kidney in patients newly transplanted with a kidney. 

Rapamycin targets a protein called the mammalian target of rapamycin (mTOR) and inhibited this. Since mTOR is a component of a signalling pathway that plays a role in cell metabolism and synthesis, interruption of mTOR can result in cell growth inhibition. 

Notably, the mTOR pathway has been implicated in developing Alzheimer’s disease and cancer. Hence, rapamycin potentially helps in treating these conditions. 

What are the current uses of rapamycin? 

The following are some of the uses of rapamycin: 

  • Treatment of cancer – rapamycin is used to treat cancer since it prevents the growth and spread of cancer cells. The most recent brand used to treat cancer is called Fyarro. 
  • Treatment of cardiovascular diseases – apart from being an anti-cancer drug, it is also used to coat heart stents that are important in opening blocked arteries. 
  • Treatment of patients who underwent a kidney transplant – initially, as an immuno-suppressant, rapamycin is prescribed along with other drugs to suppress the immune system of the patient who received a kidney transplant. When rapamycin is used, this prevents the patient from rejecting the donor kidney. 

Can rapamycin be used for antiaging? 

One of the promising drugs under study today to fight aging includes rapamycin. Initial evidence suggests that it can promote a longer and healthier lifespan. However, rapamycin may have become an antiaging drug when it was first used as an immunosuppressant. 

Understanding how rapamycin may prolong life goes back to how it interrupts the mTOR pathway. When this pathway is blocked, it promotes autophagy. In simple terms, autophagy means the body’s cells recycle or clean up damaged and broken parts of the cell. Rapamycin has been shown to hasten the process of autophagy. 

During aging, damaged and dysfunctional proteins and organelles of the cells begin to accumulate [6]. These old and dysfunctional organelles disrupt the cell’s balance or homeostasis, leading to progressive degeneration of the cell. In time, the cell dies when old organelles and dysfunctional proteins continue to accumulate. 

Moderating the accumulation of dysfunctional organelles and proteins has been the key to promoting longevity. Since rapamycin helps clean up these old parts of the cell, it is thought to play a critical role in promoting the cell’s life. Since tissues and organs are composed of cells, these also imply that organs’ lifespan is prolonged. 

Although this sounds exciting, more studies and clinical trials are needed to verify the antiaging properties of rapamycin. 

Increasing the effects of rapamycin as a potential antiaging drug is, therefore, necessary for delaying aging. Some of the interventions supported in literature to slow aging include fasting, which also blocks the mTOR pathway, intake of antioxidants from food or supplements and exercise [6]. 

To promote the effects of rapamycin, combine this drug with the following activities: exercise and a healthy diet. 

What is the current research on the effects of rapamycin? 

Since rapamycin is used initially as an anti-cancer drug and given in high doses to treat cancer, there have been concerns about whether this drug can be safely used in the long term. 

A recent study published by researchers in Germany (7) examined the effects of rapamycin given in low doses on the lifespan of fruit flies. 

Similar to studies conducted in mice, the results of the fruit fly studies also add evidence that rapamycin can prolong the lifespan of animals. However, only female fruit flies demonstrated elongation of lifespan. The fruit flies were divided into two groups, with the first group treated with low-dose rapamycin at 30 days of life. The second group received rapamycin at 45 days of life. Results indicated that treatment with rapamycin prolonged the lifespan of the female fruit flies. However, at day 60, which is equivalent to extreme old age in fruit flies, rapamycin no longer extended the life of the fruit flies. At 60 days, only 1 in 5 fruit flies was still alive. Results showed that when treatment starts later in life, the organisms’ lifespan was not prolonged to the same degree.

Interestingly, the treatment demonstrated the effects of administering rapamycin at 30 days of life; the results of the drug were less than when the treatment started during the early life or days 1 to 30 of the fruit flies and continued lifelong. In fruit flies who received the drug at days 1-30 and stopped at day 30, the drug’s effect continued lifelong. In short, this means that when the drug is administered early in life, it is no longer necessary to apply it lifelong. 

German researchers were impressed by the effect of rapamycin. When rapamycin is administered at days 1-15 of the fruit flies’ life, their lifespan is extended as if they received continual treatment. 

The scientists in the study hypothesised that the effects of early administration of rapamycin might be due to the reduced number of intestinal stem cells after short exposure to the drug. These stems actively divide when the female fruit flies age. However, these stem cells are also associated with dysplasia or the production of abnormal intestinal cells later in life. This might explain why at old age or 60 days of life, fruit flies eventually die even when given rapamycin.  

Another interesting finding of the German study showed that the old flies’ gut (intestinal) health improved after rapamycin treatment. There were a few abnormal areas in the intestine after long-term and short-term treatment with the drug. Further, the barrier between the gut and the surrounding regions also improved. The mucosa (lining) of the intestine also was healthier compared to old fruit flies not treated with rapamycin. 

The study adds more information on how lifespan is prolonged during treatment with rapamycin. Scientists in the study observed that autophagy increased during treatment. This means that the old organelles and dysfunctional proteins of the cells inside the fruit flies were destroyed. During autophagy, the mTOR pathway is disrupted, leading to the prolongation of the cell’s lifespan. Importantly, even when the drug was withdrawn, and mTOR levels returned to normal, autophagy persisted in the fruit flies. This showed that short or long-term exposure to the drug could result in prolonged autophagy and increased lifespan of the flies. 

To summarise, when rapamycin is given during adulthood, this can awaken the flies’ rapamycin memory. Notably, this event occurs even when rapamycin is shown to be short-term. As a result, the fruit flies’ lifespan is increased; it also induces abnormal changes in the gut, increased and prolonged autophagy and promoted regeneration of the intestine. When the drug is given early in the flies’ life, the effects are long-lasting, and flies exhibit fewer side effects. Interestingly, the results are also seen in mice. This suggests that rapamycin can prolong life, sustain healthier tissues in the body and may be effective as an antiaging in mammals. 

The results of the study are promising. However, there is still a need to examine the effects of the drug in animal studies and eventually in humans as an antiaging drug. Researchers in the future also need to investigate if rapamycin can improve gut health in humans. Since many patients suffer from gastrointestinal conditions, mirroring the effects of the drug on humans can promote better gut health and well-being. 

Can rapamycin potentially treat Alzheimer’s disease? 

A recent article [8] reviewed current studies on whether rapamycin can potentially treat Alzheimer’s disease. 

Alzheimer’s disease (AD) is a neurodegenerative disease that impairs adults’ cognition. Most of those who develop the disease are 60 years old and older, with the incidence highest in the 80-year-old and older age group. Family members commonly provide care to this group, with a few receiving care in nursing homes. The financial, social, and physical burden of the disease is high. Hence, researchers are finding interventions and medication to delay the progression of the disease or cure it. 

Currently, AD does not have an effective treatment. There are several reasons for the delay in finding an ultimate cure for the condition. Despite the substantial progress made in AD research, the exact molecular mechanism of the disease is not yet fully understood. This lack of understanding of the disease process might explain why it is difficult to cure this disease. 

Rapamycin is shown to be the most effective in targeting the aging process in animal model studies and increasing health span and lifespan [9]. In one study [10] of middle-aged mice, a three-month treatment regimen of rapamycin resulted in a 60% increase in life expectancy compared to mice of a similar age not treated with rapamycin. Notably, treatment with rapamycin can increase life span by up to 30% in mice treated with the drug transiently, continuously, or intermittently either early or late in life. 

Importantly, mice treated with rapamycin exhibited reversal or delay in the progression of several diseases, such as cardiac dysfunction, cancers, obesity, kidney disease, periodontal disease, cognitive decline, muscle loss, immune senescence, stem cell function and muscle loss. 

Initial reports on dementia research revealed the beneficial effects of rapamycin. Some of the beneficial effects include the following [11]: 

  • Reducing tau phosphorylation 
  • Reducing amyloid-beta deposition 
  • Reducing neurofibrillary tangles 
  • Restoring cerebral blood flow 
  • Restoring cerebral-microvascular density 
  • Preventing neuronal loss 
  • Preserving blood-brain barrier integrity
  • Improving cognitive function 

Animal model studies [11] likewise reported that treatment with rapamycin before the onset of AD symptoms or after the signs are already present resulted in improved AD symptoms. These include improvement in memory or delayed progression of memory loss and cognition. 

Effective preclinical results point to the potential of rapamycin in reversing or delaying AD progression. Although more extensive clinical trials are proposed in the future, there still needs to be a current large clinical trial studying the antiaging and AD effects of rapamycin. Although animal model studies strongly support the effectiveness of rapamycin in delaying aging and in improving symptoms of several diseases, including AD, it is still necessary to examine the effects of the drug on humans in the long term. 

Why is there a fear of using rapamycin as a clinical intervention for several diseases? 

The fear of considering rapamycin as an ultimate antiaging drug or as a treatment for AD may stem from its initial usage in the medical field. Originally, rapamycin has been used to treat cancer and is categorised as an immunosuppressant. 

At one time, it was believed that rapamycin could increase cancer risk. Despite this concern, rapamycin prevents cancer and lymphoma in patients who received donor organs [12]. In addition, this drug is widely used as an anti-cancer drug, and initial results likewise revealed that the medication could prolong the lifespan of animals with cancer [12]. 

Another fear of rapamycin could be traced to an FDA warning that immunosuppressants can increase the risk of infection and potentially increase the susceptibility of patients to malignancies resulting from immunosuppression [12]. However, carefully reading the warning does not link rapamycin, as an immunosuppressant, to cancer development. 

One more misconception is related to the assumption that taking medicine can increase the risk of type 2 diabetes mellitus [12]. However, this claim is groundless since no animal model studies link rapamycin intake with diabetes. 

What are the side effects of rapamycin? 

Side effects associated with using rapamycin are often seen in immunocompromised patients taking the drug. Potential adverse reactions include the following: 

  • Weakened immune system
  • Inflamed mouth
  • High blood pressure
  • Constipation or diarrhoea 
  • Anaemia and fatigue 
  • Swollen hands and feet 

Isolated incidents reported that some patients could experience blood clotting problems, blood clots, pulmonary embolism or stroke. 

What is the appropriate dosage of rapamycin? 

The appropriate dosage of the drug is dependent on the reason for use. In patients who received a kidney transplant, the recommended dosage is 2-5 mg/day [13]. However, doses can be lower at 1.2 mg/day to achieve recommended glomerulus filtration rate [13]. Rapamycin is taken as a liquid or tablet for patients who cannot swallow pills. The drug can be taken with orange juice or water. However, it is suggested that it should not be taken with grapefruit juice since the latter can decrease the breakdown of rapamycin. The drug should be taken at the same time each day and in the same manner, whether in tablet or liquid form. 

Cancer patients can receive rapamycin intravenously, which would take around half an hour to administer. The patient’s tolerance to the drug depends on the patient’s status, metabolism, and response to the drug. Hence, the healthcare practitioner must tailor the dose and frequency of medication intake according to the patient’s needs. Adjusting the amount is necessary to ensure the patient can tolerate the drug. 

When taking rapamycin as an anti-cancer drug, your doctor will examine if you experience any side effects with the dose given and adjust this according to how you respond to the drug. Your tolerability to the drug is necessary for determining the most appropriate quantity. Your doctor can either switch the medicine or change your medication if you experience severe symptoms. 

Since the appropriate dose of rapamycin as an antiaging drug has yet to be established, waiting for results of future studies would be the most appropriate action prior to taking this drug as a supplement. There is a need to wait for safety data to ensure that you would not suffer form any adverse events or side effects. 

When is rapamycin contraindicated? 

Not all people with a kidney transplant or cancer can take rapamycin as an immunosuppressant drug. The following are some of those individuals for whom rapamycin is contraindicated: 

  • Pregnant women 
  • Breastfeeding women 
  • Those who have sensitivity to the drug (rapamycin)

As an immunosuppressant for kidney transplant patients, some may think it can be prescribed for those with liver transplants. However, rapamycin is contraindicated in liver or lung transplant patients due to previous studies that it can lead to severe complications. 

Can rapamycin interact with other drugs or medications? 

As in other drugs, rapamycin can potentially interact with other medications. Known as drug-to-drug interactions, taking medicines with other drugs might result in adverse events and side effects. 

Some medications, when taken together, can cancel out each other’s effectiveness. Some drugs might reduce the absorption of the primary medicine, while others could limit the breakdown of the drug. 

Rapamycin’s case could not be taken along with vaccines since it could lower immunity since it is an immunosuppressant. Intake of rapamycin could reduce the vaccine’s effectiveness or render this ineffective. 

Some drugs, such as antivirals, can boost the effects of rapamycin or raise its levels to dangerous levels. Hence, taking antivirals is contraindicated when you are taking rapamycin. 

Can I take rapamycin as an antiaging drug? 

There is still a need to verify animal model studies on the antiaging effect of rapamycin in large clinical trials. Before approval of rapamycin as an antiaging drug would take several clinical trials and reviews from experts and healthcare practitioners. Altogether, it would take years before a drug is approved. 

In the meantime, it is essential to note that rapamycin is a promising antiaging drug with several benefits in delaying the progression of several long-term diseases. However, it is still unsafe to take these as supplements to slow or reverse the aging process. As soon as the results of clinical trials confirm the findings of animal model studies, supplements may be developed to help delay the progression of long-term conditions. 

Waiting for the results of large clinical trials would help inform you if this drug is safe for antiaging. Further, the results would indicate the appropriate dose for rapamycin as an antiaging drug. Findings would also help establish the drug’s safety profile and inform healthcare practitioners whether it is safe to prescribe the medication in the long term. 

In a nutshell, what is the current evidence on the effectiveness of rapamycin as a drug? 

There are studies supporting its use as an anti-cancer and immunosuppressant drug. It is approved in kidney transplant patients but not in liver transplant patients. 

Several animal model studies showed that it could reverse or delay aging and potentially cure Alzheimer’s. It has also been shown to reverse or slow the progression of several other disorders, such as cardiovascular diseases. 

This promising drug should merit a serious look as an antiaging and Alzheimer’s medicine. 

  1. https://www.science.org/doi/10.1126/science.1244360
  2. https://www.sciencedirect.com/science/article/abs/pii/S1359644607000451?via%3Dihub
  3. https://www.tandfonline.com/doi/abs/10.4161/cc.5.18.3288
  4. https://www.science.org/doi/10.1126/scitranslmed.3009892
  5. https://pubmed.ncbi.nlm.nih.gov/15460177/
  6. https://pubmed.ncbi.nlm.nih.gov/30430746/
  7. https://www.nature.com/articles/s43587-022-00278-w
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762017/
  9. https://pubmed.ncbi.nlm.nih.gov/25341517/
  10. https://pubmed.ncbi.nlm.nih.gov/27549339/
  11. https://pubmed.ncbi.nlm.nih.gov/29351469/
  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/
  13. https://pubmed.ncbi.nlm.nih.gov/33277457/
Photograph: Juan Gaertner/Shutterstock
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