Rapamycin: Benefits, Side Effects, and Research
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. It is 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 [1]. 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 for 3 years and 8 months, which would be like a human living to 140 years old!
In a 2023 preprint study by Maria K. Sobczyk and colleagues, the research team further explored the effects of inhibiting the mammalian target of rapamycin (mTOR) pathway. Doing so has been linked to the metabolism, growth, and aging of cells and the lifespan and health of humans. They used genetic tools to mimic the long-term use of rapamycin to see its potential impact on longevity and various health conditions.
The study found that reducing mTOR activity could increase the chances of living an exceptionally long life. It also seemed to lower body mass index (BMI), basal metabolic rate (BMR), height, and age at menopause while increasing bone density. However, the effects on heart disease were mixed, with some indication that it might protect against heart failure. There was no clear link between mTOR inhibition and prostate cancer, but the increased risk of type 2 diabetes was further confirmed. The research also showed that many genes in the mTOR pathway were connected to BMR.
Overall, this study showed that inhibiting mTOR could extend life and significantly affect metabolic factors and diseases. It highlighted the importance of the mTOR complex, particularly mTORC1, in influencing BMR and BMI, offering insights for new therapeutic targets [2].
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, another reliable method through which researchers have increased the lifespan of many species. Caloric restriction is known to target the mTOR pathway, and the same is true for rapamycin. It is an important signaling molecule involved in our nutrient-sensing pathways, the deregulation of which is a hallmark of aging.
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 [3].
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.
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” [4]. 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, autophagy has been found to have longevity-promoting effects [5].
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 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 [6].
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 cells can function.
Unfortunately, with aging, the number of histones begins to decrease, which means that 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 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 [7]. This includes decreased glucose tolerance and insensitivity to insulin. Some studies suggest that rapamycin treatment may also increase the risk of type 2 diabetes [8].
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 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 for neurological diseases
In an August 2023 study by Jessica Mandrioli and colleagues, researchers conducted a detailed experiment with 63 patients suffering from amyotrophic lateral sclerosis (ALS), a severe nerve disease. They aimed to test if rapamycin could help these patients by targeting inflammation in the brain and affecting cell cleanup processes, which are crucial in ALS.
The patients were divided into three groups, receiving different doses of rapamycin or a placebo. The main goal was to see if rapamycin could significantly increase a certain type of immune cell, but this was not achieved.
They also looked at various other health markers, changes in immune cells, inflammation levels, protein activity, nerve health indicators, disease progression, survival, safety, and quality of life. While rapamycin did lower some inflammation markers and affected certain immune cells, the results were not definitive. The study concluded that while rapamycin is safe for ALS patients, more research is needed to fully understand its effects [9].
In an August 2023 study by Laura Gianessi and colleagues, the researchers found a new way to deliver everolimus, which is similar to rapamycin, for treating neurological disorders like Alzheimer’s disease. Previously, rapamycin showed promise in mouse models for Alzheimer’s, but in humans, the amount that could be safely taken was very low due to risks of weakening the immune system.
The team used a method to deliver everolimus directly into the brains of mice with Alzheimer’s, which allowed for higher doses without affecting the rest of the body. However, the liquid form of the drug was unstable at body temperature, limiting the treatment duration.
To overcome this, they created a stable liquid form using a technique involving tiny particles called micelles. This new form remained effective for 14 days at body temperature. This approach suggests the possibility of short, perhaps repeated, treatments for Alzheimer’s in humans, potentially benefiting patients with other conditions like tuberous sclerosis and multiple sclerosis [10].
Rapamycin for cancer
In 2023, evidence that rapamycin had potential for the treatment of various cancers became evident in a flurry of publications. In March 2023, Ying-Yue Yang and colleagues made a significant discovery in cancer research. They developed a new type of mTOR inhibitor, a drug that disrupts cancer cell growth. Their innovative compounds, particularly effective and selective in targeting mTOR, showed promise in stopping cancer cell proliferation and spreading at low doses. Among these, a compound named 15i stood out for its effectiveness, particularly in inducing autophagy, a cellular self-cleaning process [11].
Following this, in June 2023, Mohamed El-Tanani and his team highlighted the importance of the mammalian target of rapamycin (mTOR) signaling in cancer development. Their study underscored how this cellular process, essential for cell growth and division, becomes a key driver of cancer when malfunctioning [12]. This finding opened new avenues for treatment strategies.
Xin Gao and colleagues, in August 2023, took a novel approach by combining an mTOR inhibitor with a nitric oxide donor to combat drug resistance. Among their 20 new compounds, 19f emerged as a particularly effective candidate against various cancer types, showing greater efficacy and safety compared to existing treatments [13].
In October 2023, Kewalin Posansee and her team introduced a cutting-edge method using deep learning and molecular modeling to discover new cancer drugs from Thai mushrooms. They focused on compounds inhibiting the mTOR protein, identifying a promising candidate from the Lentinus polychrous mushroom. This compound exhibited effective interaction with the mTOR protein, indicating potential as a new cancer therapy [14].
Later that month, Panwar and colleagues provided a comprehensive view of the mTOR protein’s role in cellular functions like metabolism and growth, and its implications in cancer. Their work suggested new directions for targeting mTOR in cancer therapies [15].
Finally, in November 2023, Heng Du and team introduced bi-steric mTORC1-selective inhibitors as a new cancer treatment approach. These inhibitors, targeting a specific protein involved in cancer cell survival, showed superior effectiveness in various cancer models. This breakthrough presents a promising strategy for treating cancers characterized by overactive cell growth processes [16].
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.
Disclaimer
This article is only a very brief summary, is not intended as an exhaustive guide, and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.
Literature
[1] Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K., Meza, D., Yajima, M., Beyer, R. P., Kerr, K. F., Davis, D. J., Gillespie, C. H., Snyder, J. M., Treuting, P. M., & Kaeberlein, M. (2016). Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife, 5, e16351.
[2] Sobczyk, M.K.; Gaunt, T.R. Evaluating the Life-Extending Potential and Safety Profile of Rapamycin: A Mendelian Randomization Study of the MTOR Pathway. medRxiv 2023, 2023.10.02.23296427.
[3] Brikisdóttir MB, Jaarsma D, Brandt RMC, Barnhoorn S, van Vliet N, Imholz S, van Oostrom CT, Nagaraja B, Portilla Fernández E, Roks AJF, Elgersma Y, van Steeg H, Ferreira JA, Pennings JLA, Hoeijamkers JHJ, Vermeij WP, Dollé MET. Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice. Aging Cell (2020), doi: 10.1111/acel.13302
[4] Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of Pathology, 221(1), 3-12. doi:10.1002/path.2697
[5] Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011). Autophagy and Aging. Cell,146(5), 682-695.
[6] Lu, Y. X., Regan, J. C., Eßer, J., Drews, L. F., Weinseis, T., Stinn, J., … & Partridge, L. (2021). A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing. Elife, 10, e62233.
[7] Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., … & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. science, 335(6076), 1638-1643.
[8] Johnston, O., Rose, C. L., Webster, A. C., & Gill, J. S. (2008). Sirolimus is associated with new-onset diabetes in kidney transplant recipients. Journal of the American Society of Nephrology, 19(7), 1411-1418.
[9] Mandrioli, J.; D’Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; et al. Randomized, Double-Blind, Placebo-Controlled Trial of Rapamycin in Amyotrophic Lateral Sclerosis. Nature Communications 2023 14:1 2023, 14, 1–14.
[10] Gianessi, L.; Magini, A.; Dominici, R.; Giovagnoli, S.; Dolcetta, D. A Thermostable Micellar Formulation of Rapalogs for Intracerebroventricular Delivery and the Therapy of Neurological Disorders. 2023.
[11] Yang, Y.Y.; Wang, W.L.; Hu, X.T.; Chen, X.; Ni, Y.; Lei, Y.H.; Qiu, Q.Y.; Tao, L.Y.; Luo, T.W.; Wang, N.Y. Design, Synthesis and Biological Evaluation of Novel 9-Methyl-9H-Purine and Thieno[3, 2-d]Pyrimidine Derivatives as Potent MTOR Inhibitors. Bioorg Chem 2023, 132, 106356.
[12] El-Tanani, M.; Nsairat, H.; Aljabali, A.A.; Serrano-Aroca, Á.; Mishra, V.; Mishra, Y.; Naikoo, G.A.; Alshaer, W.; Tambuwala, M.M. Role of Mammalian Target of Rapamycin (MTOR) Signalling in Oncogenesis. Life Sci 2023, 323, 121662, doi:10.1016/J.LFS.2023.121662.
[13] Gao, X.; Zhao, F.; Wang, Y.; Ma, X.; Chai, H.; Han, J.; Fang, F. Discovery of Novel Hybrids of MTOR Inhibitor and NO Donor as Potential Anti-Tumor Therapeutics. Bioorg Med Chem 2023, 91, 117402, doi:10.1016/J.BMC.2023.117402.
[14] Posansee, K.; Liangruksa, M.; Termsaithong, T.; Saparpakorn, P.; Hannongbua, S.; Laomettachit, T.; Sutthibutpong, T. Combined Deep Learning and Molecular Modeling Techniques on the Virtual Screening of New MTOR Inhibitors from the Thai Mushroom Database. ACS Omega 2023, 8, 38373–38385, doi:10.1021/ACSOMEGA.3C04827.
[15] Panwar, V.; Singh, A.; Bhatt, M.; Tonk, R.K.; Azizov, S.; Raza, A.S.; Sengupta, S.; Kumar, D.; Garg, M. Multifaceted Role of MTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease. Signal Transduction and Targeted Therapy 2023 8:1 2023, 8, 1–25.
[16] Du, H.; Yang, Y.C.; Liu, H.J.; Yuan, M.; Asara, J.M.; Wong, K.K.; Henske, E.P.; Singh, M.; Kwiatkowski, D.J. Bi-Steric MTORC1 Inhibitors Induce Apoptotic Cell Death in Tumor Models with Hyperactivated MTORC1. Journal of Clinical Investigation 2023, 133.
