Rapamycin

Rapamycin is a drug traditionally used as an immunosuppressant for organ transplant. In recent years, rapamycin has gained traction for its anti-aging properties. While there are several potential benefits of the drug, there are also some key risks to consider. This article will discuss what rapamycin is, its therapeutic potential in longevity, and its risks.

What is rapamycin?

Rapamycin is an FDA-approved medication that originates as a metabolite from Streptomyces hygroscopicus, a species of bacteria¹. It is approved as an immunosuppressant drug for the treatment of organ rejection in those receiving renal transplants and for certain rare diseases².

Pharmacologically, rapamycin belongs to a class of drug known as mammalian target of rapamycin (mTOR) inhibitors. mTOR is an enzyme and key regulator of cell proliferation and death. Studies in a multitude of organisms, including worms, yeast, and flies, suggest that mTOR plays a role in lifespan³. This relationship has sparked scientists’ interest in rapamycin as a mediator of longevity.

Overview of Rapamycin's Potential as a Longevity and Antiaging Medication

In addition to its therapeutic uses in medicine, rapamycin has demonstrated efficacy in extending life. Mouse models show that rapamycin could potentially prolong lifespan, delay age-associated conditions, and even improve cognition.

Potential to Extend Lifespan

 In mice studies, rapamycin has exemplified striking results in terms of longevity. A 2009 research study administered rapamycin to mice for either 270 or 600 days. Both tested durations prolonged the lifespan of treated mice. Further research has evaluated additional rapamycin doses in mice, with results demonstrating an extension of maximal and median lifespan in both males and females.

There are several hypotheses as to why this phenomenon occurs. A plausible reason includes rapamycin’s ability to inhibit carcinogenesis, the development of cancer, due to rapamycin’s anti-neoplastic tendencies. Rapamycin blocks cancer formation and suppresses tumor growth by promoting cell death in cancer cells and modulating tumor response³.

Potential to Delay Age-Related Diseases

Although rapamycin shows the potential to prolong lifespan in mammalian models, lifespan extension does not equate to anti-aging. Aging is associated with structural and functional changes to the body. These changes underly several diseases, including cognitive decline, cancer, osteoporosis, and diabetes.

The benefits of rapamycin in the aging process extend beyond just disease. Increased age also correlates with reduced motor function. One study showed that rapamycin administration in mice prevented decreases in mice motor activity. Another study indicated that wheel running increased in mice treated with rapamycin.

As previously stated, age can affect the structure and function of our bodies, which in turn influence one’s physical capabilities. Research has evaluated how rapamycin affects measures of physical aptitude, including muscle strength, balance, and motor coordination. Though rapamycin had minimal effects on these endpoints, other evidence suggests mTOR inhibition could promote muscle strength and motor coordination in older animals³.

Potential to Improve Cognitive Function

As aforementioned, aging is associated with neurological decline. Cognitive decline can be accompanied by memory loss. Animal studies demonstrate that rapamycin can improve performance on learning and memory assessments. These findings were present in older mice as well as younger mice who were not yet susceptible to age-related decline. Likewise, rapamycin has the potential to improve cognition³.

Potential Risks of Rapamycin

As with any drug, rapamycin use can cause side effects or adverse events. Of the more serious complications, diabetes, infection, and cancer are some of rapamycin’s primary concerns.

Diabetes

A significant concern with rapamycin treatment is its ability to increase one’s risk of diabetes. Rapamycin inhibits mTOR, and although mTOR is implicated in many age-related functions, it also plays a role in blood sugar regulation. In mice, inhibition of mTOR signaling disrupts blood sugar homeostasis, affects metabolism, and promotes insulin resistance. These impacts can contribute to the development of type II diabetes and metabolic disorders⁴. However, one should note that these findings were deduced from animal models and may not stand true for humans.

Infection

Another effect of rapamycin includes an increased risk of infection. One study evaluated if rapamycin influenced infection and if so, to what degree. The analysis concluded that individuals treated with mTOR inhibitors had two times the chance of developing an infection of any kind. Additionally, there was a 2.6-fold increase in a patient’s risk of getting a serious infection when using an mTOR inhibitor.

The mechanisms underlying this adverse effect include rapamycin’s immunosuppressant effects. As it is indicated for conditions such as organ transplant, immunosuppression is paramount with rapamycin treatment. However, rapamycin can also influence other aspects of the immune system in a negative way, increasing one’s risk of an infection. Likewise, rapamycin treatment should be supplemented with appropriate monitoring by a healthcare professional and timely management of infection complications if they arise⁵.

Cancer risk

Though rapamycin has demonstrated a potential protective effect on the development of cancer, other findings suggest that it may actually be detrimental to cancer risk. One analysis, for example, evaluated 22 studies to conceptualize cancer incidence amongst rapamycin-treated kidney transplant patients. While rapamycin was associated with a lower incidence of kidney cancer, it was also linked to an increased prostate cancer incidence. Although there is consistency in these findings, the mechanisms behind this phenomenon are unclear. Experts hypothesize that rapamycin may influence levels of prostate-specific antigen in the blood, thereby contributing to a positive prostate cancer diagnosis⁶.

Conclusion

In summary, the use of rapamycin involves a careful deliberation of its benefit versus risk profile. Rapamycin has the potential to prevent age-related disease and decline, including protecting against cancer and maintenance of cognitive function. However, it is also associated with some risks, including infection, diabetes, and cancer. It is important to note that many of these effects have been established in mice models. Animal studies cannot always be extrapolated to humans. Thus, there may be more advantages or disadvantages to rapamycin use in humans that are not yet clear. Therefore, more research is needed to further characterize it’s therapeutic and risk profile.

References:

1. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. PMCID: PMC3972801.
2. FDA Approves Rapamune (sirolimus) for the Prevention of Organ Rejection in Kidney Transplant Patients. (2017). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf
3. Cosgrove BD, Chen J, Bienemann AS, Leow MK, Lee RS, Chen J, Kuehn HS, Leow MK, Lee RS, Kuehn HS, Bienemann AS. Rapamycin Has Differential Effects on Murine T Cell Subsets and Enhances the Development of Lymphoma. JAMA. 2014;311(2):170–180. doi:10.1001/jama.2013.281071 PMCID: PMC4207939
4. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293. doi:10.1016/j.cell.2012.03.017 PMCID: PMC3324089
5. Sancho P, Ribas V, García-Martínez C, Sánchez-Martín M, Pérez-Losada J, García-Cao M, Gallois A, García-Carbonero R, Hernández-Losa J, Tabernero J, Baselga J, Cascante M. Rapamycin as a therapeutic strategy for the treatment of colorectal cancer. British Journal of Cancer. 2013;109(11):2778–2785. doi:10.1038/bjc.2013.278 PMCID: PMC4567030

Author

David J. Bauder, PA-C David Bauder, PA-C, is a certified physician assistant and the assistant medical director at Weight Loss and Vitality in Manassas and Alexandria, Virginia, Washington, DC; and Gaithersburg, MD. He enjoys helping patients optimize their physical and mental health to improve their overall well-being. He earned his physician assistant degree from the University of Texas Health Science Center at San Antonio. Afterward, he gained admission into the reputable graduate program for physician assistant studies at the University of Nebraska Health Science Center in Omaha. David has over 26 years of experience working as a physician assistant. He’s practiced in podiatry, family medicine, emergency medicine, general surgery, urgent care, and functional medicine.