Rapamycin, a drug first discovered in the soil of Easter Island, has long been used as an immunosuppressant for organ transplant patients. In recent years, however, it has gained attention for a far more ambitious purpose: extending lifespan and improving health in older age. 

What is Rapamycin and How Does it Work?

Rapamycin, also known as sirolimus, was isolated in 1972 from the bacterium Streptomyces Hygroscopicus. Initially developed as an antifungal agent, it was later found to have powerful immunosuppressive and antiproliferative properties, making it a staple in organ transplantation and cancer treatment. Its relevance to longevity stems from its ability to influence a key biological process: the mTOR pathway.

The mTOR (mechanistic target of rapamycin) pathway regulates cell growth, metabolism, and aging. When overactive, mTOR can accelerate aging and contribute to age-related diseases. Rapamycin inhibits this pathway, mimicking the effects of caloric restriction—a well-established method for extending lifespan in various organisms. By slowing metabolic processes and reducing cellular stress, rapamycin may help delay aging at the cellular level, offering a potential shortcut to the benefits of caloric restriction without drastic dietary changes.

Evidence from Animal Studies

Rapamycin’s longevity benefits are best demonstrated in animal research. Studies have shown that it extends the lifespan of diverse organisms, including yeast, worms, flies, and mice.

The results In mice are the most relevant for humans and they are pretty striking:

• When started in middle age, rapamycin has increased median lifespan by up to 26%.

• Even when initiated later in life, it boosted lifespan by 14% in female mice and 9% in males.

Beyond lifespan, rapamycin improves healthspan—the period of life spent in good health. In animal models, it reduces the incidence of age-related conditions such as:

• Cancer: Rapamycin suppresses tumor growth.

• Neurodegenerative diseases: It delays progression in models of Alzheimer’s disease.

• Cardiovascular issues: It supports heart health.

These findings suggest that rapamycin doesn’t just add years to life—it may also add life to years.

Human Studies and Anecdotal Reports

While large-scale human trials for longevity are still pending, early research into the safety of Rapamycin as a longevity drug has already been undertaken in the PEARL study which successfully showed that Rapamycin is a safe and well-tolerated drug when taken at low doses with intermittent (weekly) administration (the study tested doses of 5 mg and 10 mg, once a week over nearly a year).

While the study was testing for safety and was too underpowered for efficacy analysis, some anecdotal evidence could still be drawn from it:

• Rapamycin’s effects on visceral fat - those who took Rapamycin were more likely to lose visceral fat than those in the placebo group.

• Rapamycin effects on lean muscle mass - DEXA scans helped reveal several body composition benefits for Rapamycin. Chief among these was a statistically significant improvement to lean muscle mass.

Potential Benefits of Rapamycin for Longevity

Rapamycin’s ability to target aging processes offers several potential advantages:

1. Delaying Age-Related Diseases: By reducing cancer, Alzheimer’s, and heart disease risks in animals, rapamycin could enhance human healthspan.

2. Boosting Immunity: Improved vaccine responses suggest it may help maintain immune vigor in older age.

3. Enhancing Cellular Repair: Rapamycin promotes autophagy, the process by which cells clear damaged components, potentially slowing age-related decline.

4. Mimicking Caloric Restriction: It provides a pharmacological alternative to restrictive diets, appealing to those seeking longevity without lifestyle overhauls.

These benefits position rapamycin as a compelling option for optimizing healthy aging.

Rapamycin in a Broader Longevity Strategy

Rapamycin stands out as a tantalizing prospect in the quest for longer, healthier lives. Its ability to inhibit mTOR, mimic caloric restriction, and combat age-related diseases has sparked excitement, backed by robust animal evidence and early human findings. 

Rapamycin is however not a standalone solution. Diet, exercise, sleep, and stress management remain foundational to longevity. For those already prioritizing health, rapamycin could serve as an additional tool, complementing lifestyle efforts. 

References

1. Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976.

• Explains rapamycin’s mechanism of action by inhibiting the mTOR pathway.

2. Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes & Development, 20(2), 174-184.

• Demonstrates lifespan extension in yeast with rapamycin.

3. Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metabolism, 15(5), 713-724.

• Shows rapamycin extends lifespan in worms (C. elegans).

4. Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metabolism, 11(1), 35-46.

• Reports lifespan extension in flies (Drosophila) with rapamycin.

5. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.

• Found that rapamycin extends median lifespan in mice by 14% in females and 9% in males when started late in life (20 months).

6. Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., ... & Strong, R. (2011). Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 66(2), 191-201.

• Reports a median lifespan increase of 23% in male mice and 26% in female mice when rapamycin treatment began at 9 months.

7. Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2011). Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle, 10(24), 4230-4236.

• Shows rapamycin reduces cancer incidence and extends lifespan in mice.

8. Caccamo, A., Majumder, S., Richardson, A., Strong, R., & Oddo, S. (2010). Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. Journal of Biological Chemistry, 285(17), 13107-13120.

• Demonstrates rapamycin’s potential to reduce neurodegenerative pathology in a mouse model of Alzheimer’s disease.

9. Dai, D. F., Karunadharma, P. P., Chiao, Y. A., Basisty, N., Crispin, D., Hsieh, E. J., ... & Rabinovitch, P. S. (2014). Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell, 13(3), 529-539.

• Shows rapamycin improves cardiovascular function in aged mice.

10. Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. Science Translational Medicine, 6(268), 268ra179.

• Reports that everolimus, a rapamycin derivative, enhances immune function in adults aged 65 and older.

11. Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. Aging, 11(19), 8048-8067.

• Discusses potential benefits (e.g., delaying age-related diseases, boosting immunity) and risks (e.g., infection risk, insulin resistance) of rapamycin, along with dosing considerations like 5-6 mg weekly.

12. Kaeberlein, M. (2015). The rapamycin story: from soil to gerosuppressant. F1000Research, 4, 1400.

• Provides an overview of rapamycin’s history and its use as a gerosuppressant, including uncertainties about long-term effects in healthy humans.