Better living through drugs! In this case, we’re talking about a drug that has been used for decades but is being repurposed since we found that it does other useful things for us. We’re going to be talking about Rapamycin and why it might be useful in your longevity stack. Remember: it’s a drug so you need a real doctor, and nothing works unless you do, so maintain your healthy foundational habits.
What is rapamycin?
Rapamycin, which is known in the lab as Sirolimus and prescribed under the brand name Rapamune, is part of a class of drugs called rapalogs, which means the obvious: drugs that work by the same mechanism as Rapamycin. It was discovered by isolating compounds from Streptomyces hygroscopicus on the island of Rapa Nui, aka Easter Island, in 1972. There’s even a plaque on the island commemorating it. Upon analysis, researchers found that it was antifungal as well as antibacterial, but were most impressed by its immune-modulating capabilities. It’s currently used as an immune suppressant for organ transplant recipients to prevent rejection, especially kidneys.
Dr. Surendra Sehgal, who first isolated this compound at Ayerst Research Laboratories also discovered its powerful tumor-suppressing effects. If it were simply an immune suppressant, it would not also suppress tumors, which means it’s mechanism is more complicated. The mechanism that inhibits tumor growth when this drug is administered is creatively called Mammalian Target of Rapamycin, or mTOR. This is a highly conserved signaling pathway that exists in non-mammals as well, where it’s just referred to as TOR, such as yeast, worms, fungus, and plants.
mTOR is a type of enzyme called a protein kinase and plays a role in cellular metabolism, survival, growth, and programmed death. It’s a calorie restriction mimetic, which means it mimics the effects of calorie restriction without having to starve yourself. (That’s not an excuse to binge on cake.) When it’s disrupted over time, we see the symptoms associated with aging. There are two mTOR pathways, and you can make the logical jump that they are named mTORC1 and mTORC2.
Behold, these two excellent videos explaining how it all works! There’s more to read below them so don’t go anywhere just yet.
https://www.youtube.com/watch?v=EnIerDljc7g
What makes rapamycin a potential longevity therapy?
Rapamycin turns down mTOR activity and decreases the rate of cellular senescence, which is a type of prolonged cell death where the cell can no longer divide but performs essential functions, unfortunately sending out inflammatory signaling molecules in the process to trigger impaired function in surrounding cells. It seems to revert cells to a younger state and improves immune responses. This can be measured by various methylation aging clocks as well as more traditional biomarkers like DXA scans, lipids, inflammation, microbiome health, and an immune function panel.
The PEARL trial is being sponsored by AgelessRX and is spearheaded by Dr. Sajad Zalzaza, a physician licensed in all 50 states who sees patients in person and through telemedicine. PEARL stands for Participatory Evaluation of Aging with Rapamycin for Longevity. It’s a large-scale, double-blind, randomized, placebo-controlled phase IV trial, which is the gold standard for testing compounds on humans. Part of the trial is safety at the proposed dosing schedules, the other part is efficacy, to see what benefits it can confer. The dosage comparisons range from 1.5mg/day, 3 days a week, to 5mg twice a week, and the best dosage will move on to a second trial. These dose schedules are far below what’s used for organ transplants, and they are pulsed to ensure a trough effect (essentially a recovery period between doses). They are currently planning and enrolling subjects, so we’ll get to see the results of this study in the not-too-distant future.
What are the risks of taking it?
Side effects have been reported in those taking rapamycin for immune modulation after organ transplant and those using it as a treatment for cancer. Some people have reported mouth sores which resolved when taking a break from the treatment. Headaches, digestive discomfort, edema, rashes, and joint pain have been reported by less than 20% of users. There are some possible serious side effects, but they are incredibly rare (and come from transplant patients). However, the possibility of serious side effects is why you need a prescription for Rapamycin and why you’ll work with a physician to make sure it’s a good idea for you, and not just order it from some internet pharmacy of dubious source. Working with a physician means you’ll get regular testing of the relevant biomarkers to ensure optimal health.
Obligatory note:
I am not a doctor, and this is not medical advice. This is information I’ve found through research. It discusses what a hypothetical rapamycin protocol might look like, and why you might be interested in such a thing to positively impact your longevity. This is a Level 4 therapy and there is no set protocol for using rapamycin; usage requires a professional and individual testing because there is risk involved. Some physicians who may be able to discuss personalized rapamycin therapy include Dr. Alan Greene, Dr. Sajad Zalzaza, and Dr. Peter Attia. This is not a complete list and it is likely that there are more physicians specializing in longevity that can discuss this topic with you.
References:
Apelo, S. A., Pumper, C. P., Baar, E. L., Cummings, N. E., Brar, H. K., Kimple, M. E., Lamming, D. W., & Neuman, J. C. (2016). Id: 21: alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system, and extends lifespan. Journal of Investigative Medicine, 64(4), 932–933. https://doi.org/10.1136/jim-2016-000120.45
Arriola Apelo, S. I., Neuman, J. C., Baar, E. L., Syed, F. A., Cummings, N. E., Brar, H. K., Pumper, C. P., Kimple, M. E., & Lamming, D. W. (2016). Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell, 15(1), 28–38. https://doi.org/10.1111/acel.12405
Bibee, K. P., Cheng, Y.-J., Ching, J. K., Marsh, J. N., Li, A. J., Keeling, R. M., Connolly, A. M., Golumbek, P. T., Myerson, J. W., Hu, G., Chen, J., Shannon, W. D., Lanza, G. M., Weihl, C. C., & Wickline, S. A. (2014). Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. The FASEB Journal, 28(5), 2047–2061. https://doi.org/10.1096/fj.13-237388
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. https://doi.org/10.7554/eLife.16351
Blagosklonny, M. V. (2018). Disease or not, aging is easily treatable. Aging (Albany NY), 10(11), 3067–3078. https://doi.org/10.18632/aging.101647
Blagosklonny, M. V. (2019). Rapamycin for longevity: Opinion article. Aging (Albany NY), 11(19), 8048–8067. https://doi.org/10.18632/aging.102355
Chang, G.-R., Wu, Y.-Y., Chiu, Y.-S., Chen, W.-Y., Liao, J.-W., Hsu, H.-M., Chao, T.-H., Hung, S.-W., & Mao, F. C. (2009). Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed kk/hlj mice. Basic & Clinical Pharmacology & Toxicology, 105(3), 188–198. https://doi.org/10.1111/j.1742-7843.2009.00427.x
Deblon, N., Bourgoin, L., Veyrat-Durebex, C., Peyrou, M., Vinciguerra, M., Caillon, A., Maeder, C., Fournier, M., Montet, X., Rohner-Jeanrenaud, F., & Foti, M. (2012). Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. British Journal of Pharmacology, 165(7), 2325–2340. https://doi.org/10.1111/j.1476-5381.2011.01716.x
Diseases, R. T. for A. R. (n.d.). The medical practice of alan s. Green. Rapamycin Treatment for Age Related Diseases. Retrieved November 6, 2020, from https://rapamycintherapy.com/
Ferriss, T. (2018, June 5). The tim ferriss show transcripts: Peter attia, david sabatini, and navdeep chandel(#193). The Blog of Author Tim Ferriss. https://tim.blog/2018/06/05/the-tim-ferriss-show-transcripts-peter-attia-david-sabatini-and-navdeep-chandel/
Foster, D. A., & Toschi, A. (2009). Targeting mTOR with rapamycin: One dose does not fit all. Cell Cycle, 8(7), 1026–1029. https://doi.org/10.4161/cc.8.7.8044
Hebert, M., Licursi, M., Jensen, B., Baker, A., Milway, S., Malsbury, C., Grant, V. L., Adamec, R., Hirasawa, M., & Blundell, J. (2014). Single rapamycin administration induces prolonged downward shift in defended body weight in rats. PLoS ONE, 9(5). https://doi.org/10.1371/journal.pone.0093691
Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: Does rapamycin deliver? Science Translational Medicine, 5(211), 211fs40-211fs40. https://doi.org/10.1126/scitranslmed.3007316
Kaeberlein, M. (2014). Rapamycin and aging: When, for how long, and how much? Journal of Genetics and Genomics = Yi Chuan Xue Bao, 41(9), 459–463. https://doi.org/10.1016/j.jgg.2014.06.009
Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., Benavides, A. D., Curiel, T. J., Javors, M. A., Musi, N., Chiodo, L., Koek, W., Gelfond, J. A. L., & Kellogg, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Experimental Gerontology, 105, 53–69. https://doi.org/10.1016/j.exger.2017.12.026
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013). Rapalogs and mTOR inhibitors as anti-aging therapeutics. The Journal of Clinical Investigation, 123(3), 980–989. https://doi.org/10.1172/JCI64099
Mitteldorf, J. (2016, June 13). Rapamycin redux. Josh Mitteldorf. https://joshmitteldorf.scienceblog.com/2016/06/13/rapamycin-redux/
Mukhopadhyay, S., Frias, M. A., Chatterjee, A., Yellen, P., & Foster, D. A. (2016). The enigma of rapamycin dosage. Molecular Cancer Therapeutics, 15(3), 347–353. https://doi.org/10.1158/1535-7163.MCT-15-0720
The longevity research institute. (n.d.). Retrieved November 6, 2020, from https://thelri.org/blog-and-news/rapalogs/
Ye, L., Widlund, A. L., Sims, C. A., Lamming, D. W., Guan, Y., Davis, J. G., Sabatini, D. M., Harrison, D. E., Vang, O., & Baur, J. A. (2013). Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging, 5(7), 539–550. https://doi.org/10.18632/aging.100576