In the 1970s, a Canadian pharmacologist discovered a new antibiotic he called rapamycin in soil samples from Easter Island. Tens of thousands of patients who have had to undergo an organ transplant owe their lives to this drug. Forty years later, that same rapamycin is quickly gaining popularity in the longevity scene. Does rapamycin extend life span?

By Willem Koert

In the 1960s, a microbiologist from Canada’s McGill University in Canada collected 73 soil samples from Easter Island and sent them to the lab of pharmacologist Suren Sehgal in Montreal, then associated with the pharmaceutical company Wyeth. Wyeth has since been acquired by Pfizer. In the samples, Seghal found the bacterium Streptomyces hygroscopicus, which fought off competing fungi and bacteria by producing a surprising toxin effect. Rapamycin, Seghal’s lab called the substance. Initially, Seghal thought he had discovered a new antibiotic and antifungal agent, but the side effects of rapamycin turned out to be a bit too harsh for this application. The new substance also inhibited the immune system, and this effect was certainly interesting from a medical point of view. The US Medical Authority approved rapamycin in 1999 as an immunosuppressant, useful in helping to prevent organ transplant rejection.[1]

Research in the early 1990s revealed the mechanism of action of rapamycin. Rapamycin blocked one of the most crucial signaling molecules in cells. It is noteworthy that molecular biologists were able to discover that molecule when they performed in vitro experiments with rapamycin. In mammals and humans, this signaling molecule is called Mammalian Target of Rapamycin (mTOR or also sometimes referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1)).

Extending life span

When cells receive stimuli in the form of insulin, growth factors such as IGF-I, amino acids or a large supply of nutrients, all these signals activate mTOR. It is mTOR that prompts the cell to activate growth and proliferation processes. Rapamycin stops mTOR from functioning. In this way, rapamycin interferes with the functioning of the immune system, including the immune cells that would normally attack and break down foreign tissues. Of course, the biological effects of rapamycin go even further than this. Rapamycin imitates the effects of fasting, but in a much more rigorous way than AKG or resveratrol.

Fasting reduces the risk of death and, at least in animal models, extends lifespan. This is why anti-aging researchers suspected that the administration of rapamycin has a similar effect. In 2009, American researchers published an animal study in Nature that confirmed this suspicion. The researchers fed rapamycin to old lab mice at the end of their natural lifespan and found that the immunosuppressant was able to extend the lifespan of animals by up to 14 percent.[3] If the mice had been adult humans, they would have received 12-20 milligrams of rapamycin daily. Scientists use doses of the same order of magnitude in other animal studies.

Effects

It should be noted that the doses at which patients use rapamycin are considerably lower than the human equivalent of the doses used in the animal studies. Organ recipients use 1-2 milligrams of rapamycin per day, one-tenth the human equivalent of the doses of rapamycin that anti-aging researchers give their mice. Even at those doses, side effects such as malaise, poor wound healing, nausea, diarrhoea, anemia, elevated cholesterol and increased insulin resistance are by no means rare.

Despite this, the biological effects are impressive. Even in animal studies in which rapamycin was not able to inhibit hormonal, cardiological and immunological signs of aging across the board, administration of the drug did extend lifespan.[4] In other animal studies, conducted with older and not very fit lab rats, rapamycin did increase muscle strength and endurance.[5] In yet other animal studies, everolimus, a slightly modified variant of rapamycin, appeared to rejuvenate the immune system of older test animals.[6] Although strict caloric restriction can weaken the immune system and make successful infection attempts by viruses, bacteria and other germs more likely, rapamycin seems to strengthen the immune system of laboratory animals.[7] By administering rapamycin, test animals reacted to a flu vaccine as if they were still young. And in yet another animal study, conducted with a type of lab mouse that is prone to cancer, rapamycin reduced the chance of developing tumors.[8]

In animal studies, it is not necessary to administer rapamycin for life to still achieve good results. When researchers give middle-aged lab mice rapamycin for 3 months, the dosing regimen increases their lifespan by up to 60 percent.[9]

Trials

If administration of a drug that was already approved several decades ago in animal studies has such good results, it is obvious that physicians will study in clinical trials whether administration of rapamycin can also counteract aging symptoms in humans. At the time of writing this post, the National Center for Biotechnology Information’s clinicaltrials.gov database listed ten trials. Two of them had already been completed.

In one such study, cardiologists at the American Mayo Clinic found that rapamycin in the blood of elderly people with coronary artery disease reduced markers of inflammation and aging at the molecular level.[10] In this study, the subjects took 2 milligrams of rapamycin daily for 12 weeks. In another completed trial, researchers at Texas A&M University at Galveston gave elderly people a single dose of 16 milligrams of rapamycin and then measured its effects on muscle growth. The results of this trial have not yet been published.

While the scientific evidence of a life-prolonging effect of rapamycin is piling up, the pharmaceutical industry seems at first to stay aloof from the emerging longevity drug. That may be because pharmaceutical researchers view rapamycin as having too many side effects to be marketed as a lifestyle drug. Another possible factor is that the patents on rapamycin have expired, which has lost the opportunity for attractive profit margins for the industry.

However, on closer inspection it is evident that the industry is following developments. For example, innovators have filed patents in recent years for applications where rapamycin is delivered via other routes, such as via the lungs.[11] At the same time, a pharmaceutical company such as Novartis, which has a long history with rapamycin, is working on rapamycin analogs that “selectively inhibit” mTOR.[12]

Longevity scene

Meanwhile, in the global longevity scene, tens of thousands of individuals have already started experimenting with rapamycin on their own initiative. One of them is Ross Pelton, pharmacist and author of the book Rapamycin, mTOR, Autophagy & Treating mTOR Syndrom. In an interview with Life Extension Magazine, Pelton said that in the summer of 2021 he himself started taking a weekly dose of 6 milligrams of rapamycin.[13] In November of that year he thought it wise to take this dose once every two weeks.

“I had blood drawn for routine lab work in November 2021 and discovered that I was anemic,” says Pelton. “My red blood cell count, hemoglobin, and iron levels were below normal and my lymphocyte count was slightly low, which is an indicator of immune status. Based on my lab values, I reduced my rapamycin intake to 6 mg every other week. I rechecked my labs a month later and everything had returned to normal.”

Pelton’s protocol is in line with protocols currently in vogue in the longevity scene. In addition, users take a dose of 3 to a maximum of 10 milligrams of rapamycin once a week or once every 2 weeks.[14]

Taking a small dose once for 2 weeks seems like a very small intake, which may seem to be modest to be effective, but you should bear in mind that rapamycin remains in the body for a long time. The half-life of rapamycin is 2-3 days. By taking a dose of rapamycin once every 2 weeks, the body gets enough time to literally get rid of all rapamcyin.[15]

Those schedules in which users take a single dose of rapamycin every 1-2 weeks are based, among other things, on the theory that it is not necessary – and indeed not possible – to use rapamycin to completely inactivate the mTOR molecule for an extended period of time. During a limited period of mTOR inactivity, cells repair themselves. Health cells clear out non-functional molecules and repair damaged structures.[16] Senescent and malfunctioning cells kill themselves. It is these processes, which cell biologists classify as ‘autophagy’, that according to most rapamycin experts underlie the anti-aging effects of rapamcyin. These effects are still present for some time after taking rapamycin.

Rapamycin users in the longevity scene experience a variety of positive health effects, according to a survey by the (excellent) website Rapamycin.News.[14] They range from less pain, less joint pain, more energy, improved sexual function, more stamina and improved sleep.

The same survey also shows that just over half of users experience side effects, such as a sore mouth, skin problems such as acne, nausea, diarrhea, headache and fatigue. For some users, these adverse effects are reason to stop. A limited number of users also stop after tests showed that values such as lipids or insulin resistance markers deteriorated.

There are not yet many rapamycin users who also train with weights. There are therefore still insufficient user experiences on the basis of which it can be deduced whether, and if so: to what extent, rapamycin reduces anabolism. In a clinical study, in which subjects did weight training a few hours after taking a single dose of 16 milligrams of rapamycin, rapamycin reduced the anabolic response by several tens of percent.[17] However, what this means in practice is not yet clear.

‘A serious drug’

Since it is still not completely clear whether rapamycin indeed extends lifespan, it is not possible to properly weigh up the positive health effects on the one hand and adverse effects on the other. However, according to Rapamycin.News, it is beyond dispute that rapamycin is ‘a serious drug’, ‘that can have serious side effects if you dose too high’.[18]

“This is not a risk-free drug”, the website warns. “If you are considering using rapamycin be sure to spend a few months reading all the information here and elsewhere on it so you can make an informed decision, ideally working in concert with a doctor. Don’t just rush into taking rapamycin because you heard a podcast mention it.”

[1] Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S.

[2] Abraham RT, Wiederrecht GJ. Immunopharmacology of rap. Annu Rev Immunol. 1996;14:483-510.

[3] 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. Sirolimus fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5.

[4] Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Hölter SM, Moreth K, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Höfler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D.. Sirolimus extends murine lifespan but has limited effects on aging. J Clin Invest. 2013 Aug;123(8):3272-91.

[5] Xue QL, Yang H, Li HF, Abadir PM, Burks TN, Koch LG, Britton SL, Carlson J, Chen L, Walston JD, Leng SX. Sirolimus increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats. Aging (Albany NY). 2016 Apr;8(4):769-76.

[6] Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179.

[7] Phillips EJ, Simons MJP. Sirolimus not dietary restriction improves resilience against pathogens: a meta-analysis. Geroscience. 2023 Apr;45(2):1263-70.

[8] Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Sirolimus increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011 Dec 15;10(24):4230-6.

[9] Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, Kerr KF, Davis DJ, Gillespie CH, Snyder JM, Treuting PM, Kaeberlein M. Transient Sirolimus treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016 Aug 23;5:e16351.

[10] Singh M, Jensen MD, Lerman A, Kushwaha S, Rihal CS, Gersh BJ, Behfar A, Tchkonia T, Thomas RJ, Lennon RJ, Keenan LR, Moore AG, Kirkland JL. Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J Frailty Aging. 2016;5(4):204-7.

[11] An inhalable RAP formulation for treating age-related conditions. European Patent EP 325875 B1.

[12] Cambrian Biopharma. Cambrian Biopharma Announces Licensing Agreement to Develop Selective mTOR Inhibitors. Press Release, 16 Feb, 2022.

[13] The RAP Story. Life Extension Magazine, 2022 June.

[14] RAP User Poll | Survey. LINK.

[15] Modern Healthspan. RAP: Practical Dosage & Benefits | Dr Alan Green Episode 4. YouTube, 2021 August 21.

[16] Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett. 2010 Apr 2;584(7):1287-95.

[17] Gundermann DM, Walker DK, Reidy PT, Borack MS, Dickinson JM, Volpi E, Rasmussen BB. Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by RAP. Am J Physiol Endocrinol Metab. 2014 May 15;306(10):E1198-204.

[18] New To RAP? LINK.