Rapamycin is starting to become the new hot name in the biohacking industry… and for a very good reason.
It fulfills three major roles as an anti-aging drug: Inhibits aging cells from forming, stops or slows down age-related diseases, and extends lifespan.
But is it possible for humans to experience life-extension from this drug? Do we have enough evidence to make this claim?
Or will this benefit only be seen in mice and other mammals?
This article will take the Jay Campbell deep dive and see if Rapamycin is worth adding to your toolbox of Golden Age agents.
What Is Rapamycin?
Rapamycin (a.k.a. Sirolimus as its generic name, or Rapamune as its brand name) has its name derived from two parts:
- “Rapa” from its place of discovery, an island in the southeastern Pacific Ocean called Rapa Nui (now known as Easter Island)
- “mycin” because it is produced by a species of bacteria known as Streptomyces
The history of this naturally-occuring compound dates back to the 1960s, when scientists were looking at the soil and attempting to figure out why the island’s inhabitants were seemingly unaffected by the bacterial infection known as tetanus:
“Scientists at Ayerst Pharmaceuticals in Canada discovered that Streptomyces hygroscopicus produced a compound that would kill fungi, which they named rapamycin after the name of Easter Island, Rapa Nui. The initial interest in rapamycin focused on its antifungal properties. When it was found that rapamycin inhibited the growth of eukaryote cells, research on rapamycin turned to rapamycin’s immunosuppressive and anticancer properties”
There’s a long and rich history behind this drug, including a rogue scientist from Ayerst keeping a few samples of Rapamycin when he was initially ordered to get rid of them.
Anyhow, Rapamycin would go on to be FDA approved for numerous health problems:
“Sirolimus was first approved by the FDA in 1999 for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants. In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids. In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis (LAM).
In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). Sirolimus was also investigated in other cancers such as skin cancer, Kaposi’s Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis.”
For more information about how Rapamycin works for its two indicated conditions of LAM and avoiding kidney transplant rejection, go here.
It wasn’t until the late 1990s when its mechanism of action was discovered, and a groundbreaking study in 2009 showing extension of life in mice, where Rapamycin’s anti-aging benefits became apparent to the public.
The video below from Dr. Peter Attia summarizes the history of Rapamycin and why the biohacking community has taken such a large interest towards this compound:
Rapamycin Mechanism Of Action
The workings of Rapamycin revolve entirely around an enzyme known as the mechanistic target of rapamycin (mTOR):
“mTOR, as the catalytic subunit of two distinct protein complexes, mTORC1 and mTORC2, is the major regulator of growth in animals and controls most anabolic and catabolic processes in response to nutrients and nutrient-induced signals, like insulin.
As such, it plays critical roles in physiology, metabolism, and aging, and is deregulated in common diseases, including cancer and epilepsy. Pharmacological and genetic data show that inhibition of mTORC1 increases lifespan in multiple model organisms, making it the best-validated aging regulator, and raising the tantalizing possibility that suppressing it might promote healthspan and longevity in humans.”
And in particular, it’s the mTORC1 complex we are interested in within the context of lifespan extension:
“In the context of biological ageing, inhibition of mTORC1 is consistently associated with increased lifespan, whereas inhibition of mTORC2 is associated with reduced lifespan, at least in mice. mTORC1 regulates several key homoeostatic processes including autophagy, mRNA translation, and metabolism, each of which affects the hallmarks of ageing and, therefore, the lifespan of different model organisms.
The macrolide antibiotic rapamycin (sirolimus) is an allosteric inhibitor of mTORC1 that acts by binding to the FK506 binding protein (FKBP12).
…Importantly, the effects of rapamycin extend beyond increasing lifespan in mice, with evidence of reduction in hallmarks of ageing. These effects include fewer age-related cancers, protection against cognitive decline, improved cardiovascular function, restoration of immune function, and improved renal function, oral health, intestinal function and reduced gut dysbiosis, and preserved ovarian function.”
The diagram above explains why it’s possible for Rapamycin to have positive and negative effects with mTOR inhibition — mTORC1 is sensitive to Rapamycin, whereas mTORC2 in select cell types is only affected with chronic long-term exposure to Rapamycin:
“mTORC1 senses amino acids, glucose, and oxygen and controls cellular processes including protein translation, ribosomal biogenesis, and autophagy. mTORC2 is less well-understood, but it functions downstream of insulin/IGF-1 through PI3K and controls cellular processes including metabolism and stress resistance.
…it has been proposed that most of the longevity benefits of rapamycin treatment come from its inhibition of mTORC1 signaling while some, but not all, common side effects, such as metabolic dysfunction, are due to mTORC2 inhibition”
And in case you’re wondering, yes, Metformin also inhibits mTOR activation but via a different pathway… which explains why both drugs offer similar anti-aging benefits.
(This paper here is a good look into the similarities and the differences between Rapamycin and Metformin)
Other known mechanisms of Rapamycin include immunosuppression via the mTOR inhibition pathway, thus explaining how it works for kidney transplantation:
“Rapamycin exerts its immunosuppressive effects by inhibiting the activation and proliferation of T cells. It acts specifically on FK-binding protein 12 (FKBP12), a substance commonly referred to as an immunophilin because it binds to immunosuppressive drugs. In turn, the rapamycin-FKBP12 complex binds to the mammalian target of rapamycin (mTOR), a kinase (an enzyme that adds phosphate groups to other molecules) that plays a fundamental role in regulating the progression of the cell cycle. The rapamycin complex inhibits mTOR and, by doing so, disrupts cell division and hence the proliferation of T cells.”
“Rapamycin downregulates STAT3 [an oncogenic transcription factor], which leads to lower expression of STAT3’s downstream target, c-Myc. Rapamycin also directly downregulates c-Myc in addition to its more widely known anti-mTOR activity. Together, these result in slower cell proliferation, inhibiting tumor growth.”
If you want to go deeper into mTOR and its relationship with Rapamycin, I highly recommend watching the video below:
Additoinally, this section of a 2016 paper goes into detail about “rapalogs” — new-generation analogs of Rapamycin designed to have better specificity and effectiveness with fewer side effects.
Rapamycin Anti-Aging Benefits
Rapamycin has nearly 50,000 scientific papers on PubMed published between 1975 and 2022… so clearly there’s a lot to be said for its health benefits.
But the majority of the attention has been directed towards Rapamycin’s ability to extend lifespan and healthspan in humans.
Which is why we’re in the middle of the PEARL trial (Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study) designed to see if Rapamycin can work as well in humans as it does in mice at a dose optimized for safety and effectiveness.
Here are some more details about the trial from Lifespan.io, who has funded the trial:
“Interested patients will be screened for eligibility using AgelessRx‘s telemedicine platform. Eligible patients include those aged 50-85 of any sex or ethnicity, in relatively good health, and with only well-managed, clinically stable chronic diseases.
Once entered into the trial, the 200 patients will be divided into four dosing arms: 2.5mg Rapamycin 3 times a week, 5mg Rapamycin once a week, 5mg Rapamycin twice a week, or 10mg Rapamycin once a week
…the following tests will be conducted for evaluating efficacy [after 6 and 12 months]: Autonomic health tests (ex. heart rate variability), blood tests (ex. markers of inflammation), body composition tests via DXA scans (ex. bone density, visceral fat), fecal microbiome testing, immune health tests (ex. IL-6 and TNF-alpha), methylation age, skeletal muscle tests (via lean body mass), and physiological data obtained via wearable devices.”
In the meantime, we do have one pilot study where Rapamycin appears to have some noticeable effect in humans:
“We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men.
Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased. Adipose tissue expression of mRNAs (arbitrary units) for MCP-1 (3585 vs 2020, p=0.06), PPAR-γ (1257 vs 1166), PAI-1 (823 vs 338, p=0.08) increased, whereas interleukin-8 (163 vs 312), TNF-α (75 vs 94) and p16 (129 vs 169) decreased. Cellular senescence-associated beta galactosidase activity (2.2% vs 3.6%, p=0.18) tended to decrease.
We observed some correlation between some senescence markers and physical performance but no improvement in frailty with rapamycin was noted”
And for a while, scientists pursued Rapamycin and other mTOR inhibitors as possible repurposed drugs for treating COVID-19:
“…the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Maiese  in the review showed that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction and the onset of hyperinflammation, a significant disability associated with COVID-19″
Of course… when I talked about COVID-19 back in March 2020, I mentioned resveratrol and quercetin as viable agents for the very same reason:
“Like any virus, SARS-CoV-2 will “hijack” the components of the host cell so it can replicate itself via the mTOR (mammalian target of rapamycin) enzyme. mTOR is primarily responsible for controlling cell growth, and is one of the main reasons why cancer cells grow and replicate far faster than the body can handle. “
So let’s see what Rapamcyin has done for the animals thus far!
Rapamycin and Longevity Studies
The first major study demonstrating Rapamycin’s lifespan-extending properties in mammals was published in 2009:
“Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown.
Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males“
“…Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders.”
It was considered one of the top 10 scientific breakthroughs of 2009 by Science, but critics were quick to note that extending lifespan without improving health is pointless:
“In addition to increasing lifespan, Neff and colleagues show that while rapamycin improves several functions/pathologies that change with age, it has little effect on the majority of the physiological and structural parameters they evaluated. What do these data tell us about the ability of rapamycin to delay aging and improve quality of life?”
“…it is necessary to demonstrate that the agent does not produce a “Tithonus phenotype,” where the increase in lifespan is accompanied by more disability and disease and a greater loss of physiological functions, i.e., a reduced quality of life.“
“(A) Healthspan is the period of life without diseases. Diseases (black color) terminate lifespan. Subclinical aging (white color) progresses to pre-diseases (gray) and diseases (black). X axis: age. Y axis: loss of health (a sum of diseases) in log scale.
(B) Longevity intervention slows aging and extends healthspan, automatically extending lifespan.
(C) Unrealistic scenario “Healthspan without lifespan”. Compressed morbidity (black). Either diseases progress instantly, or animals die from “health” rather than from diseases.”
Several more mouse studies have been published since, consistently reproducing this lifespan-extending effect and showing Rapamycin is most effective when given to older mice:
I won’t be able to fit in every single mouse study after 2014, but here are some of the publications that highlight the potency of Rapamycin for improving lifespan and/or healthspan:
“Bitto et al. show that treating mice with rapamycin for a short period during middle age increases the life expectancy of the mice by up to 60%. In the experiments, mice were given two different doses of rapamycin for only three months starting at 20 months old (equivalent to about 60-65 years old in humans). After receiving the lower dose, both male and female mice lived about 50% longer than untreated mice, and showed improvements in their muscle strength and motor coordination.” (Source)
“To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice.”
“…administering male mice every other month with rapamycin beginning at age 20 months and giving rapamycin continuously from age 20 to 23 months was as effective at improving survival as continuous exposure starting at age 20 months. Intermittent and continuous exposure increased female survival, but intermittent was not as effective as a continuous exposure.” (Source, Source)
“In one short-lived mutant strain of mice, the mTOR inhibitor rapamycin (known in the clinic as Sirolimus) extends maximum life span nearly three-fold. Albeit less spectacularly, rapamycin also prolongs life in normal mice as well as in yeast, worms and flies, and it prevents age-related conditions in rodents, dogs, nonhuman primates and humans. Rapamycin and its analog, everolimus, are FDA approved for human use and have been used safely for decades. In 2006, it was suggested that rapamycin could be used immediately to slow down aging and all age-related diseases in humans, becoming an “anti-aging drug today”. (Source)
What do the humans have to say about this?
Anecdotal Benefits Reported In Human Test Subjects
Rather than list hundreds of messages here, I’ll just summarize some of the reported benefits from using this anti-aging compound over a few months, with or without other compounds such as Metformin:
- Weight loss
- Lower reliance on pain medications
- Improvements in strength and endurance
- More energy throughout the day
- Higher testosterone levels
- Better blood work (ex. lowered LDL readings)
- Noticeably improved skin health
- Reduced blood pressure
- Improved mood
- Decreased bodily inflammation
- Lower biological age
- Better sleep at night
We would need a HUGE clinical trial spanning several decades to see if frequent Rapamycin users end up outliving non-users… while also excluding the influence of other lifestyle factors as much as possible.
But if it happens, we could have definitive proof of a must-have Golden Age agent for anybody in their 40s and above!
Rapamycin Dosage for Longevity and Life Extension
There seems to be some variation among doctors who use Rapamycin as an anti-aging tool, but the dosing regimens are somewhat similar:
Dr. Alan Green: 6 mg taken as an oral tablet once a week to help elderly patients prevent or delay onset of Alzheimer’s and/or improve immune function (+500 patients treated and counting).
That’s a very sharp contrast to using Rapamycin for its prescribed purposes — 2 mg per day for treating Lymphangioleiomyomatosis or as high as 5 mg for organ transplant rejection treatment.
It should be noted that certain substances will increase blood levels of Rapamycin (ex. grapefruit juice) or decrease them (ex. phenobarbital), so be careful when you use Rapamycin.
Since this is a brand new way to use Rapamycin, the jury is out on whether Dr. Attia or Dr. Green have discovered the optimal anti-aging protocol for Rapamycin in humans:
“An additional consideration for ongoing studies are the important sex-dependent differences in the magnitude of effect of rapamycin on biological outcomes, including lifespan, with female mice generally showing a larger effect than males at lower doses of the drug. Our dose-response studies suggest that the differential impact of rapamycin on male and female mice is primarily a result of greater sensitivity of females to rapamycin, with higher doses attenuating gender differences in the phenotypic outcomes we have examined so far. Further studies, particularly at higher doses of the drug, will be required to definitively answer this question.
In summary, while remarkable beneficial impact of rapamycin on longevity and disease have now been firmly established in mice, additional studies are needed to define the relative importance of dose, delivery method, and treatment regimen. These studies are critically important for successful translation to human biology, both for understanding how to optimize beneficial effects, but equally importantly, for reducing adverse outcomes.”
Or to illustrate this differently with a separate image:
“Three potential outcomes of a rapamycin dose response trial for effects on lifespan. The solid blue line represents the published data from the Interventions Testing Program for the effect of encapsulated rapamycin on mean lifespan of UMHET3 mice when provided in the diet beginning at 9 months of age (average of effects in males and females combined). Dashed lines represent a few possible outcomes of a dose response trial for rapamycin at higher doses.”
We’ll have to wait and see what data emerges from additional clinical trials in humans..
Rapamycin Side Effects and Safety
Thanks to the full FDA approval Rapamycin has, we have a good idea of what its side effect profile looks like.
The most commonly reported side effects of Rapamycin include:
- Back ache
- Sore throat
- Lack of appetite
- Runny nose
Some of the more serious Rapamycin side effects requiring immediate medical attention include chest pain, difficulty breathing, slurred speech, and painful mouth sores.
There are also clear drug contraindications (i.e. drugs you should NOT take alongside Rapamycin), such as ketoconazole and dexamethasone.
But there are a few potential side effects not mentioned in the official product monographs that are worth your attention:
- Human cancer cells acquiring resistance against Rapamycin treatment
- Possible inhibition of muscle growth via mTOR inhibition (along with muscle insulin resistance)
- Joint pain, acute renal toxicity, and more when used in high doses for kidney transplant patients
Yet it’s worth noting that with the limited testing done in humans outside of rare medical needs, Rapamycin proves to be safe:
“… mTOR inhibitors such as rapamycin has also been tested in healthy elderly with little to no side effects reported after up to 8 weeks of treatment. A main concern inhibiting mTOR in the elderly is the possibility of immune suppression.
However, six-week treatment with an mTOR inhibitor revealed promising results in 264 elderly individuals. Whole blood mRNA sequencing analysis showed that genes involved in anti-viral immune response were upregulated significantly in the treatment group, and infections rates were reduced significantly compared to placebo treatment”
Furthermore, as mentioned in the previous section, the dose makes the poison:
“Intermittent rapamycin administration (pulse treatment) was proposed in 2008, as a means of rejuvenating stem and wound-healing cells, thereby improving wound-healing instead of impairing it, as chronic treatment with rapamycin did. Intermittent administration (e.g., once a week) can be considered a single dose repeated over time. In mice, a single dose of rapamycin does not cause glucose intolerance, but a single dose of a dual mTORC1/mTORC2 antagonist does causes it.
Consistent with that finding, weekly treatments with rapamycin for 22 weeks inhibited mTORC1 and protected against insulin resistance in C57BL/6 mice fed a high-fat diet, whereas mTORC2 activity remained intact. Higher single doses of rapamycin can be used when administration is intermittent than when it is chronic, and it appears that it is the peak concentration of rapamycin that is especially beneficial. This is in part because high peak levels enable rapamycin to cross the blood–brain barrier.”
And the Rapamycin doses being used for anti-aging/longevity are NOT the same as what’s being used for ill patients:
“Because Rapamycin has historically been used mostly for immunosuppressive applications / organ donor situations – at a level that is ~10 to 40 times higher than is currently being used in longevity applications. (e.g. 2 to 6 mg/week in Longevity, vs. 5 to 40 mg / day in organ rejection / immunosuppressive application) and the side effects are pretty horrible.”
To make a long story short… we’re starting to find out that weekly personalized yet maximum doses of Rapamycin allow us to experience its full range of anti-aging benefits without suffering any unwanted side effects:
Case in point: When a study went viral in 2021 purporting to show Rapamycin lowers bone density, it turns out the study was being incorrectly interpreted.
(I highly recommend reading the link because it shows you how the opposite — Rapamycin helps reverse age-associated bone loss — is actually true).
One final note… Rapamycin alone will NOT be sufficient to add years to your lifespan.
Take a look below at the table that shows five healthy lifestyles extending lifespan more than 10 years starting at age 50:
In the scientific review this table comes from, caloric restriction (CR) has the same or slightly larger effect than all 5 lifestyles put together.
And from the review: “If rapamycin, resveratrol, metformin, or a combination thereof, prove capable of reproducing even half the years of life extension that CR extension can, it would be a multi-billion dollar market (USD) and could be among the best therapeutics measured on the Quality Adjusted Life Years (QALY) scale.”
Even though Rapamycin is additive alongside caloric restriction with respect to slowing age-related skeletal muscle wasting, it still doesn’t compare to caloric restriction for extending lifespan when weighted head-to-head:
Something to keep in mind if you think Rapamycin is a magic pill that will solve all your problems!
How To Buy Rapamycin
Due to Rapamycin’s status as a prescription drug, you will not be able to reliably buy it online.
You’ll need to be lucky enough to run into a physician who will prescribe Rapamycin off-label, as there’s no profit to be made in anti-aging:
“No rigorous large-scale clinical trials have been conducted aimed at aging. The FDA so far has not agreed that a treatment could be approved for delaying the onset of aging or age-related diseases, citing questions about whether research can demonstrate an overall effect on aging rather than just on a specific disease.
Given such reservations, pharmaceutical companies have little incentive to fund costly, large-scale trials. Also, both metformin and rapamycin are generic and relatively cheap.”
Even then, you’d best hope your co-pay – in combination with the right pharmacy – can lower the price per tablet by a dollar or two.
So be prepared to pay out-of-pocket for a visit to an anti-aging physician and don’t assume your insurance will offset the cost.
The only online source I AM comfortable recommending is The Anti-Aging Store ($1.6 per mg), and you can save 15% off your purchase with code JAY15
Additional Reading Resources For Rapamycin
Despite being in existence since the 1970s, Rapamycin still remains a newcomer in the anti-aging space.
Unlike Metformin and its thousands of patient-years in demonstrated anti-aging benefits for humans, we’re just tapping the potential of what Rapamycin can offer outside of its two FDA-approved indications.
So much of what you’ve seen here today is a brief summary of what we know for sure.
But if you want to go even deeper than I did and see what the hype behind Rapamycin is about, check out the links below…
Genetic Lifehacks has a list of genetic variants that dictate how your body will respond to Rapamycin.
Dr. Peter Attia did an hour-long podcast with Dr. David Sabatini, one of the few people who has worked with Rapamycin and the mTOR protein since he discovered the latter in 1994.
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