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Rapamycin (Sirolimus) Supplements

Rapamycin (Sirolimus) supplements. Are they safe and effective? What are the risks?

For those wondering if Sirolimus, a.k.a. Rapamycin would provide them with anti-aging benefits, the answer may be the opposite. The present level of scientific understanding in humans is insufficient to justify the risk. Here’s what is known and when new anti-aging clinical trial results are expected.

History and Purpose

Sirolimus is produced by the bacterium Streptomyces hygroscopicus and was isolated for the first time in 1972, from samples of Streptomyces hygroscopicus found on Easter Island. The compound was named rapamycin after the native name of the island, Rapa Nui. 

Sirolimus was developed as an antifungal agent. However, this target was discontinued when it was discovered to have potent immunosuppressive and antiproliferative properties as it inhibits mTOR. mTOR (mammalian or mechanistic target of rapamycin) regulates cellular metabolism, growth, and proliferation. In September 1999, rapamycin was approved by the U.S. Food and Drug Administration (FDA) as an immunosuppressant.

Why Supplement?

Rapamycin studies extended the lifespan of some mice by about 10%. This occurred when given doses early in mouse development because it slowed their growth rate and limited their body size. When given later in life to animals, German researchers did not find significant benefit.

Some leading-edge scientists such as Joan Mannick and Nir Barzilai then wondered if it could also increase longevity in humans. However, sirolimus is classified as an immunosuppressant, lowering the effectiveness of your adaptive immune system. Rapamycin has serious adverse side effects for over 30% of people who take high doses.

Those who supplement for anti-aging purposes take low doses to avoid immuno-suppression. They are attempting to immuno-modulate their bodies by inhibiting hyper-activation of mTOR. Hyper-activation of mTOR weakens the immune system.

Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood. It is difficult to continuously measure your immune system to determine what level of mTOR inhibition is appropriate, if any, AND how you measure if rapamycin produces desired anti-aging effects.

Positive Impact

Medically, rapamycin has been used to:

  • reduce fibrosis from cystic kidney disease.
  • prevent the body from rejecting a transplanted kidney.
  • treat lymphangioleiomyomatosis, a rare lung disease that predominantly affects women of childbearing age.

Those who are pushing for rapamycin use in humans claim that by inhibiting mTOR and activating autophagy, all cells in the body begin to detoxify more effectively and undergo revitalization and renewal. They believe that results from animal models suggest that rapamycin will improve symptoms for chronic degenerative diseases. This includes metabolic syndrome and type 2 diabetes, neurological diseases such as Parkinson’s disease and multiple sclerosis, inflammatory conditions like rheumatoid arthritis and systemic lupus erythematosus, macular degeneration, glaucoma, obesity, hearing loss, periodontal disease, cognitive decline, and Alzheimer’s disease.

Others believe there are benefits to bone, muscle and metabolism.

How much, if any, of this is true, is not yet proven in human clinical studies.

Which Rapamycin Vendor?

Sirolimus is a prescription-only drug under the brand name Rapamune from Pfizer. Generic versions are available as well. This article explains how people manage to get prescriptions.

The wholesale price to pharmacies for a bottle of 100 2 mg sirolimus tablets is over $3,000. Some people manage to get their prescription covered by insurance.

Sirolimus Dosage

Sirolimus is an FDA approved prescription drug provided in daily doses of 0.5, 1 and 2 mg and as an 1 mg / mL oral solution. Medical dosage varies by person and procedure. 

There is no recommended dosage for anti-aging, although those who do attempt this path aim for 5mg once weekly, adjusted for body size. 

Anti-aging clinical trials are dosing in the following groups:

1. 2.5mg rapamycin 3 times a week2. 5mg rapamycin once a week3. 5mg rapamycin twice a week4. 10mg rapamycin once a week

Frequent dose adjustments based on nonsteady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a 63 hour half-life.

Rapamycin Clinical Trials

In 2014, a study by Dr. Joan Mannick, titled mTOR inhibition improves immune function in the elderly,  evaluated the effects of mTOR inhibition on 218 healthy elderly volunteers. They received a synthetic version of rapamycin (a rapalog) to see if it might impact the human immune system.

In this 6-week placebo-controlled trial, 218 volunteers who were 65 years of age or older were divided into four groups. The doses administered were 0.5 mg daily, 5.0 mg once weekly, 20 mg once weekly, or placebo. Following 6-weeks of therapy, there was a 2-week drug-free interval followed by administration of the seasonal flu vaccine.

The immune system of the elderly adults who received a 5 mg dose of RAD001 once weekly exhibited a 20% enhanced response to the influenza vaccine with virtually no side effects. Some people have interpreted the results of this clinical trial to believe that the ability of rapamycin or similar rapalogs to enhance immune function in elderly adults might delay the onset of age-related diseases in humans.

As of January, 2023, there are 1070 human clinical trials for rapamycin. Over 500 have been completed. However, there is one which is getting the most attention.

The first anti-aging human rapamycin trial is the Participatory Evaluation of Aging with Rapamycin for Longevity (PEARL). It started in January 2020 and is fully enrolled with 200 participants split across 4 trial groups. Double-blind, randomized placebo controlled results are expected in December, 2023

Trial subjects will be monitored to detect changes in their health and biological age using:

1. Autonomic health tests – including baseline (am) heart rate and baseline (am) heart rate variability testing.
2. Blood tests – Standard measures of risk of age-associated diseases (glucoregulatory markers, lipids), and markers of inflammation.
3. Body composition testing with DXA scans – measuring bone density as well as visceral fat content.
4. Fecal Microbiome testing.
5. Immune Health Tests – including CD4/CD8 ratio, CMV IgG, TNFɑ, hsCRP, and IL-6.
6. Methylation age – clock testing (e.g. Horvath clock, GrimAge).
7. Skeletal muscle tests – including lean body mass on DXA scan.
8. Physiological data – wearable devices (steps, HRV, etc).

Rapamycin Side Effects

At high doses for medical treatments and in clinical studies, most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.

Rapamycin Drug Interactions

There are 636 drugs known to interact with sirolimus, along with 9 disease interactions, and 2 alcohol/food interactions. Of the total drug interactions, 169 are major, 459 are moderate, and 8 are minor.

Data Sources

ClinicalTrials.Gov

Drugs

Mayo Clinic

PubMed

Rapamycin, mTOR, Autophagy Treating Syndrome

Rapamycin Rap Video (this is bizarre…)

RXList

ScienceDaily

WebMD

Wikipedia

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