The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In our fifth episode of the R-Files, Matt shares insights from his recent course of off-label rapamycin use, which he started in January 2024 and plans to continue for at least the next month or two. He describes improvements in joint pain and body fat loss as well as an unexpected bacterial infection, and speculates about whether rapamycin may have contributed to any of these effects. He also discusses rapamycin's half-life in his blood, which is significantly lower than that reported in the published literature.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients

Sirolimus is the common name for the pharmaceutical formulation of rapamycin, so for our purposes we can consider sirolimus and rapamycin to be interchangeable. This paper reports an elimination half-life of 63 hours for sirolimus, which means it should take around 63 hours for the concentration of the drug in the bloodstream to decrease by half. After another 63 hours, half of the remaining drug should be eliminated, and so on, until the drug is cleared from the body. The half-life of a drug can vary depending on factors such as an individual's metabolism, the route of administration, and whether an individual takes the drug regularly, and is an important pharmacokinetic parameter that helps determine dosing frequency and duration of action.

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

This paper reports a rapamycin half-life of 58–63 hours, or around three days.


Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

This study found that administering a single dose of rapamycin to rats was enough to inhibit their food intake and daily weight gain in the first three to five days post-injection, with a greater reduction observed for higher rapamycin doses. The rapamycin dose also brought about a body weight reduction that lasted for about two months without any additional rapamycin injection. The authors speculate that the effect may be due to a rapamycin-induced change in body weight set point. A single rapamycin dose did not induce any glucose tolerance changes in the rats.


Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats

This study also reported inhibited food intake and weight loss in rats receiving rapamycin, but found that rapamycin also brought about various metabolic defects including glucose intolerance (difficulties metabolizing glucose), hyperinsulinemia (too much insulin in the blood), and hyperglycemia (too much sugar in the blood). These defects were particularly pronounced in rats eating a high-fat diet.