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 this second episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, discusses his own journey to using rapamycin off-label and how it all began with a persistent pain in his right shoulder that a doctor suggested might take a year to resolve. Matt conducted an n=1 experiment to test whether a short course of rapamycin might improve the age-related inflammation that was the likely cause of his shoulder issue.

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!

mTOR is a key modulator of ageing and age-related disease

This paper reviews the mechanistic target of rapamycin (mTOR) pathway, a nutrient sensing pathway that shows promise as a target for interventions to increase life- and healthspan. The mTOR pathway acts as a control center that helps cells decide what to do based on the nutrients available. When nutrients are abundant, mTOR tells cells to grow and divide; when nutrients are scarce, it signals cells to conserve energy and not grow too much. The article delves into the mechanisms by which the mTOR pathway influences longevity, including mRNA translation, autophagy, stress resistance and xenobiotic metabolism, mitochondrial function, inflammation, and stem cell rejuvenation.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

The age-associated decline in function of hematopoietic stem cells (HSCs), cells in the bone marrow that give rise to all types of blood cells in the body, can lead to issues such as anemia and increased cancer risk. This study demonstrates that the mTOR pathway in HSCs is more active in older mice than in younger mice, and that activating this pathway accelerated HSC aging in young mice. Treating older mice with rapamycin, an mTOR inhibitor, extended their life- and healthspan. Taken together, these findings provide further evidence to suggest that the mTOR pathway plays a key role in aging.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This study found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more

In this episode of the Peter Attia Drive podcast, Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini to talk about the discovery of rapamycin, its first uses in humans, the mTOR pathway, potential mechanisms by which rapamycin might influence human longevity, recent studies of the effects of rapamycin in model organisms, potential side effects, and more.