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 first episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, will discuss how fortuitous conversations, an appetite for unexplored territory, and an opportunity to look where others weren't looking helped him get deep into the study of rapamycin and uncover some interesting insights into how rapamycin can affect lifespan.

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!

Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle

Published in 1975, this landmark paper describes the discovery of a new antifungal antibiotic called rapamycin, and characterizes rapamycin's morphological, physiological, and cultural properties and the streptomycete strain that produces it. It detailsthe isolation of the streptomycete strain AY B-994 from an Easter Island soil sample as well as the strain's antimicrobial activity.

Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients

This 2005 paper was the first to describe the molecular pathway by which caloric restriction could influence yeast lifespan. Caloric restriction extended yeast replicative lifespan—that is, the number of times a yeast cell can divide and produce daughter cells before it stops dividing—by downregulating signaling through TOR1 and Sch9 genes. In yeast, the TOR1 gene codes for the TOR1 protein, a protein analogous to the mTOR protein in mice. Rapamycin inhibits mTOR1.

Extension of chronological life span in yeast by decreased TOR pathway signaling

This is the experiment involving nearly 5,000 yeast strains that Matt describes in the podcast.

The discovery & first uses of rapamycin | Peter Attia, David Sabatini, & Matt Kaeberlein

Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini in this rapamycin-themed episode of the Peter Attia Drive podcast. In this clip, three longevity experts dig into the history of rapamycin’s discovery. They also discuss rapamycin’s clinical path as an immunosuppressant and how that path may have impacted the development of rapamycin for other uses, the decades-long gap between the discovery of rapamycin and its eventual use in the clinic, and the difficulty of disentangling side effects that come from rapamycin use versus that of other drugs.