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 the fourth episode of the R-Files, Matt discusses research demonstrating that rapamycin rejuvenates the aged mouse immune system to respond to a flu vaccine as if it were in a youthful state. He also discusses papers suggesting that rapamycin may have similar effects on human immune systems.

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 fed late in life extends lifespan in genetically heterogeneous mice

This is the study that Matt describes at the beginning of this episode as one of the first demonstrations of lifespan extension via a treatment that starts in middle age. Researchers 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.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

Lots of big immunology words in this one—thankfully, Matt breaks them down for us in the podcast. This paper focuses on mouse hematopoietic stem cells (HSCs), which are cells that give rise to all types of blood cells. It describes two core findings that, taken together, strengthen the evidence for the role of mTOR (mammalian target of rapamycin) signalling in HSC aging. First, genetic manipulation in young mice over-activates mTOR activity and leads to an aged mouse HSC phenotype; and second, rapamycin rejuvenates HSC function, improves vaccination response, and increases lifespan.

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, validating previous work on this question.

TORC1 inhibition enhances immune function and reduces infections in the elderly

This paper investigated the effects of rapamycin treatment on elderly humans. It found that a rapamycin derivative improved vacination response and decreased infection rates in healthy people over 65, with minimal adverse effects.

Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

This study describes a clinical trial of an oral mTOR inhibitor’s effects on antiviral immunity in people aged over 65. Patients who took the drug demonstrated a greater upregulation of antiviral responses compared to those who took a placebo drug. Those receiving the mTOR inhibitor also suffered from fewer respiratory tract infections, including coronavirus, rhinovirus, and the flu.