Sirolimus (rapamycin)

Sirolimus, better known as rapamycin, binds the immunophilin FKBP-12 and through that complex inhibits mTOR, the central growth and nutrient sensor of the cell. It is approved as an immunosuppressant after organ transplantation, but its reputation comes from ageing research.

There the mouse evidence is unusually strong and has been reproduced independently several times. In humans it looks different, and that difference is the core of this page.

This information is for research and educational purposes only. No medical advice.

mTOR exists in two complexes. mTORC1 is the growth switch that drives cell growth and protein synthesis when nutrients are abundant, while braking autophagy, the cellular clean-up. mTORC2 matters among other things for immune function and insulin signalling.

Rapamycin acutely inhibits mainly mTORC1. Only at persistently high levels does mTORC2 get caught too, and that is exactly where the typical problems of the transplant dose come from. Weekly dosing uses the long half-life of around 62 hours to hit mTORC1 regularly while letting mTORC2 go again in between.

The difference from transplant medicine is therefore not a detail, it is the entire concept. There it is dosed daily and levels are deliberately held high, with immunosuppression as the goal. Anyone transferring the approved dose to themselves is suppressing their immune system.

In mice the evidence is extraordinary. In the Interventions Testing Program of the American ageing research institute, rapamycin extended lifespan even when started late in life: plus 14 percent in females and 9 percent in males, reproduced across three independent sites (Nature 2009).

The follow-up analysis (J Gerontol A 2011) confirmed plus 10 to 18 percent, while resveratrol and simvastatin in the same programme showed no effect at all. That matters, because the same testing system produced both results. The dose investigation (Aging Cell 2014) found plus 23 to 26 percent at triple dose, meaning a clear dose dependence.

In humans that proof is missing. The PEARL trial (Aging 2025) is the largest and longest investigation in normally ageing humans: 48 weeks, randomised and placebo-controlled. The primary endpoint, reduction of visceral fat, was missed. What PEARL demonstrated is safety over a year of weekly dosing, not benefit. Safety is not efficacy, and that sentence belongs at the start of any consideration of this substance.

• Mouth ulcers: the most common report and a direct sign of too much. Dose-dependent.
• Inhibited muscle growth: not a side effect, it is the mechanism. In a building phase you are working against your goal.
• Delayed wound healing: stop before planned procedures.
• Shifts in the lipid profile: cholesterol and triglycerides can rise.
• Immunosuppression: real with daily dosing or too high a weekly dose. The approved dose is made for exactly that.
• Interactions: runs through CYP3A4, correspondingly sensitive to grapefruit and some antibiotics and antifungals.

Store dry, at room temperature and protected from light. Keep out of reach of children.