Rapamycin In Aging And Disease: Maximizing Efficacy While Minimizing Side Effects
Research Summary
A short research perspective by two ageing researchers. It argues that, now that rapamycin’s lifespan and healthspan effects in mice have been repeated by many groups, the key question for translation is how to get the benefits while reducing side effects. The authors use their own mouse work on mitochondrial disease to show how much dose and delivery method matter.
Who Or What Was Studied?
The article reviews published mouse lifespan studies and summarises the authors’ earlier work in Ndufs4 knockout mice, a model of Leigh syndrome (a severe mitochondrial disease). It compares rapamycin given in food as an encapsulated form (eRAPA) with daily injection into the abdomen (intraperitoneal).
What Did The Research Show?
- Most mouse ageing studies used one dietary dose, 14 ppm eRAPA. The one partial dose-response study found 42 ppm extended lifespan more than 14 ppm, and 4.6 ppm less.
- Daily injection of 8 mg/kg rapamycin had earlier more than doubled survival in the Ndufs4 knockout mice.
- Dietary doses similar to those used in lifespan studies had no effect in these mice; the authors estimate that about 378 ppm eRAPA, roughly 27 times the usual dose, is needed to match the injected dose.
- Transplant patients on rapamycins can develop mouth ulcers, low platelets, raised triglycerides and cholesterol, and poor wound healing; lifespan doses in mice can cause altered glucose tolerance, gonadal atrophy and cataracts.
- Female mice generally respond more at lower doses, which the authors attribute mainly to greater sensitivity to the drug.
Limitations And Interpretation
- An opinion piece, not a new trial; most supporting data are from mice.
- Dietary and injected rapamycin have different blood and tissue levels, so the doses are not directly comparable.
- Studies of short-term or intermittent dosing were described as ongoing and unpublished at the time.
Summary prepared from the published paper (abstract and full text where accessible). This is not medical advice — always consult the original publication.