The PEARL trial of rapamycin was crowdfunded by Lifespan.io, something that we should see happen more often, at a much larger scale, for all of the presently available low-cost treatments that might influence aging. While results were initially published late last year, the researchers have had some months since then to refine the paper and further follow up on some of the questions raised about dosing. The compounded form of rapamycin used in the trial turns out to be much less bioavailable than the commercially produced options for this drug, which is an important point for anyone thinking about trying this themselves.
Few clinical trials to date have evaluated the effects of rapamycin and its derivatives in generally healthy individuals, and those that have been conducted are often challenged by small cohort size, short-term follow-up, or both. While the most robust of these studies have suggested improvements in age-related immune decline in healthy elderly individuals administered low-dose everolimus for 6 to 16 weeks, many questions regarding low-dose rapamycin for supporting healthy aging in normative aging individuals remain, particularly regarding the safety of long-term low-dose use. The PEARL trial represents one of the largest efforts to date for evaluating the long-term safety of low-dose rapamycin (5 mg and 10 mg once weekly for 48 weeks) for longevity in a normative aging cohort, and provides preliminary support for the suggestion that low-dose rapamycin may be useful in combating age-related decline by improving healthspan measures.
Importantly, in the midst of this trial, we learned that compounded rapamycin, which was used for this work due to placebo generation considerations, could have reduced bioavailability relative to commercial formulations. This trial was temporarily paused while we explored this possibility in an independent cohort. It was subsequently discovered that compounded rapamycin did indeed have approximately 1/3 the concentration in blood after 24 hrs relative to commercial.
The primary goal of the current study was to evaluate the relative safety of low-dose rapamycin use over 48 weeks, and to evaluate whether any clear patterns of concerning side effects emerged in a preliminary cohort. Overall, reports of adverse events (AEs) were relatively consistent across all groups. While rapamycin users appeared to have more gastrointestinal symptoms than placebo users, no other clear patterns of AEs for rapamycin users emerged. Particular attention was given to immune challenge symptoms for rapamycin users; however, overall reports of cold/flu-like illness and slowed recovery were similar across all groups.
We saw strong improvements in the secondary outcome measure of lean tissue mass, and in self-reported pain symptoms for women taking 10 mg of compounded rapamycin (equivalent to ~3.33 mgs of generic Sirolimus). We further observed modest improvements in other measures of self-reported well-being for some groups in both genders (general health and emotional well-being). These effects are largely in keeping with the suggested benefits of low-dose rapamycin use in the longevity community, and provide some measure of clinically validated support for rapamycin's reputed effects on this front despite the small sample numbers.
Link: https://doi.org/10.18632/aging.206235
View the full article at FightAging
