Rapamycin has been shown to have longevity-enhancing effects in murine models, but clinical data on its gerotherapeutic effects in humans remains limited. We performed a 48-week double-blinded, randomized, and placebo-controlled decentralized study (Participatory Evaluation of Aging with Rapamycin for Longevity [PEARL]; NCT04488601; registration date 2020-07-28) to evaluate the safety and efficacy of rapamycin in mitigating clinical signs of aging in a normative aging cohort. Participants received 5 or 10 mg / week of compounded rapamycin, or placebo for 48 weeks. Safety, adverse events (AEs) and blood biomarkers were collected. Efficacy was assessed using DEXA scan-based measures and standardized surveys assessing quality of life (QoL) and frailty. We did not detect significant differences in safety blood biomarkers, or moderate to severe AEs between the rapamycin treatment groups and placebo after 48 weeks. We detected dose-dependent (10 mg group) and sex-specific improvements in lean tissue mass, pain, social functioning, overall QoL, and overall osteoarthritis score in females, and in bone mineral content in men. Additionally, some individuals receiving rapamycin experienced significant improvements in body composition metrics that were associated with beneficial changes in gut health and lipid metabolism. We conclude that low-dose, intermittent rapamycin administration over the course of 48 weeks is safe and induces sex-specific improvements in multiple aspects of healthspan, with the most robust improvements in lean tissue mass in women taking 10 mg rapamycin/week. Future work will aim to identify biometric signatures of clinical effectiveness to inform personalized treatment strategies that more broadly maximize efficacy and minimize side effects.
There was a difference in bone mineral density (DEXA) between placebo and 10mg compounded rapamycin in male subjects.
I suspect the compounded rapamycin was kind of a trash intervention in terms of the effective dose being tested. Consider their updated protocols to get a sense of how effective they think their compounded rapamycin is:
Our protocol is:
Generic tabs: start 2mg (1 tab) the first 4 weeks, then 4mg x 4wks, then 6mg/wk thereafter
Compounded: start 5mg x4wks, then 10mg x4wks, then 15mg there after
If they effectively tested 2mg per week and 4mg per week then just by body weight it would make sense the 4mg per week equivalent would be in the effective range for women on average but not for men. (Remember they are testing for a significant average effect.)
I guess we have to wait until August 27 for the positive spin version from the AgelessRX team, but that’s my conclusion. They just didn’t test a dose high enough to answer the questions we’re all navel gazing about on here. If they had equivalents of generic tablet 6mg and 8mg in addition to the 2mg and 4mg they seem to have tested, then we’d be in business.
That said, I imagine it’s helpful to have a 48 week trial showing no AEs at the doses tested to lay groundwork for the choice to test higher doses.
The dose that worked in women at 10mg is actually equivalent to 2.9mg if you are using rapamune, zydus, or rapacan.
From the preprint:
Across all measures in this study, a remarkable level of variability in response was
observed for all rapamycin users, regardless of dose. Given our recent work on the variability of
rapamycin bioavailability in individuals, we expect that it played a meaningful role in the results
observed here, though this trial concluded prior to our findings on bioavailability. Further, we
have discovered since the conclusion of this trial that compounded rapamycin is approximately 3.5x less bioavailable than commercially available formulations, suggesting that the 5mg and
10mg rapamycin groups received an average equivalent of 1.4mg and 2.9mg respectively [48].
Although both doses are relatively low, making the observation of benefits in the treatment
group more striking, the 10mg rapamycin cohort in this study was more firmly in the range of
what is thought to be an optimal longevity dose range for rapamycin [8, 41, 47, 54]. While
future studies will be necessary to draw clear conclusions on whether even higher doses lead to
improved effects, we expect that this is a key factor in the often stronger and more reliable
patterns of improvement seen for the 10mg rapamycin cohort relative to the 5mg cohort. We
highlight this to emphasize the importance of personalized rapamycin dosing and continual
routine monitoring of blood rapamycin levels in users to ensure maximal benefits, until such
time as the optimal longevity dosing dynamics for rapamycin are more clearly understood.
Can anyone let us know why they don’t test the bioavailability of the compound before they test it? Seems counter intuitive to not know before hand exactly how much each participant was receiving.
Fair enough, although to my mind, wouldn’t you check for that first off, regardless, just to know that everyone is on the same page, just to get a baseline, especially after the ITP brouhaha, where they had to fight to get rapa into their mice systems… that would make me double paranoid when designing a trial using compounded rapa, rather than tried and true pharma versions. But maybe I’m overthinking it.
People have been using rapamycin for the past 20 years. It’s not obvious to me we would need to double check bioavailability. Maybe the compounded options are new and not well validated.
It seems that they used too low of a dose to be able to see anything in men and that they started to see some benefits in women (who respond better at lower doses) at 10 mg. I think this makes a strong argument for a higher dose of Rapamycin being used for average-sized men (14-20 mg equivalent weekly) and women (10-15 mg equivalent weekly). It may generate more side-effects but you also get the benefits. If your dose is too low, you’re just wasting your time, IMHO.
For me, I have found a sweet spot at 5 mg + GFJ (17.5 mg equiv) weekly dose. Once I go to 6 mg +GFJ (20 mg equivalent), hives start popping up and at 7 mg + GFJ (25 mg equivalent), it’s like I sat naked in a horde of mosquitoes.
Though the study is on healthspan, it will be more inspiring to measure the aging factors to see if the value goes back to youth.
The GlyNac clinc trial measures the length of telomeres of the subjects and finds a few weeks of taking 8mg NAC and 8mg Glycine made the telomeres length increase very noticeable.
This is my first comment on the trial. I will write a more deeper post later on.
Really great work with getting the results published as a preprint! It’s lots of hard work behind so big thumbs up for that! I will write down more of my thoughts around the trial after the PEARL trial webinar on 27th of August. The probably most important thing to point out in this trial to begin with is that it’s a very low dosing. The highest dosing schedule which is 10 mg/weekly is equivalent to around 3 mg/weekly of generic rapamycin. It’s few males that take such low doses of Rapamycin but I know there are females who take that dose. Females mice as you mentioned seem to respond better on low doses than male mice. This has also been seen in the ITP where the lowest dose of Rapamycin tested was 4.7ppm and the result was median lifespan 17% in females and 3% in males and maximum lifespan 14% in females and 6% in males (pubmed: 22587563).
It’s really great also that we now have even more data on that Rapamycin is well tolerated even if it’s on very low doses. This trial is a very important milestone in the field and step by step more data will come from AgelessRx. One thing I really like with that longevity clinic is that they try to push longevity research forward and they are not afraid of sharing the data. So more clinics should inspire from this approach and by that we increase the chances of living a longer and healthier life!
