Here’s what we’ll cover in this blog post:
- What is the PEARL trial
- What are the results of the PEARL trial
- What the results mean
- What’s next for Rapamycin research
After a year-long trial and years of careful analysis, the results of the PEARL trial are finally here!
The PEARL trial, which is the first nationwide telemedicine trial, is also one of the largest and longest randomized control trials testing Rapamycin for healthy human aging.
Led by AgelessRx and supported by Lifespan.io, with the University of California, the PEARL trial is among the first of its kind, providing scientists with valuable, real-world data to expand research into Rapamycin.
So, what are the results of the PEARL trial? Is Rapamycin safe and effective for human longevity, and what does this mean for the future of Rapamycin research?
Here, we’ll summarize the discussion from our PEARL webinar, where our experts and partners answer all these questions and more.
Setting the Stage for PEARL
In recent years, Rapamycin has been championed by researchers and longevity enthusiasts alike for its potential as a gerotherapeutic agent. That’s because Rapamycin has improved the lifespan of every organism that researchers have tested thus far, including yeast, worms, mice, and monkeys. As Dr. Matt Kaeberlein describes, “it really is the gold standard for pharmacological interventions that can positively modulate the biology of aging.”
The only problem? There’s very little research and clinical studies on longevity doses of Rapamycin in humans. That means researchers don’t know what dose is best to promote healthy aging and functioning while minimizing side effects.
Of the few clinical trials with Rapamycin in humans, one of the most significant was a 2014 study led by Joan Mannick, in which researchers showed that Everolimus, a derivative of Sirolimus, improved the immune system of elderly patients.
This, in part, led to growing interest in the longevity community. However, there weren’t many other studies supporting proper prescription or dosing, and some within the clinical and scientific community had concerns about its safety.
All these questions and concerns are what led to the PEARL trial, which was conceived to provide some of the first science-backed answers to these questions.
What Is the PEARL Trial?
The PEARL trial (Participatory Evaluation of Aging with Rapamycin for Longevity) is a randomized, double-blind, placebo-controlled clinical trial studying the safety and efficacy of Rapamycin for healthy aging
The trial was organized by AgelessRx, Lifespan.io, and the University of California, with the primary goal of exploring various dosing options for Rapamycin, assessing side effects, and determining overall safety. It’s notable as one of the largest and longest randomized control trials for Rapamycin in human aging, as well as one of the first crowd-funded clinical trials.
PEARL is among the largest and longest studies on human Rapamycin use currently available. While other studies have been short and narrow, the PEARL trial analyzes a broad range of healthspan metrics in aging individuals, providing real-world human evidence.
The study followed 114 healthy individuals aged 50-85 over a period of 12 months, starting before the pandemic. Some individuals received 5-10mg of Compounded Rapamycin once weekly, which is equivalent to 1.4-2.9mg of Generic Rapamycin. Other participants received a placebo.
Researchers observed the participants for evidence of side effects or adverse reactions, like changes in blood biomarkers for cholesterol, sugar metabolism, inflammation, and liver and kidney function.
The participants also went through regular testing for additional health and quality of life benefits, including DEXA scans measuring body composition changes, lean muscle mass, bone density, and visceral fat.
The key questions that PEARL aimed to answer were:
- How safe and well-tolerated is Rapamycin?
- What is the optimal dose for slowing age-related decline?
- Are there sex-specific differences?
- Does Rapamycin show potential as an effective healthspan-enhancing intervention in normal, aging adults?
Because all the participants were longevity enthusiasts who were interested in Rapamycin, the average baseline health was higher than normal for this trial. Still, the results showed noteworthy changes, even among a group that was already quite healthy.
What Are the Results of the PEARL Trial?
Overall, the results from the PEARL trial were just as reaffirming as they were surprising, though there was also a substantial variability in some of the results. Here are the key findings that our partners and resident experts noticed during the PEARL trial:
Rapamycin’s effects on visceral fat
Loss of visceral fat was one of the primary clinical endpoints for the PEARL trial.
Though there were no statistically significant differences to visceral fat by the end of the trial, those who took Rapamycin were more likely to lose visceral fat than those in the placebo group. After 48 weeks, more participants in the Rapamycin groups lost visceral fat than in the placebo groups. But researchers need more data to determine whether Rapamycin is truly effective at reducing visceral fat content.
Rapamycin is safe
The PEARL trial successfully showed that Rapamycin is a safe and well-tolerated drug when taken at low doses with intermittent (weekly) administration.
There were very few individuals who displayed adverse events or side effects in the Rapamycin group compared to the placebo group. Of the side effects that participants did experience, mild gastrointestinal issues were the most common.
May boost lean muscle mass
DEXA scans helped reveal several body composition benefits for Rapamycin. Chief among these was a statistically significant improvement to lean muscle mass, specifically in women taking the 10mg dose.
That means Rapamycin may help boost or maintain overall muscle mass. As Dr. Kaeberlein noted during the study, “the one piece of data that jumps out to me is the change in lean mass. These results seem real to me.”
Bone mineral content & density
This is where the benefits showed the most inconsistency and variability. Members of all groups saw both increases and decreases to bone mineral content and bone mineral density, regardless of sex or dose.
Men in the 10mg group saw the most improvement, but not all men saw the same benefits, and none were statistically significant. Further, the age range of the participants may have affected the results, as bone degeneration and osteoporosis are especially prevalent in post-menopausal women. It’s also possible that such benefits may take much longer to fully materialize.
Quality of life & joint health
Participants took several self-reported surveys, including the SF-36 for quality of life, and WOMAC for joint health and mobility.
Because most were already quite healthy, most of the quality-of-life results weren’t statistically significant, but there were still some improvements in all groups over the trial period, with women seeing the most benefits. Women in the 10mg group showed a statistically significant improvement in self-reported pain, which is consistent with previous reports on the effects of Rapamycin. There were also noticeable improvements in the 5mg Rapamycin group for general health and emotional well-being, neither being gender specific.
Results for group WOMAC scores were largely underwhelming, however, as there were no statistically significant differences between treatment groups and placebo for any of the measures including physical function, stiffness, or pain.
Sex-specific differences
Of all the benefits mentioned above, women participants showed the most benefit overall, especially for the 10mg dose.
This was especially true for benefits to lean muscle mass, where all women in the 10mg group saw significant improvements. Women also saw better results across measures of pain, with the 10mg female group exhibiting the strongest self-reported benefits in this measure.
However, the PEARL trial had much fewer women participants than men, with only eight women in the 10mg group. Further, it’s not clear if men could benefit from higher doses, which would suggest patients may need unique and personalized dosing protocols to see the best benefits. Because we haven’t seen a correlation with weight, height, or BMI with how one responds to Rapamycin in any of our studies, there could be underlying biological factors that inform this difference, beyond a size difference between men and women.
Still, this could be evidence that Rapamycin benefits may be more pronounced in women than in men.
What Do These Results Mean?
So, what can we take away from the PEARL trial? As a safety and efficacy trial, the PEARL trial shows that Rapamycin, when taken weekly for one year, is safe for healthy adults to take for longevity. It also shows that Rapamycin may be able to reduce some aspects of age-related decline in generally healthy adults.
But we’ve only just taken our first steps into the world of human Rapamycin testing. That means it’s still too early to draw any certain conclusions from the results of the PEARL trial, and still too early to assume that any of these findings are certain benefits of Rapamycin. However, we need more rigorous clinical trials that independently validate and expand on results from the trial.
The PEARL trial is also setting the stage for myriad follow-up studies, providing a foundation for other researchers to build upon. That’s the true value of the PEARL trial: blazing a trail for other researchers to follow and expand, so we can confirm once and for all whether all the longevity potential seen from Rapamycin in animal studies can be translated to humans.
How PEARL Was Funded, and What Comes Next
PEARL wasn’t just an academic exercise; it was made possible in large part through a crowdfunding campaign organized with Lifespan.io, which raised well over $180,000 from members of the longevity community. That grassroots support helped get one of the largest human Rapamycin trials off the ground, and the trial itself is registered as an official study on the U.S. National Library of Medicine’s ClinicalTrials.gov, where anyone can review the protocol and eligibility details firsthand.
With results now in hand, the team behind PEARL is looking to build on this foundation. Plans include expanding biobanking efforts to study biomarkers of aging more closely, gathering additional Sirolimus blood level data from people who have continued their Rapamycin prescriptions, and exploring whether Rapamycin may help support weight maintenance for people tapering off other treatments. Researchers also had to stop routinely checking Sirolimus levels partway through the trial, since doing so risked revealing which participants were on Rapamycin versus placebo, a good reminder of how many practical details go into designing a rigorous, blinded study.
Generic vs. Compounded Rapamycin: What’s the Difference?
Rapamycin, Sirolimus, generic, compounded: it’s easy to see how the terminology can get confusing. Sirolimus and Rapamycin are effectively interchangeable names for the same medication, but the way it’s dispensed can differ. Generic Rapamycin is pre-manufactured, meaning a pharmacy can fulfill a prescription right away, typically starting around 2mg per week and adjusting over time at a prescriber’s discretion. Compounded Rapamycin, on the other hand, is prepared fresh by a compounding pharmacy for each prescription, which allows for more customized, individualized dosing, often starting closer to 5mg per week.
Neither option is inherently better than the other. The right choice often comes down to personal preference and how a prescriber wants to approach dosing, since researchers are still working to understand whether the body absorbs generic and compounded formulations differently, which brings us to bioavailability.
How Much Rapamycin Actually Reaches Your Bloodstream?
To help answer that absorption question, the AgelessRx Applied Science team ran a dedicated bioavailability study comparing generic and compounded Rapamycin. The findings suggest both formulations are absorbed into the bloodstream, which helps address earlier concerns about compounded Rapamycin’s quality and potency. However, generic Rapamycin appeared to produce roughly three times higher blood levels than the same dose of compounded Rapamycin, and blood levels varied widely even among people taking an identical dose of the same formulation.
Rapamycin blood levels also appeared to peak around day two after dosing and were largely cleared from the blood by around day six, information that may help inform weekly dosing schedules. Because individual responses can vary so much, this research points toward the value of measuring blood levels and working with a prescriber to personalize an off-label Rapamycin protocol for healthspan support, rather than assuming one dose works the same for everyone.
Understanding Sirolimus Blood Level Testing
Because Rapamycin and Sirolimus are the same medication, Sirolimus blood tests are the clearest available way to see how a person’s body is processing Rapamycin. AgelessRx routinely includes Sirolimus testing as part of ongoing labs for people on a Rapamycin protocol, both to help monitor safety and to contribute to the broader research effort on how differently people absorb and metabolize the medication.
It’s worth setting expectations here: at this stage, Sirolimus levels are used mainly as a safety and research tool rather than a lab value with an established “ideal” target, so results don’t typically lead to an immediate change in someone’s protocol on their own. Taking Rapamycin around the same day and time each week can help produce more consistent, comparable blood level results over time, which is part of why prescribers often recommend a set weekly routine.
Practical Tips for Taking Rapamycin
Beyond the clinical trial data, AgelessRx prescribers have picked up some practical, everyday guidance for people taking Rapamycin. Grapefruit juice is one to watch closely, since it may interfere with how Rapamycin is metabolized and could lead to higher-than-intended levels in the bloodstream. Rapamycin can generally be taken with or without food, but staying consistent, and taking it around the same day and time each week, may help support more predictable absorption. Many people also prefer to take their weekly dose on a rest day, since Rapamycin may temporarily blunt some of the benefits of resistance training. Regular blood work and paying attention to slow-healing cuts or sores are also commonly recommended, since some people may be more prone to minor infections when first starting treatment.
On the question of dosing schedules, weekly administration currently has the most support behind it, including from research on Rapamycin analogs showing improvements in immune-related measures with consistent weekly dosing. Some in the longevity community instead try scheduled breaks from Rapamycin, such as cycling weeks on and off, but there currently isn’t clinical data confirming whether this approach offers any advantage over continuous weekly dosing. As with any Rapamycin protocol, this is a conversation worth having directly with a prescriber, who can help weigh personal health goals against what the current research does and doesn’t support.
Could Rapamycin Support Heart Health in Dogs?
Rapamycin research isn’t limited to humans. The Dog Aging Project, led by longevity researcher Matt Kaeberlein, has been studying Rapamycin’s effects in pet dogs, with early, preliminary findings suggesting it may help ease pain and stiffness in older dogs. Researchers are now also looking into whether Rapamycin could support cardiac function in dogs, since heart disease is a common concern that can affect an aging dog’s mobility and quality of life.
The TRIAD trial was designed to look at this question more directly, studying dogs in their own homes to get a real-world sense of how Rapamycin may affect canine heart health over time. This research is still ongoing and is intended to inform veterinary understanding, not to serve as guidance for treating a specific pet; anyone considering Rapamycin for a dog’s heart health should talk with their veterinarian first. Interestingly, some researchers see this dog-focused research as a helpful complement to human studies like PEARL, since both are exploring how the same medication may support healthy aging in a living-at-home, real-world setting.
Rapamycin and Fertility Research
Fertility naturally declines with age, largely due to a gradual decrease in ovarian reserve, the limited supply of eggs a person is born with. Researchers have been exploring whether Rapamycin could help slow this process. A 2018 study found that daily Rapamycin appeared to delay ovarian aging in mice, and a follow-up human study, registered on ClinicalTrials.gov, gave a weekly dose of Rapamycin or a placebo to a small group of perimenopausal participants ages 35 to 45.
Early results from this first phase suggested that those taking Rapamycin lost fewer primordial follicles per cycle compared to reported averages for their age group, hinting that Rapamycin may help preserve ovarian reserve over time. That said, this research is still in an early, exploratory phase with a small group of participants, and Rapamycin is not an approved or recommended fertility treatment. It is not a substitute for established options like IVF or hormone therapy, and its safety during pregnancy or breastfeeding has not been established, so it should not be taken by anyone who is pregnant, trying to conceive, or breastfeeding.
A Brief History of Rapamycin
Rapamycin has a surprisingly natural origin story. In 1964, researchers traveled to the remote Rapa Nui (Easter Island) to study why its inhabitants rarely developed tetanus despite frequent exposure. Soil samples collected during that trip eventually led to the discovery, in 1969, of a naturally occurring compound produced by a soil bacterium, later named Rapamycin after the island itself. By the late 1980s, scientists were studying Rapamycin as an immunosuppressant for organ transplant patients, and it was approved by the FDA for that use in 1994.
Around that same time, researchers discovered that Rapamycin acts on a previously unknown protein complex, later named mTOR, which plays a central role in cellular growth and aging. That discovery opened the door to decades of healthspan-focused research: a 2009 study found Rapamycin was the first compound shown to extend lifespan in mammals even when started later in life, a 2010 study reported fewer cognitive deficits in a mouse model of Alzheimer’s disease among Rapamycin-treated mice, and a 2014 study suggested Rapamycin may help support immune function in older adults. That body of research, built up over decades, is part of what eventually led AgelessRx to help launch the PEARL trial.
What’s Next for Rapamycin Research?
The PEARL trial establishes one of the first safety and efficacy profiles for Rapamycin in humans, which researchers can use as a basis for future studies. Now, other scientists will have more information to optimize the design of future studies and build upon the results of the PEARL trial.
From there, more and more studies on Rapamycin can be funded, in turn expanding access to this potential longevity-enhancing medication.
It’s true, though, that plenty of questions remain for Rapamycin. We have evidence that it’s safe, and likely effective for some users; we just don’t fully understand why. That’s why we’re planning our own follow-up studies in the coming months.
Our Applied Science department is currently organizing a longitudinal study of Rapamycin. Using the telehealth data provided by approving participants, our experts will observe any reported benefits and monitor the overall, long-term experience. This will help us understand what dose and regimen is best for Rapamycin, and whether benefits build and improve over time.
If you’d like to learn more about Rapamycin and see if it’s right for you, get started with a free visit with one of our prescribers today. Your experience could help shape the future of Rapamycin research.
FAQs
What made the PEARL trial different from other Rapamycin studies?
Unlike earlier studies, the PEARL trial was one of the first large-scale, long-term, placebo-controlled trials testing Rapamycin specifically for healthy aging—not for disease. It also used a telehealth model, involved a relatively healthy, aging population, and was partially funded by the longevity community, making it one of the most accessible and real-world relevant trials to date.
Did PEARL find the “best dose” for Rapamycin?
No, the results support the need for personalized dosing based on age, sex, goals, and tolerance.
What’s the biggest limitation of the PEARL trial?
Sample size and duration. Though large for a longevity trial, PEARL still had limited statistical power for some outcomes, especially sex-specific results. Some aging-related benefits may take longer than 12 months to show up clearly. Therefore, more additional research is needed to expand upon the potential longevity benefits of Rapamycin.
Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
All information as presented here is sourced from the AgelessRx PEARL Trial Results Webinar, hosted August 27, 2024, unless another source is provided.