Study: “Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results”
Publisher: Aging
Published date: April 2025
PubMed link to study: https://pubmed.ncbi.nlm.nih.gov/40188830/
Summary of the Clinical Trial
PEARL was a Phase 2 clinical trial (NCT04488601) investigating the effects of rapamycin intervention on longevity in humans.
It was a 48-week randomized, placebo-controlled, double-blinded clinical trial aimed at evaluating the long-term safety and potential health benefits of intermittent low-dose rapamycin (5 mg and 10 mg weekly) in a cohort of healthy, normative-aging adults. The primary endpoint was changes in visceral adiposity (abdominal fat), while secondary endpoints included measures such as lean tissue mass, bone mineral density, various blood biomarkers, and self-reported quality of life assessments.
The PEARL trial concluded that low-dose rapamycin administered intermittently is generally safe and well-tolerated, showing minimal adverse events similar to placebo. Notably, the primary outcome related to visceral adiposity did not change significantly.
However, significant secondary benefits were observed for women at the 10 mg dose, including increased lean muscle mass and reduced self-reported pain. The 5 mg group showed improved general health and emotional well-being. The authors note limitations such as relatively small sample size and self-reported adherence to medication, which could impact the findings.
PoI Perspective
Low-dose Rapamycin Enhances Lean Tissue Mass and Reduces Pain in Women
The trial highlighted a noteworthy finding that intermittent low-dose rapamycin significantly improved lean tissue mass and reduced pain, particularly in women receiving the higher dosage of 10 mg per week.
Increased lean muscle mass is a crucial factor for longevity because sarcopenia (age-related muscle loss) significantly contributes to frailty, reduced mobility, higher fall risk, and decreased overall quality of life in older adults. Improved lean muscle mass directly counters these negative impacts of aging.
These findings showing rapamycin’s ability to enhance lean mass is consistent with animal studies demonstrating that rapamycin can extend lifespan, improve physical performance, and reduce frailty in mice and other model organisms. These outcomes are often attributed to rapamycin’s inhibitory effects on the mTOR (mammalian target of rapamycin) pathway. This pathway plays a central role in cellular growth, metabolism, and aging processes, with its partial inhibition associated with slowed aging and improved healthspan across multiple species.
Broader Perspective:
Previous studies in model organisms repeatedly indicate that rapamycin’s influence on mTOR signaling is beneficial for healthspan, particularly due to its role in autophagy, which is a process where the body clears damaged cells and proteins, enhancing tissue repair and regeneration. The PEARL trial’s results align with this concept that improvements in muscle mass suggest an underlying enhancement of tissue quality and regeneration capacity.
Notably, the observed reduction in self-reported pain is particularly interesting and aligns with rapamycin’s potential anti-inflammatory effects, another well-established hallmark of aging. Chronic inflammation (“inflammaging”) contributes significantly to the development and progression of multiple age-related diseases, including arthritis and sarcopenia. Thus, rapamycin’s potential to reduce chronic pain symptoms suggests its broader utility in improving quality of life through anti-inflammatory mechanisms, a hypothesis that would be of interest for future studies to explore further.
Minimal Side Effects with Intermittent Dosing
Another key point from the PEARL trial is the minimal occurrence of adverse effects observed with intermittent, low-dose rapamycin regimens.
Historically, the clinical adoption of rapamycin for longevity has been restrained due to concerns of side effects such as immunosuppression and metabolic disturbances, frequently reported in high-dose, daily regimens used in transplantation medicine. The PEARL trial demonstrates that intermittent low-dose rapamycin regimens do not significantly compromise immune function nor provoke notable metabolic disturbances over a prolonged period (48 weeks).
This finding is significant because the primary barrier to broader rapamycin adoption is precisely the potential risks associated with its chronic use, however, a longer follow up period would be more convincing.
Critical Perspective on the Trial
While the clinical trial showed some interesting findings there were also limitations that may be addressed in future research:
- Adherence to the dosing schedule in the PEARL trial was largely self-reported. Participants may have forgotten doses or taken them irregularly, potentially introducing significant variability that undermines trial validity.
- A significant limitation of the PEARL trial is the relatively small sample size (n = 114 participants who completed the study). The author’s themselves note that a larger cohort sample would be needed for definitive conclusions.
- Though relatively long for initial human trials (48 weeks), the trial duration remains limited when evaluating interventions targeting aging, which is inherently a slow and progressive process.
- Participants were described as notably “health-conscious” at baseline, with relatively good health habits and lower adiposity. Such selection bias limits the applicability of results to the general aging population.
In Summary
The PEARL trial did not meet its primary endpoint to reduce visceral adiposity (abdominal fat) through a rapamycin dosing regime, however, there were some interesting findings from the trial.
The PEARL trial supports intermittent low-dose rapamycin as a safe and potentially beneficial intervention, particularly highlighting benefits for women in muscle health and pain reduction.
In the broader context of longevity research, rapamycin continues to demonstrate promise as a potential anti-aging candidate. Although, it is clear from these results that more clinical research will be needed to establish its therapeutic potential.
Feel welcome to share your own thoughts on this research in the comment section below as well. I will be happy to discuss and learn more about how you see its potential in this field.
