Research Review: PEARL Study on Rapamycin for Age-Related Healthspan Improvements

Introduction

The PEARL (Participatory Evaluation of Aging with Rapamycin for Longevity) study, launched in 2020, has since been collecting data on the effects of low-dose rapamycin in middle-aged and older adults. The study was designed to examine whether low-dose rapamycin could delay or reverse age-related changes in the volunteer participants. Over the course of 48 weeks, the study aimed to measure rapamycin’s impact on key markers of aging, including physical function, body composition, metabolic health, and inflammation. These measures were chosen because they are critical indicators of healthspan—how long a person remains healthy and independent as they age.

In this research review, Kristen Race, MS, Patient Education Specialist at Healthspan, will explore the study’s design, outcomes, and its broader significance for aging research. The review will also address key findings, including recent insights on bioavailability challenges with compounded rapamycin, as well as limitations such as the relatively small sample size. Understanding these aspects is essential for interpreting the results of this study and guiding future research.

Study Background and Objectives

The PEARL (Participatory Evaluation of Aging with Rapamycin for Longevity) study was developed to examine the impact of low-dose rapamycin on various age-related biomarkers, physical function, and quality of life. Rapamycin is an mTOR inhibitor known for its ability to modulate aging processes by reducing chronic low-grade inflammation (inflammaging), preserving lean muscle tissue, and enhancing metabolic function. The primary objective of the PEARL study was to assess whether rapamycin could delay or reverse signs of aging, with a specific focus on middle-aged and older adults over the course of 48 weeks. This study represents a significant step forward in understanding rapamycin’s potential as a therapeutic intervention for improving healthspan in aging populations, contributing critical insights into its role as a geroprotective agent [1].

Study Design

The PEARL study was a phase 2, interventional clinical trial that followed a randomized, double-blind, placebo-controlled model. It enrolled 150 healthy adults between the ages of 50 and 85, with participants randomly assigned to either a rapamycin or placebo group. Over the span of 48 weeks, the study sought to evaluate rapamycin’s effects on a range of age-related health indicators, including physical function, body composition, and metabolic health. Participants were divided into three distinct groups: one receiving a low dose of 5 mg of rapamycin per week, another receiving a higher dose of 10 mg per week, and the final group receiving a placebo. The choice of doses aimed to explore both lower and higher thresholds for rapamycin’s effects on aging processes.

Primary Outcomes Measured

The study focused on several key outcomes to determine the efficacy of rapamycin in improving healthspan. Physical function, a critical measure in aging populations, was assessed through objective tests evaluating strength, mobility, and frailty. These markers provide a comprehensive view of participants' functional independence and overall well-being as they age. Body composition was another primary measure, with changes in lean muscle mass (LMM), visceral adipose tissue (VAT), and total body fat monitored using dual-energy X-ray absorptiometry (DEXA) scans. This allowed the researchers to track whether rapamycin could mitigate age-related muscle loss and fat redistribution, two common concerns in older adults.

Biomarkers related to aging and metabolism were also measured through blood tests, which provided insights into lipid profiles (LDL, HDL, and ApoB), glucose metabolism (A1c and insulin), and inflammatory markers like C-reactive protein (CRP). These biomarkers are essential for understanding how rapamycin influences cardiovascular and metabolic health, as well as its potential to reduce inflammation—a key driver of many age-related diseases. Additionally, quality of life (QoL) was evaluated through validated questionnaires that assessed participants' overall well-being, social functioning, and pain levels, providing a subjective but valuable perspective on the drug's impact.

Secondary Outcomes Measured

In addition to the primary outcomes, the study also monitored several secondary measures. Safety and adverse events were closely tracked, including common side effects of rapamycin such as the development of canker sores. Blood safety biomarkers were regularly evaluated to ensure that liver and kidney functions remained stable throughout the study.

Another area of interest was the composition of participants' gut microbiota, given rapamycin’s known effects on the immune system. Changes in gut health are increasingly recognized as key indicators of immune function, especially in older adults. The emerging relationship between gut dysbiosis and systemic inflammation, particularly in the context of immunosenescence, underscores the relevance of this measure, particularly in aging populations.  

In addition to physical health parameters, the study evaluated cognitive function and emotional well-being using standardized assessments of memory, executive function, and mood. Given the common cognitive decline and the increased prevalence of mood disorders such as depression and anxiety in older adults, this aspect of the study offered critical insights into rapamycin’s potential neuroprotective and psychotropic effects

Dosing Adjustments and Bioavailability Challenges

During the course of the PEARL study, a parallel investigation was published that compared the bioavailability of compounded rapamycin, which was used in the PEARL study, with generic rapamycin. The findings revealed that the compounded formulation exhibited threefold lower bioavailability per milligram than its generic counterpart [2]. This discrepancy is largely attributed to the degradation of rapamycin in the acidic environment of the gastrointestinal tract, which significantly reduces its absorption and systemic availability.

Despite this limitation, the PEARL study continued with the compounded version, meaning that the 5 mg and 10 mg doses used in the study were effectively closer to 1.5 mg and 3 mg, respectively. This difference in bioavailability likely influenced the study’s results, highlighting the need for future trials to employ encapsulated formulations for improved absorption and more effective dosing strategies. These findings have practical implications for individuals considering compounded rapamycin for healthspan interventions—highlighting that compounded versions may not be ideal due to their lower bioavailability and that standardized, encapsulated formulations should be prioritized for more effective dosing strategies.

Improvements in Lean Muscle Mass and Body Composition

Despite the dosing limitations, the PEARL study produced several important findings, especially regarding body composition and lean muscle mass. Notably, women who received the higher 10 mg dose demonstrated significant improvements in lean muscle tissue, indicating that rapamycin may play a role in combating age-related sarcopenia. 

These results align with the research of Professor David Glass, which showed that intermittent, low-dose mTOR inhibition using a rapalog reduced anabolic resistance and preserved anabolic sensitivity in aging individuals. This suggests that rapamycin's ability to maintain muscle mass could be mediated by its capacity to restore mTOR sensitivity to anabolic stimuli, which typically decline with age [3]. The findings reinforce the potential of rapamycin as a therapeutic tool for preserving muscle health and improving physical function in aging populations, despite challenges related to bioavailability and dosing.

Additionally, participants across both rapamycin groups showed favorable changes in body composition, particularly with reductions in visceral adipose tissue (VAT) and increases in lean tissue mass (LTM) as measured by DEXA scans. These findings point to rapamycin’s potential as an intervention to address age-related muscle loss and fat redistribution, which are critical for maintaining metabolic health and physical function in older adults.

Impact on Metabolic Health and Inflammation

Participants in the higher-dose group also exhibited trends toward improved metabolic health. Specifically, there were indications of improved LDL cholesterol levels, gut microbiota composition, and immune readiness. While these changes did not reach statistical significance, they suggest that higher doses of rapamycin may positively influence metabolic markers and gut health, areas of growing interest in aging research. Rapamycin’s anti-inflammatory properties are also noteworthy, as chronic inflammation is a significant contributor to aging and age-related diseases. However, an interesting observation was the potential increase in A1c levels among participants, despite no corresponding increase in blood glucose levels. This rise in A1c may be attributed to increased red blood cell turnover, a known side effect in some rapamycin users, underscoring the need for careful interpretation of glycemic markers in clinical practice.

Gender-Specific Benefits

One of the most striking findings of the PEARL study was the gender-specific response to rapamycin, particularly among women. Females in the higher-dose group reported significant improvements in quality of life, including reductions in pain and enhancements in social functioning. Women also showed marked improvements in frailty measures, including mobility and muscle function. Given that women are more susceptible to autoimmune dysfunction and hormonal changes during perimenopause and menopause, these findings suggest that rapamycin may be particularly beneficial for mitigating the health impacts of these life transitions.

Safety and Adverse Events

The safety profile of rapamycin in the PEARL study was largely positive. Over the 48-week period, no significant differences in adverse events were observed between the rapamycin and placebo groups. Even at the higher 10 mg dose, rapamycin was well tolerated. The most common side effect reported was the development of canker sores, affecting about 20% of participants. While these sores were not considered a definitive sign of excessive dosing, clinical experience suggests that temporarily lowering the dose and then gradually increasing it can help alleviate this issue without compromising treatment efficacy.

Limitations and Future Directions

The PEARL study faced several limitations, including the relatively small sample size, which may have underpowered certain analyses. Furthermore, the bioavailability challenges with compounded rapamycin likely impacted the study's outcomes, emphasizing the need for future trials to use more standardized and effective formulations. Future research should also explore gender-specific dosing protocols, as the study hinted at differing responses between men and women. Additionally, there is a growing interest in exploring rapamycin’s potential when combined with other therapies, such as ketamine, for the treatment of chronic pain and depression. These combinations could offer a broader therapeutic benefit, particularly for individuals with complex health conditions.

Rapamycin for Healthspan Extension

The PEARL study contributes valuable data to the growing body of research supporting rapamycin’s role in improving body composition, metabolic health, immune function, and quality of life, particularly in women. As researchers like Dr. Matt Kaeberlein have suggested, rapamycin holds significant promise for extending healthspan, offering the possibility of an additional decade of quality living for some individuals. By reducing chronic inflammation—a key driver of many age-related conditions—rapamycin may become a cornerstone therapy in the field of longevity research. Future studies with more refined dosing strategies and larger, more diverse populations will be essential to fully understand rapamycin’s potential for extending healthspan and improving the aging process.