Abstract
Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11357-023-00818-1.
Keywords: Sirolimus, Healthspan, Rapamune, Side effects, Aging, COVID-19, SARS-CoV-2, Longevity
Introduction
Geroscience is a rapidly emerging field that aims to better understand the mechanisms linking biological aging with age-related functional decline and disease [1–3]. Several hallmarks or pillars of aging have been identified that contribute to or reflect biological aging. Interventions targeting these hallmarks of aging are being developed for potential clinical application to increase healthspan and delay the onset of age-related morbidities [4–7]. The long time frames and large cohort sizes required to demonstrate efficacy in clinical trials evaluating age-related endpoints in otherwise disease-free adults are a particular challenge associated with development of novel geroscience therapies [8, 9]. A variety of strategies are being applied to address this challenge, including combining multiple age-related diseases into a single composite endpoint, development of biomarkers or biological aging “clocks” that may one day serve as surrogate endpoints, and targeting individual age-related disorders using traditional clinical trial structures.
Repurposing and off-label use of drugs already approved by the US Food and Drug Administration (FDA) has become a popular approach in translational geroscience [6, 10, 11]. Among the FDA-approved drugs being used in this way are metformin and rapamycin (sirolimus, Rapamune). Both agents have been reported to extend lifespan and healthspan in laboratory animals and are being actively tested in geroscience clinical trials. Based on early data and what appears to be a relatively modest side effect profile, some physicians have begun prescribing these medications off-label for putative healthspan-promoting benefits. While there is no concrete data on the prevalence of off-label use for such medications, metformin is likely more commonly used in this manner compared to rapamycin, both because it is a more widely known drug and is perceived as comparatively safe. Off-label use of rapamycin has been gaining increasing attention, however, due to its efficacy and reproducibility for longevity and healthspan extension in preclinical studies [12, 13].
Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR), and has been shown to increase lifespan in laboratory organisms including yeast [14, 15], nematode worms [16], fruit flies [17, 18], and mice [19–29]. In addition to increasing lifespan, rapamycin has numerous healthspan benefits in rodents such as lower cancer incidence [20, 30], improved cognitive function [31, 32], improved kidney function [33], preservation of tendon [34], improved intestinal function and reduced gut dysbiosis [28, 35], preservation of ovarian function [36], and protection against hearing loss [37]. Transient treatment with rapamycin in middle age is sufficient to robustly extend lifespan in mice [28] and reverse a subset of age-related declines including in the heart [38–40], immune system [41], and oral cavity [42, 43]. Initial evidence supports the idea that rapamycin or rapamycin derivatives (rapalogs) may have similar beneficial effects on aging heart in companion dogs [44] and restoration of age-related declines in immune function in older adults [45, 46].
Rapamycin (used clinically under the name sirolimus) is FDA approved for kidney transplant rejection, for use in cardiac stents, and for the treatment of patients with lymphangioleiomyomatosis [47]. Dosing in this context is generally 6–15 mg loading dose followed by daily dosing of 2–5 mg/day. Side effects in these patients include dyslipidemia, mouth sores, thrombocytopenia, leukopenia, and diarrhea [48]. Rapamycin is commonly referred to as an immune suppressant [49]; however, other studies suggest that rapamycin and rapalogs also have the ability to boost at least some aspects of immune function at different doses and delivery schedules [45, 46, 50, 51]. For example, once weekly dosing of the rapalog everolimus (RAD001) at 5 mg/week for 6 weeks was found to boost influenza vaccine response in otherwise healthy older adults without significant side effects [45]. Likewise, few side effects appear to be associated with lower-dose, short-term rapamycin use in healthy adults [52], but safety concerns about off-label use of rapamycin persist within the clinical and regulatory community.
In order to begin to capture real-world data on people using rapamycin off-label for putative healthspan-promoting benefits, we established an online data bank where people could self-report their experiences taking rapamycin. The project was open to both current and prior users of rapamycin as well as individuals who had never used rapamycin. Between March and June 2022, a total of 505 people completed the entire survey, of whom 333 had taken rapamycin and 172 had not. Here, we provide an overview of the results obtained from this study.
Methods
Survey design and collection
The study was approved by the University of Washington Institutional Review Board (STUDY00014726). Participants were recruited to the study by direct email from participating physicians, through social media posts, via targeted recruitment within rapamycin user groups such as the Rapamycin Users Facebook page and the Rapamycin News website (https://www.rapamycin.news/), word of mouth, and the study website. Prior to accessing the survey modules, participants were required to provide a working email address and complete an Informed Consent via DocuSign. Participation in the study was available to anyone with an active email account and internet connection from March 1, 2022, through June 30, 2022.
A HIPAA-compliant web-based survey system was constructed consisting of 10 survey modules, each expected to require less than 10 min to complete. The survey modules consisted of questions designed to obtain data about participant demographics, perceived health status, rapamycin usage, medical and dental history, and overall quality of life. The modules and the order in which participants took them are shown in Table 1.
Table 1.
Description of survey modules used in the UW Rapamycin Study
| Survey module | Purpose |
|---|---|
| 1. Demographics | Obtain basic information about each participant |
| 2. Rapamycin use history | Obtain information about prior use of rapamycin or other mTOR inhibitors |
| 3. Experiences with rapamycin | Obtain participant perception on quality of life factors since taking rapamycin |
| 4. Recent health history/potential side effects | Obtain information about perceived overall health and specific health experiences over the past 3 months that might be side effects of rapamycin use |
| 5. 10-year reflection | Obtain participant perception of current health status compared to 10 years ago |
| 6. Sleep quality | Obtain information about sleep quality |
| 7. Immune status | Obtain information about immune function |
| 8. COVID-19 | Obtain information about SARS-CoV-2 exposure, infection, and severity |
| 9. Medical health | Obtain basic information about medical care and conditions |
| 10. Oral health | Obtain basic information about oral health care and conditions |
Upon completion of the Informed Consent, participants were randomly assigned a unique 6-digit identification code that was required to access the survey modules and were also provided a direct URL to access Module 1 of the survey. Upon completion of each Module, participants were automatically directed to the next Module in numerical order. If participants indicated in Module 2 that they had never taken rapamycin, they were automatically directed to Module 4 and did not complete Module 3. Participants were not required to complete all modules in one sitting and received at least two email reminders if they had completed some, but not all, modules. Only those participants who completed all of the offered modules were included in the analysis. A dedicated study coordinator was available by email to answer any questions that participants had throughout the entire process from Informed Consent through survey completion. The results presented here correspond to data from Modules 1–4 and the COVID-19 module (Module 8). Analysis of results from the other modules will be presented elsewhere.
Statistical analysis
For comparison of potentially negative health conditions experienced in the past 3 months by survey respondents, only rapamycin users who had been taking rapamycin for at least 90 days (n = 245) were included in this analysis along with all non-users who completed the survey modules (n = 172). Chi-square tests or Fisher’s exact tests (when the expected frequency of a frequency cell is less than 5) were used to compare the differences in these health conditions. False discovery rate (FDR) adjusted p-values were calculated for multiple comparisons.
The frequency and percentage of the severity of SARS-CoV-2 infection were described among non-users (Non-users), rapamycin users who only took rapamycin after recovering from infection (After only), rapamycin users who took rapamycin prior to but not during infection (Prior not during), and rapamycin users who took rapamycin continuously before, during, and after infection (Continuous). The distribution differences of the severity of COVID-19 among these groups were tested using Fisher’s exact tests.
Results
A total of 505 participants successfully completed the survey modules and were included in the final data set. Of these, 333 had previously used rapamycin, while 172 had never used rapamycin. A description of the basic demographic and self-reported lifestyle characteristics of study participants is provided in Table 2.
Table 2.
Demographic and basic lifestyle features of the study participants. For age, height, BMI, and weight, values are shown as average ± standard deviation. For other categories, values shown as percent of respondents (n). BMI, body mass index; TRF, time-restricted feeding. ∆ = Change in
| Rapamycin users | Non-users | |||
|---|---|---|---|---|
| Men | Women | Men | Women | |
| Gender at birth | 260 | 73 | 109 | 63 |
| Age (years) | 61.1 ± 11.6 | 60.7 ± 10.5 | 51.8 ± 14.6 | 56.4 ± 12.2 |
| Height (inches) | 70.8 ± 2.6 | 65.0 ± 2.6 | 70.6 ± 2.8 | 65.7 ± 2.8 |
| Current weight (lbs) | 178.0 ± 29.5 | 136.9 ± 24.1 | 180.2 ± 25.8 | 143.1 ± 21.6 |
| Current BMI | 24.9 ± 3.6 | 22.8 ± 3.9 | 25.4 ± 3.3 | 23.4 ± 3.7 |
| ∆Weight (age 25-current, lbs) | 8.7 ± 23.2 | 8.1 ± 17.4 | 11.6 ± 18.5 | 12.3 ± 17.4 |
| Exercise regularly | 89.6% (233) | 84.9% (62) | 84.4% (92) | 87.3% (55) |
| Healthy diet | 97.3% (252) | 93.2% (68) | 97.2% (106) | 98.4% (62) |
| Fasting/TRF | 70.4% (183) | 63.0% (46) | 61.5% (67) | 71.4% (45) |
| Tobacco use | 1.2% (3) | 0% (0) | 1.8% (2) | 4.8% (3) |
| > 2 alcoholic drinks/day | 12.7% (33) | 8.2% (6) | 7.3% (8) | 4.8% (3) |
| Cannabis > 1/wk | 8.5% (22) | 11.0% (8) | 10.1% (11) | 6.3% (4) |
| Medical exam in last 12 months | 83.8% (218) | 90.4% (66) | 76.1% (83) | 85.7% (54) |
| Dental exams in last 12 months | 78.8% (205) | 90.4% (66) | 75.2% (82) | 87.3% (55) |
Rapamycin users
Among rapamycin users, 77.7% (202) of men and 82.2% (60) women reported taking rapamycin under the supervision of a physician. Among the reasons given for taking rapamycin, the most common answer was “healthy longevity/anti-aging” reported by 95% (313) of users. Other responses included 62 individuals who reported taking rapamycin as a potential preventative for higher risk of dementia as a result of carrying one or more APOE4 alleles, 27 individuals selected “cardiovascular disease,” 12 individuals selected “cancer,” and 2 individuals reported taking rapamycin for PTEN Hamartoma Syndrome. None of the study participants reported taking rapamycin for organ transplant rejection.
Participants reported a variety of different dosing strategies (Supplemental Table 1) and lengths of rapamycin use (Table 3). By far, the most common current dosing interval among rapamycin users is once weekly dosing, with 88.1% (229) of male and 91.8% (67) of female respondents reporting using this strategy. The second most common interval for dosing was 14 days, reported by 5.8% (15) of men and 2.7% (5) of women. Only four participants (three men and one woman) reported using rapamycin daily. Other dosing intervals reported by users were 5, 6, 8, 9, 10, 15, 16, and 17 days.
Table 3.
Reported length of rapamycin usage among men and women at the time the survey was completed
| Length of rapamycin usage | Women | Men |
|---|---|---|
| < 1 month | 23.3% (17) | 11.9% (31) |
| 1–6 months | 26% (19) | 30.4% (79) |
| 6 months–1 year | 16.4% (12) | 19.2% (50) |
| 1–3 years | 23.5% (18) | 24.7% (61) |
| > 3 years | 15.0% (7) | 9.6% (39) |
Similar to the case for dosing intervals, respondents reported a wide range of rapamycin doses taken. Among the individuals taking rapamycin weekly, 6 mg was the most common dose, with 101 out of 229 men and 25 out of 67 women reporting taking this dose. The minimum weekly dose for both men and women was 1 mg and the maximum weekly dose was 20 mg and 14 mg, respectively. Due to the wide range in dosing intervals and concentrations, we normalized dosing to estimate the equivalent weekly amount of rapamycin taken across all respondents rounded to the nearest milligram (Fig. 1). The median length of time on rapamycin among all survey respondents was 218 days (228.5 for men, 183 for women), with a range of 1–3890 days.
Fig. 1.
Weekly dose of rapamycin usage reported by survey respondents. Dosing was determined based on self-reported usage of rapamycin. When more than one dose was reported by a single participant, the most recent dose reported was used. When dosing intervals other than weekly were reported, the dose was normalized to the equivalent weekly dose and rounded to the nearest milligram
Rapamycin user experiences
Survey respondents who indicated that they had taken rapamycin were asked in Module 3 to reflect on their perception of experiences taking rapamycin. For each of the questions asked in Module 3, participants were prompted to “Please consider your overall experience with rapamycin and any changes that you associate with rapamycin. Please select the option that best describes your experiences:”. The options given for each question were “Strongly Agree, Agree, Neither Agree nor Disagree, Disagree, Strongly Disagree.” For questions that were gender specific, “Not Applicable” was also an option. The results of this module are shown in Table 4 with “Strongly Agree/Agree and Strongly Disagree/Disagree” shown as combined categories. The ratio of combined (Strongly)/Agree to (Strongly)/Disagree is also shown and questions are ranked according to this ratio.
Table 4.
Reported perceptions of user experiences with rapamycin. Ratio equals the percent of users who agreed divided by the percent who disagreed
| Agree | Disagree | Neither | Ratio | |
|---|---|---|---|---|
| Rapamycin has anti-aging properties | 65.5% (218) | 0% (0) | 34.5% (115) | - |
| My health has improved since taking rapamycin | 44.7% (149) | 5.7% (19) | 49.5% (165) | 7.8 |
| I’m happier | 34.8% (116) | 4.8% (16) | 60.4% (201) | 7.3 |
| My brain works better | 35.4% (118) | 5.1% (17) | 59.5% (198) | 6.9 |
| I feel younger | 37.5% (125) | 5.7% (19) | 56.8% (189) | 6.6 |
| I have more energy | 38.7% (129) | 6.3% (21) | 55% (183) | 6.1 |
| Family/friends have commented that I look good | 38.7% (129) | 7.2% (24) | 54.1% (180) | 5.4 |
| I feel more confident | 28.8% (96) | 6.3% (21) | 64.9% (216) | 4.6 |
| I’m calmer and less likely to get upset or angry | 25.2% (84) | 7.5% (25) | 67.3% (224) | 3.4 |
| My anxiety is lower | 24.3% (81) | 7.5% (25) | 68.2% (227) | 3.2 |
| I have fewer aches and pains | 35.4% (118) | 12% (40) | 52.6% (175) | 3 |
| It’s easier to lose weight | 35.1% (117) | 13.2% (44) | 51.7% (172) | 2.7 |
| My relationships have improved | 12.6% (42) | 6% (20) | 81.4% (271) | 2.1 |
| I have reduced frequency of hot flashes (women) | 24.4% (10) | 12.2% (5) | 63.4% (26) | 2 |
| I have reduced severity of hot flashes (women) | 25% (10) | 12.5% (5) | 62.5% (25) | 2 |
| I have more erections on waking (men) | 27.3% (72) | 16.3% (43) | 56.4% (149) | 1.7 |
| My arthritis has gotten better | 18.3% (61) | 10.5% (35) | 71.2% (237) | 1.7 |
| I have more interest in sex | 23.7% (79) | 16.2% (54) | 60.1% (200) | 1.5 |
| My quality of sleep improved | 23.7% (79) | 15.6% (52) | 60.7% (202) | 1.5 |
| I have improved urinary flow (men) | 20.2% (54) | 16.9% (45) | 62.9% (168) | 1.2 |
| I have more stronger vaginal bleeding during menstruation (women) | 11.5% (3) | 15.4% (4) | 73.1% (19) | 0.8 |
| My vision got better | 11.4% (38) | 19.2% (64) | 69.4% (231) | 0.6 |
| I have decreased tinnitus (ringing of the ear) | 8.7% (29) | 18.6% (62) | 72.7% (242) | 0.5 |
| My hearing got better | 6% (20) | 13.5% (45) | 80.5% (268) | 0.4 |
| I have increased menstrual cramping (women) | 9.5% (2) | 28.6% (6) | 61.9% (13) | 0.3 |
Because many of the survey respondents had only recently begun taking rapamycin, a similar analysis was performed for those respondents who had reported rapamycin use for at least two months. These results are provided in Supplemental Table 2.
Recent health history
We sought to assess whether off-label use of rapamycin is associated with any significant side effects by asking both rapamycin users and non-users to recall if they had experienced any of 44 common health conditions in the past 3 months. For the purposes of this analysis, only those rapamycin users (n = 245) who had been taking rapamycin for longer than 3 months (the experience recall period) were included (Table 5). Similar analyses for only men (n = 196) and only women (n = 49) are provided in Supplemental Tables 4 and 5, respectively.
Table 5.
Reported frequency of potentially negative health conditions experienced in the past 3 months by survey respondents. Only rapamycin users who had been taking rapamycin for at least 90 days (n = 245) were included in this analysis. False discovery rate (FDR) adjusted p-values shown. Shading indicates p < 0.05 with green being more frequent in non-users and yellow being more frequent in rapamycin users
A total of 7 conditions were significantly different between non-users and rapamycin users. The only condition that was significantly more common in rapamycin users was presence of mouth ulceration, a known common side effect of rapamycin usage [53, 54]. Several conditions were significantly less frequent in rapamycin users compared to non-users: abdominal cramps, depression, abdominal pain, muscle tightness, anxiety, and eye pain. A trend toward a higher frequency of infections (respiratory tract, skin, fungal, and urinary tract) among rapamycin users was noted, but did not reach statistical significance.
COVID-19
Among all study participants, 29.5% (n = 149) reported experiencing a SARS-CoV-2 infection. Reported infection rates were similar between groups, with 31.3% (n = 54) of non-users and 28.5% (n = 95) of rapamycin users reporting a prior infection. Survey respondents were asked to characterize their COVID-19 case as either mild (less than 1 week of symptoms), moderate (more than 1 week of symptoms), or severe (requiring a trip to the hospital). Additionally, respondents were asked whether they suffered prolonged symptoms consistent with long-COVID.
Because many rapamycin users did not begin taking rapamycin until after their SARS-CoV-2 infection, we examined three different groups of rapamycin users and compared them to non-users. We defined 37 individuals as continuous rapamycin users based on their reported use of rapamycin continuously before, during, and after their SARS-CoV-2 infection. Seventeen individuals took rapamycin before their SARS-CoV-2 infection but stopped during the course of their infection. The remaining 41 rapamycin users did not start taking rapamycin until after their SARS-CoV-2 infection. Aggregate results are presented in Fig. 2 with percentages and number of participants in each category provided in Supplemental Table 6 (all participants), Supplemental Table 7 (men only), and Supplemental Table 8 (women only).
Fig. 2.
Severity of COVID-19 outcomes among survey participants reporting an infection. Survey participants self-reported SARS-CoV-2 infection as mild (less than 1 week of symptoms, no hospitalization), moderate (more than 1 week of symptoms, no hospitalization), or severe (trip to hospital). Participants also noted whether they suffered from prolonged symptoms consistent with long-COVID. A All participants. A total of 54 individuals who have never take rapamycin are included in the “Non-users” group. Rapamycin users are split into three groups to reflect their use of rapamycin relative to the timing of SARS-CoV-2 infection. Rapamycin users who did not begin rapamycin use until after their SARS-CoV-2 infection (n = 41) are included in the “After infection only” group. Rapamycin users who stopped taking rapamycin during their SARS-CoV-2 infection (n = 17) are included in the “Prior but not during” group. Rapamycin users who took rapamycin continuously throughout their SARS-CoV-2 infection (n = 37) are shown in the “Continuous” group. B Men only. C Women only. Percentages and number of participants in each group are provided in Supplemental Tables 6–8
The 37 respondents who took rapamycin continuously before, during, and after SARS-CoV-2 infection had the lowest rate of moderate or severe infections among all groups. Only 5 individuals (13.5%) reported a moderate infection while the rest (88.5%) reported a mild case. There were no reports of hospitalization or long-COVID among this group.
Among the 17 individuals who took rapamycin prior to but not during their SARS-CoV-2 infection, 10 (58.8%) reported mild symptoms, 6 (35.3%) reported moderate symptoms, and 1 reported a (5.9%) severe case (trip to hospital). Only one of these individuals did not resume rapamycin use after SARS-CoV-2 infection. There were no reports of long-COVID among this group.
A total of 41 rapamycin users had not yet started taking rapamycin prior to or during their SARS-CoV-2 infection. Thus, this group can be considered similar to the non-users for assessing potential impacts of rapamycin on COVID-19 severity, although rapamycin use could impact risk of long-COVID in this group. Among this group, 15 (36.6%) individuals reported a moderate infection and 26 (63.4%) reported mild symptoms. There were no reports of severe infection or long-COVID among this group.
There were a total of 54 reported SARS-CoV-2 infections among non-users. Of these, 27 (50.0%) were reported as mild, 25 (46.3%) were reported as moderate, and 2 (3.7%) were reported as severe. A total of 3 (5.6%) non-users report that they are still experiencing symptoms consistent with long-COVID. Among the individuals reporting long-COVID symptoms, one experienced a mild infection, one experienced a moderate infection, and one experienced a severe infection requiring hospitalization.
Among all survey respondents, continuous rapamycin users were significantly less likely to have experienced a moderate or severe infection or long-COVID symptoms, compared to non-users (p < 0.005). Continuous rapamycin users were also significantly less likely to have experienced moderate or severe infection compared to rapamycin users who took rapamycin prior to but not during their infection (p = 0.039) or those who took rapamycin only after recovering from infection (p = 0.037). Comparisons among other groups were not statistically significant.
Discussion
Survey-based data of 333 off-label rapamycin users indicates a high perceived quality of life and good health status. No major differences in basic demographics or lifestyle features were noted between the rapamycin users and non-users. Among survey respondents, rapamycin users were on average slightly older than non-users for both men (9 years) and women (6 years). Rapamycin users reported consuming more alcohol than non-users, and a greater percentage of rapamycin users were male (78% male) compared to non-users (63% male).
Rapamycin users generally reported perceived improvements in quality of life since beginning off-label use of rapamycin. Ratios of greater than 3:1 in agreement were observed for self-reported improvements in health, happiness, brain function, feelings of youthfulness, confidence, calmness, anxiety, and generalized aches and pains. Interestingly, greater than fivefold more rapamycin users agreed with the comment that “family/friends have commented that I look good” than disagreed, suggesting that these perceived self-benefits may also be apparent to others.
Rapamycin use by organ transplant patients is associated with a long list of potential side effects, including immune suppression, mouth sores, hypertriglyceridemia, anxiety, abdominal pain, nausea, dizziness, and many others. Organ transplant patients typically also take additional strong immunosuppressants such as tacrolimus, cyclosporine, or mycophenolate mofetil along with rapamycin or rapalogs, potentially exacerbating side effects or inducing side effects which would not be present in the absence of these drugs Interestingly, among survey respondents, only mouth sores was significantly more prevalent in rapamycin users compared to non-users. Unexpectedly, several supposed side effects associated with rapamycin use were significantly less frequent in rapamycin users, including abdominal cramps, other abdominal pain, anxiety, and eye pain. While it is difficult to know the extent to which self-reporting may have biased these results, it seems plausible that any bias could act to both increase and decrease the reported frequency of rapamycin-associated side effects. For example, rapamycin users are likely to know that mouth sores and infection are common side effects associated with rapamycin use in organ transplant patients, and therefore may be more likely to note and recall such events than non-users. Indeed, several rapamycin users reported that their prescribing physician specifically warned them to be watchful for signs of infection and to begin taking antibiotics if they suspected an infection, suggesting a heightened awareness for certain potential side effects among this group. The lack of apparent side effects associated with off-label rapamycin use here is also consistent with prior reports that once weekly administration of 5 mg of the rapamycin derivative everolimus has side effects comparable to placebo among healthy older adults [45].
Of particular interest was the analysis of COVID-19 severity among rapamycin users and non-users. Rapamycin has been proposed as a potential therapy for preventing and treating severe COVID-19 cases via its possible effects on anti-viral gene expression and attenuation of the “cytokine storm” [51, 55, 56]. No obvious difference in risk of infection was apparent between groups. Interestingly, continuous rapamycin use throughout the SARS-CoV-2 infection period was associated with a significant reduction in moderate or severe COVID-19 cases, and rapamycin users did not report any cases of long-COVID, despite being an average of 7.5 years older than non-users.
More research is needed to determine whether this represents a clinically meaningful benefit from rapamycin use for reducing severity and long-term consequences of infection with SARS-CoV-2 and other viruses. Long-COVID in particular is being recognized as having a substantial detrimental effect on quality of life for many people [57]. We speculate that the anti-inflammatory effects of rapamycin may be helpful in reducing symptoms and restoring immune homeostasis in people suffering from long-COVID. Additionally, mTOR inhibitors including everolimus (RAD001) and dactolisib (RTB101) have repeatedly shown beneficial effects on vaccine response and subsequent viral infections in otherwise healthy people in placebo-controlled clinical trials [45, 46, 51]. Given the long history of clinical use, low cost, and low risk profile associated with off-label use of rapamycin observed here, we propose that controlled clinical trials to assess benefits of rapamycin for long-COVID should be prioritized.
This study has several limitations that make the data less reliable than what would be obtained from a double-blind, randomized clinical trial. The self-reported nature of the data and the possibility of unintended bias in the participant pool reduce confidence that these results would be recapitulated in a larger, more heterogenous population. In particular, we cannot rule out the possibility that the population of rapamycin users is self-selected against people who started taking rapamycin and stopped because of negative experiences; however, we attempted to recruit as broadly as possible to include such individuals both through social media and through direct recruitment of prior patients who had been prescribed rapamycin in the past.
It is also possible that individuals taking rapamycin off-label are more likely to practice healthy lifestyle habits or take other substances that could confound this analysis. We attempted to evaluate this and found no major differences between groups. Indeed, both rapamycin users and non-users in this study appear to be atypical in that they report higher rates of exercise and healthy dietary habits, lower body mass index, and lower rates of alcohol consumption and tobacco use, relative to the general population. It is possible that potential benefits and side effects from off-label rapamycin use would be different in a less healthy population. For example, there are several reports that rapamycin or genetic inhibition of mTOR can reduce weight gain and improve metabolic parameters in mice subjected to diet-induced obesity [58–61], but paradoxically, has negative effects in a murine genetic model of obesity caused by mutation of the leptin receptor [62].
An additional limitation of this study is that was large variation in dose and duration of rapamycin use. Approximately 20% of rapamycin users also reported taking rapamycin without the supervision of a physician. Unsupervised use of prescription medications appears to be common within the biohacking community, based on comments found in multiple online forums, and is unlikely to be unique to rapamycin. We chose not to exclude these individuals from the analyses because none of the data collected here is derived from medical records or underwent prior physician review. While it is possible that obtaining rapamycin from sources that do not require a valid prescription could influence bioavailability or purity of the product, a cursory examination of the data suggests there are no obvious differences based on prescription versus non-prescription use.
Despite these limitations, we find no evidence for significant increases in health risks, other than mouth sores, from off-label rapamycin use. A trend toward increased risk of bacterial and fungal infection was associated with rapamycin use, but did not reach statistical significance and appear to be small in magnitude. Overall, the risk of side effects from off-label use of rapamycin may compare favorably with other drugs commonly used off-label, such as statins [63] and metformin [64]. Interestingly, several positive effects were associated with off-label rapamycin use, including significant reductions in eye pain, stomach pain, anxiety, and depression relative to non-users. We also found a significant reduction in severity of COVID-19 and risk of long-COVID among respondents who took rapamycin continuously during the time of their SARS-CoV-2 infection. Rapamycin users expressed overwhelmingly positive impressions of their experiences with rapamycin. Taken together, these observations support further study of rapamycin as a potential intervention to improve quality, and perhaps quantity, of life in otherwise healthy older adults.
Supplementary Information
Below is the link to the electronic supplementary material.
Funding
This work was supported by a Longevity Impetus Grant from Norn Group to M.K. and J.Y.A.
Declarations
Conflict of interest
MK and GH are co-founders of Optispan Geroscience, which has no material interest in rapamycin or rapamycin derivative production or sales at this time. ASG and BSR are practicing physicians who may prescribe rapamycin off-label for certain patients when appropriate. AI, AN, and SZ are employees and/or shareholders of AgelessRX, a longevity-focused telemedicine platform that sponsors several clinical trials, including interventional and observational efforts for the repurposed use of rapamycin.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Sierra F, Kohanski R. Geroscience and the trans-NIH Geroscience Interest Group, GSIG. Geroscience. 2017;39:1–5. doi: 10.1007/s11357-016-9954-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lee MB, Kaeberlein M. Translational geroscience: from invertebrate models to companion animal and human interventions. Transl Med Aging. 2018;2:15–29. doi: 10.1016/j.tma.2018.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sierra F. The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. Cold Spring Harb Perspect Med. 2016;6:a025163. doi: 10.1101/cshperspect.a025163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–1217. doi: 10.1016/j.cell.2013.05.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kennedy BK, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159:709–713. doi: 10.1016/j.cell.2014.10.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kulkarni AS, et al. Geroscience-guided repurposing of FDA-approved drugs to target aging: a proposed process and prioritization. Aging Cell. 2022;21:e13596. doi: 10.1111/acel.13596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kaeberlein M, Rabinovitch PS, Martin GM. Healthy aging: the ultimate preventative medicine. Science. 2015;350:1191–1193. doi: 10.1126/science.aad3267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Justice JN, et al. Development of clinical trials to extend healthy lifespan. Cardiovasc Endocrinol Metab. 2018;7:80–83. doi: 10.1097/XCE.0000000000000159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wissler Gerdes EO, Misra A, Netto JME, Tchkonia T, Kirkland JL. Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev. 2021;200:111591. doi: 10.1016/j.mad.2021.111591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Romashkan S, Chang H, Hadley EC. National Institute on Aging Workshop: repurposing drugs or dietary supplements for their senolytic or senomorphic effects: considerations for clinical trials. J Gerontol A Biol Sci Med Sci. 2021;76:1144–1152. doi: 10.1093/gerona/glab028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vaiserman A, Koliada A, Lushchak O, Castillo MJ. Repurposing drugs to fight aging: the difficult path from bench to bedside. Med Res Rev. 2021;41:1676–1700. doi: 10.1002/med.21773. [DOI] [PubMed] [Google Scholar]
- 12.Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–345. doi: 10.1038/nature11861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab. 2016;23:990–1003. doi: 10.1016/j.cmet.2016.05.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Powers RW, 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006;20:174–184. doi: 10.1101/gad.1381406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Medvedik O, Lamming DW, Kim KD, Sinclair DA. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 2007;5:e261. doi: 10.1371/journal.pbio.0050261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Robida-Stubbs S, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012;15:713–724. doi: 10.1016/j.cmet.2012.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Bjedov I, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46. doi: 10.1016/j.cmet.2009.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lu YX, et al. A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing. eLife. 2021;10:e62233. [DOI] [PMC free article] [PubMed]
- 19.Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–395. doi: 10.1038/nature08221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Anisimov VN, et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011;10:4230–4236. doi: 10.4161/cc.10.24.18486. [DOI] [PubMed] [Google Scholar]
- 21.Komarova EA, et al. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/- mice. Aging (Albany NY) 2012;4:709–714. doi: 10.18632/aging.100498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wilkinson JE, et al. Rapamycin slows aging in mice. Aging Cell. 2012;11:675–682. doi: 10.1111/j.1474-9726.2012.00832.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Livi CB, et al. Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY) 2013;5:100–110. doi: 10.18632/aging.100533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Neff F, et al. Rapamycin extends murine lifespan but has limited effects on aging. J Clin Investig. 2013;123:3272–3291. doi: 10.1172/JCI67674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Fok WC, et al. Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS ONE. 2014;9:e83988. doi: 10.1371/journal.pone.0083988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Miller RA, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468–477. doi: 10.1111/acel.12194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Popovich IG, et al. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol Ther. 2014;15:586–592. doi: 10.4161/cbt.28164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Bitto A, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016;5:e16351. [DOI] [PMC free article] [PubMed]
- 29.Miller RA, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011;66:191–201. doi: 10.1093/gerona/glq178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Zhang Y, et al. Rapamycin extends life and health in C57BL/6 mice. J Gerontol A Biol Sci Med Sci. 2014;69:119–130. doi: 10.1093/gerona/glt056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Halloran J, et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience. 2012;223:102–113. doi: 10.1016/j.neuroscience.2012.06.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Majumder S, et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell. 2012;11:326–335. doi: 10.1111/j.1474-9726.2011.00791.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Shavlakadze T, et al. Short-term low-dose mTORC1 inhibition in aged rats counter-regulates age-related gene changes and blocks age-related kidney pathology. J Gerontol A Biol Sci Med Sci. 2018;73:845–852. doi: 10.1093/gerona/glx249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zaseck LW, Miller RA, Brooks SV. Rapamycin attenuates age-associated changes in tibialis anterior tendon viscoelastic properties. J Gerontol A Biol Sci Med Sci. 2016;71:858–865. doi: 10.1093/gerona/glv307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Yilmaz OH, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012;486:490–495. doi: 10.1038/nature11163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Garcia DN, et al. Effect of caloric restriction and rapamycin on ovarian aging in mice. Geroscience. 2019;41:395–408. doi: 10.1007/s11357-019-00087-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Altschuler RA, et al. Rapamycin added to diet in late mid-life delays age-related hearing loss in UMHET4 mice. Front Cell Neurosci. 2021;15:658972. doi: 10.3389/fncel.2021.658972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Chiao YA, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY) 2016;8:314–327. doi: 10.18632/aging.100881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Dai DF, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014;13:529–539. doi: 10.1111/acel.12203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Flynn JM, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12:851–862. doi: 10.1111/acel.12109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Chen C, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2:ra75. [DOI] [PMC free article] [PubMed]
- 42.An JY, et al. Rapamycin rejuvenates oral health in aging mice. eLife. 2020;9e54318. [DOI] [PMC free article] [PubMed]
- 43.An JY, et al. Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience. 2017;39:457–463. doi: 10.1007/s11357-017-9994-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Urfer SR, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience. 2017;39:117–127. doi: 10.1007/s11357-017-9972-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Mannick JB, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6:268ra179. [DOI] [PubMed]
- 46.Mannick JB, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10eaaq1564. [DOI] [PubMed]
- 47.Kaeberlein M. mTOR inhibition: from aging to autism and beyond. Scientifica (Cairo). 2013;2013:849186. [DOI] [PMC free article] [PubMed]
- 48.Kuypers DR. Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf. 2005;28:153–181. doi: 10.2165/00002018-200528020-00006. [DOI] [PubMed] [Google Scholar]
- 49.Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transpl Proc. 2003;35:7S–14S. doi: 10.1016/S0041-1345(03)00211-2. [DOI] [PubMed] [Google Scholar]
- 50.Cox LS, et al. Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults. Lancet Healthy Longev. 2020;1:e55-e57. [DOI] [PMC free article] [PubMed]
- 51.Mannick JB, et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2021;2:e250–e262. doi: 10.1016/S2666-7568(21)00062-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Kraig E, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018;105:53–69. doi: 10.1016/j.exger.2017.12.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.de Oliveira MA, et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011;47:998–1003. doi: 10.1016/j.oraloncology.2011.08.009. [DOI] [PubMed] [Google Scholar]
- 54.Saigal B, Guerra L. Prevention of stomatitis: using dexamethasone-based mouthwash to inhibit everolimus-related stomatitis. Clin J Oncol Nurs. 2018;22:211–217. doi: 10.1188/18.CJON.211-217. [DOI] [PubMed] [Google Scholar]
- 55.Bischof E, Siow RC, Zhavoronkov A, Kaeberlein M. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. Lancet Healthy Longev. 2021;2:e105–e111. doi: 10.1016/S2666-7568(20)30068-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Blagosklonny MV. From causes of aging to death from COVID-19. Aging (Albany NY) 2020;12:10004–10021. doi: 10.18632/aging.103493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Mehandru S, Merad M. Pathological sequelae of long-haul COVID. Nat Immunol. 2022;23:194–202. doi: 10.1038/s41590-021-01104-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Bitto A, Tatom N, Krivak T, Grotz P, Kaeberlein M. Evidence that C/EBP-beta LAP increases fat metabolism and protects against diet-induced obesity in response to mTOR inhibition. Front Aging. 2021;2:738512. doi: 10.3389/fragi.2021.738512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Um SH, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431:200–205. doi: 10.1038/nature02866. [DOI] [PubMed] [Google Scholar]
- 60.Chang GR, et al. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci. 2009;109:496–503. doi: 10.1254/jphs.08215FP. [DOI] [PubMed] [Google Scholar]
- 61.Makki K, et al. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS ONE. 2014;9:e92684. doi: 10.1371/journal.pone.0092684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Sataranatarajan K, et al. Rapamycin increases mortality in db/db mice, a mouse model of type 2 diabetes. J Gerontol A Biol Sci Med Sci. 2016;71:850–857. doi: 10.1093/gerona/glv170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Jacobson TA, et al. The STatin Adverse Treatment Experience Survey: experience of patients reporting side effects of statin therapy. J Clin Lipidol. 2019;13:415–424. doi: 10.1016/j.jacl.2019.04.011. [DOI] [PubMed] [Google Scholar]
- 64.de Vries ST, Denig P, Ekhart C, Mol PGM, van Puijenbroek EP. Sex differences in adverse drug reactions of metformin: a longitudinal survey study. Drug Saf. 2020;43:489–495. doi: 10.1007/s40264-020-00913-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.