We are very excited to be crowdfunding PEARL, one of the few human trials of rapamycin, which is probably the most promising anti-aging molecule known today.
Dysregulation of nutrient sensing (the ability of cells to adjust their metabolism to the amount of nutrients available) is thought to be one of the nine hallmarks of aging.
Rapamycin affects mechanistic target of rapamycin (mTOR), a complex protein involved in nutrient sensing as well as autophagy, the process that cells use for waste recycling. Rapamycin was discovered on Easter Island (Rapa Nui) and is named after it. Rapamycin is an established drug and is currently used for preventing organ transplant rejection. However, probably the most exciting feature of rapamycin is its proven ability to prolong the lifespans of various model organisms, sometimes drastically.
PEARL (Participatory Evaluation of Aging with Rapamycin for Longevity) is a relatively large-scale trial, one of the first of its kind, that aims at recapitulating the amazing effects of rapamycin in humans. If successful, PEARL could have a dramatic impact on the longevity field and, potentially, on our lifespans.
The PEARL study is run by AgelessRx, a company operating in the field of telemedicine and dietary supplements based on popular compounds with possible anti-aging qualities, such as metformin and NAD+. Last year, when PEARL was already in the works, its chief scientist Dr. Sajad Zalzala gave a fascinating talk at our virtual conference, Ending Age-Related Diseases 2020. Now, we asked him for an update on PEARL, rapamycin, and telemedicine.
Could you explain the design of the study?
PEARL is a randomized, double-blind, placebo-controlled trial. This is the “gold standard” of clinical trials. We selected four different rapamycin dosing schedules plus a placebo group. We are hoping to enroll between 200 to 400 participants – 40 to 80 participants per group. This number was chosen based on what we think is needed for the study to be sufficiently powerful. This estimate was based on previous studies.
PEARL is a telemedicine study, which is unusual. How do telemedicine studies work? What are the benefits and potential problems, compared to conventional studies?
The major difference between a virtual and a conventional trial is the location. In conventional studies, a patient needs to leave their home and travel to the trial site (usually a clinic or a hospital). With a virtual trial, everything comes to the patient who has almost no need to travel.
There are several advantages to virtual trials. Participants can be almost anywhere in the US. This helps resolve any geographical or environmental influences and confounders. For example, with Dr. Watson’s small rapamycin trial, he suspects that the California wildfires’ adverse effect on patients’ health may have washed out any benefit from the rapamycin. [Dr. James P. Watson of UCLA is the principal investigator of PEARL.]
Virtual trials are not just more convenient for participants but also much more cost-effective than conventional trials. Still, if planned properly, they can provide very useful data.
There are some possible downsides too. Virtual trials can be limited in the types of data that can be gathered. For instance, it is much more challenging to do things like biopsies or echocardiography if patients are remote. Same about types of interventions that can be assessed, since you obviously can’t perform a joint injection or other relatively invasive procedures.
Subjects in a telemedicine trial would also need to be technically proficient to some degree, which might exclude some participants.
Presumably, most participants are people interested in longevity, so they could be using dietary or lifestyle strategies (supplements, fasting of various sorts, keto) that might affect some of the same pathways as rapamycin. How will you control for this potentially confounding issue?
We encourage participants not to make any changes to their routine during the trial other than taking the study drug. Presumably, those in the placebo group would be just as inclined towards various supplements and lifestyle strategies as the active treatment group. In that case, the effects of rapamycin will hopefully shine through these potential confounders.
Since last year, have you recruited any new research collaborators?
The list of potential collaborators continues to grow. Our most exciting potential collaborators include the Mayo Clinic’s Robert and Arlene Kogod Center on Aging, and the NIH’s National Institute on Aging. We hope to have more official announcements in the months to come. We equally appreciate all our potential partners and all their hard work and dedication.
There seems to be a major problem with repurposing existing drugs: it is not lucrative for Big Pharma, so we don’t get to have large scale trials of potentially impactful compounds, such as rapamycin and metformin. What can be done to incentivize this kind of research?
While it is true that Big Pharma may not be interested in repurposing drugs (and if they are – watch out, you can bet they will make it incredibly expensive when they are done), it is our hope that the longevity community, as well as anybody with an enthusiastic interest in longevity, will step up to support and/or participate.
Ultimately, the best incentive will be the results. If we can show that one or more compounds can slow or reverse aging, I think that will be enough of an incentive for people to support further research.
You assume that rapamycin is a caloric restriction mimetic, but we’ve seen some research lately that suggests otherwise. Could this affect the study?
If I am interpreting these studies properly, it seems that rapamycin affects mostly, but not exclusively, some of the same pathways as caloric restriction. Actually, I think this is promising because it hints at a potential synergy between different longevity therapies.
One such combination that keeps coming to mind is rapamycin and metformin. They might both affect the mTOR system, but I hope we will find that their combination is more beneficial than either one alone, since they might have effects that do not completely overlap but rather are independent of each other.
I do not believe this new data will change the outcomes of PEARL. Rapamycin seems to stand on its own regardless of how exactly it works.
In your talk last year, you did mention combination strategies, such as rapamycin and metformin. Could you expand on that? Why might this one work, and do you have others in mind?
It is possible that rapamycin might “play well” with loads of other molecules and interventions. I specifically mentioned metformin because it seems to be the “next best thing to rapamycin”, but it also has the potential to overcome some of the possible weaknesses of rapamycin, such as potential insulin resistance (although it is not certain that we will actually see insulin resistance in our study in any of our dose groups).
For example, the combination of growth hormone, metformin, and DHEA (dehydroepiandrosterone) seemed to work really well in Dr. Watson’s TRIIM trial. We need that same kind of thinking to formulate better trials and therapies.
I have not yet thought that far ahead in terms of exactly which combinations to try next – it would probably require collaboration with other experts to be able to cleverly choose the combinations. I think we would also want to wait and see what we get back in terms of biomarkers and other data to determine if there are opportunities for synergy that have not yet been explored.
Could you explain the study’s endpoints?
There are primary endpoints and secondary endpoints. The primary is the change in visceral adipose tissue (VAT) by DXA scan, while the secondary is assessing changes in various biomarkers and other age-related markers.
These are not to be confused with our objectives, which are evaluation of the safety profile of our dosing schedule for an otherwise healthy adult population, evaluation of the effectiveness of rapamycin on various markers of aging, and determining the best dose in terms of safety and effectiveness. Ultimately, we want to be able to offer rapamycin prescriptions for patients who would like to use it for its longevity benefits.
We also hope to create a foundation for a telemedicine research “machine” that churns out high-quality studies and data on all sorts of therapies and interventions.
Aren’t studies like this one, due to their combination of potential importance and cost effectiveness, ideal for crowdfunding? After all, they allow citizens to make a real impact in an important field where neither Big Pharma nor governments are currently present.
In a perfect world, governments and large institutions would realize the importance of such studies and provide all the funding that is needed – and then roll those therapies out to all their citizens as a part of a public effort to stamp out the tragedy of premature aging. But until this utopian dream comes true, crowdfunding seems to be the only viable option.
You draw a distinction between participants of a trial and citizen scientists. Can you explain this to our readers? Who are citizen scientists and how can a person become one?
Generally, citizen science is a public participation in scientific research. Participation in a clinical trial is not commonly thought of as “citizen science”. Moreover, I think that traditional trials funded by the government or Big Pharma are largely incompatible with citizen science; they violate its spirit. In my opinion, the difference between the traditional model and the crowdfunded model is like between building a house while working for a large commercial company like Pulte Houses and volunteering through Habitat for Humanity.
PEARL’s model keeps the spirit of citizen science intact in several ways: how we attract the funding and how we ask the participants to fund certain parts of the study. It’s also in our commitment to open access to the data and in how we collaborate with various organizations.
We also strongly encourage participation in our patient registry for those who are already on rapamycin (and therefore excluded from our trial), or who may not qualify for the trial for other reasons – or just anybody who has valuable data on their health and longevity.
Rapamycin research is going strong, new papers are published all the time. Have you seen anything important during this year?
I think the most intriguing and potentially promising research during the last year has been on rapamycin’s and rapalogs’ ability to bolster immunization response and protect against viral diseases, potentially including COVID-19 [which we have reviewed in this article].
A paper from Matt Kaeberlein’s lab, showing that rapamycin rejuvenates oral health in mice, also comes to mind [read our recent interview with Dr. Kaebelein].
How was your work, and the trial in particular, affected by the pandemic? You are in the telemedicine business, which has predictably expanded during this year. How much more popular has telemedicine become? How do you see its future? What role can it play in extending healthspan and lifespan?
We started planning PEARL shortly before the pandemic – but like almost everything, it was put on hold for a while during “The Great Pause”. Fortunately, we were able to pick up the work quickly and get back on track.
Before the pandemic, telemedicine was growing steadily but slowly, and there was still quite a bit of resistance from some conventional medicine circles. The pandemic “imposed” telemedicine on all medical providers and health care systems.
One of the most significant changes I encountered was in a state which I shall not name. Their medical board went from being one of the most anti-telemedicine in the country to essentially saying to healthcare providers during the pandemic: “Do whatever you think is in the best interest of the patient”. But isn’t this how it’s supposed to be all the time, pandemic or not? So, telemedicine is definitely here to stay – many of the changes we saw during the pandemic will be made permanent.
When it comes to things like monitoring a person’s health status and the rate of aging, I think there is so much that can be done remotely. Many tests can be done remotely (or locally for the patient). Limiting longevity therapies to brick-and-mortar locations would be a huge disservice to the millions of people who are interested in such therapies.
To conclude, I think that the only way to reach as many people as possible and to make the biggest impact on human longevity is to do it at least in part through telemedicine. When done correctly, telemedicine can be safe, effective, and cost-efficient.
Do you have a message for people thinking about donating to PEARL?
This is a unique trial which can advance the whole field of longevity. Many parties have joined forces to bring it to life: Mayo Clinic Translational Geroscience Network, Better Humans, DexaFit, TruDiagnostic, GERO.ai, Young.ai, and many others that we are not at liberty to name yet. All have come together to provide their services and products at steep discounts or even free to make this project viable. Donor support is the last missing piece that will make this a success. Yet another key point is that if this project succeeds, it will pave a way for other collaborative, speedy and cost-effective trials.
We would like to thank Dr. Zalzala for taking the time to speak with us about the PEARL project. If you would like to get involved by supporting the project you can visit the PEARL campaign page.
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