Dr. Stefanie Morgan joins Dr. Robert Dudley from AgelessRx to discuss a #research paper she co-authored that was #published in Volume 17, Issue 4 of Aging, entitled “Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results.”
Behind the Study is a series of transcribed videos from researchers elaborating on their recent studies published by Aging (Aging-US). Visit our YouTube channel for more insights from outstanding authors.
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Hi everyone. My name is Dr. Robert Dudley. I’m a senior researcher at AgelessRx, and I’m here today talking with Dr. Stefanie Morgan, our VP of Research and Applied Science at AgelessRx. Hey Stefanie.
Hello. It’s great to be here.
So today we’re going to talk about the recent paper that we published in Aging. Can you just give us a little bit of background about what the paper is, what it’s titled, and the overall focus of the paper?
Yeah, so this paper talks about one of the earliest trials that we ran as a company, the PEARL clinical trial, and it looks at using low-dose rapamycin for longevity instead of what — Usually you’d use high-dose rapamycin for immunosuppression or cancer therapy or something similar, very therapeutic applications. But we were one of the biggest trials to date of the low-dose version, specifically the gerotherapeutic.
Awesome. And what made you and the company interested in taking on this topic? I know low-dose therapies are in vogue right now, right?
Yeah, so amongst the longevity field, there are a lot of people who take low-dose rapamycin. A lot of people report that it helps them with pain. But this is very things we find on blogs and conversation with people who are longevity enthusiasts. They’re taking it way below a clinically standard dose. It’s usually between two and eight per week, and it’s so popular and so many people are a fan of it, we were like, we have to dive into this further.
And then as we did, we found a lot of evidence that supports its use in that manner in animals, in all different kinds. Mice, there’s marmosets, there’s a few other species I can’t think of off the top of my head, but there’s a whole bunch of different places where it’s been studied. A couple of really great human trials, but they were kind of small or they were in very old populations, so they were limited in scope, but really fundamental landmark first papers there. And so we said, “Well, we have all this huge exposure, we should take advantage of it to do a bigger trial for a longer period of time.” And we really just wanted to start the ball rolling in understanding the use of this medication in longevity medicine better, even though it’s a little tiny first step.
Great. So lots of real world anecdotal evidence, and then let’s take that and run with it and say, “Let’s expand out the rigorous science and actually run a legitimate clinical trial.” That’s the first step into really investigating this topic.
Correct.
Awesome.
At the time, it was definitely the biggest decentralized trial for rapamycin for longevity medicine. I am not confident that that’s still the case because we collected this data a few years ago and talked about it a lot. A lot of other people got really excited. But at the time, it was definitely very set a standard as the first one there. Then it also just had a lot of patients, they were all fairly healthy, so very novel in a number of ways.
Great. What were some of the most notable parts, or the things that surprised you the most about the process of this clinical trial and some of the results?
The trial actually started before I was part of the AgelessRX team, so I was in a really unique and great position to come into the data with no preconceived biases. I came into it and I was just like, “I don’t know what happened here. I’m going to figure it out from the answers.” So looking through the data, my first reaction was, “Wow! These people are super healthy, which was surprising.” The baseline before any intervention, these are people who care about their diet, they exercise, they’re generally not overweight or obese. These are some real healthy longevity enthusiast types of people, so I think that that ended up feeding into the … We didn’t see any results that were mind-blowing or really amazing, but it’s hard to move the needle. When you’re at a 95, moving to a 98 is not statistically significant, but the fact that you’re already at a 95 is pretty great.
Would you expect to see different results had the participants been more unhealthy upfront?
You can’t know for sure without doing the study. That would be my hypothesis, but it’s something that we’re interested in exploring in more depth in a future trial. We also didn’t do a particularly robust job of tracking dietary habits. So like, “Do you eat a lot of grapefruit? Do you take the rapamycin on an empty stomach? Do you take it 30 minutes away from food? Do you take it with food, with fats?” And people have very strong opinions about how they take this, but to my knowledge, there’s not a lot of data to actually support any one of the ideas. And maybe it’s different for every individual, but that’s probably the one big weakness that we had in the data that was collected that I think would also go a long way towards making an impact in a broader number of individuals.
Great. Did you see any differences between male and female subjects in the trial?
Surprisingly, we did, which was striking because there were so few women in the trial. I think we had almost two thirds of our participants were men, which is consistent with enthusiasm for longevity, tends to be more men than women. But the women, as small as their numbers were, did have all the same effect, which was very beneficial. In fact, that was the group that had statistically significant differences in the measures that we took, whereas men were just generally improved, but not to the level of significance. Which the study was designed for safety, not so much for efficacy. We did look at outcomes to see if we could determine any amount of, is this a good signal that heads in a positive direction or not? But the study wasn’t powered for conclusive statistical outcomes.
Right. So you mentioned that one of the big focuses was the safety. And so this trial concluded that rapamycin in these low doses is super safe to use. But what are some of the variables that you analyzed in terms of the efficacy? I know you mentioned it was a little underpowered given the sample size, but what were some of those variables that were trending in the right direction?
Lean muscle mass for women and reports of improvements in pain symptoms were the ones that actually got to a statistically significant threshold, which again, surprising, seeing we had so few women in the study.
Amazing. Any other interesting points you want to share about the study?
There were a lot of interesting things. I think it’s important to keep in mind that a lot of it was like a first pass. It’s the beginning. There should be a lot of follow-up work done. We learned a lot, but we also discovered we have a lot more to learn. Some of the interesting things to me were what wasn’t correlated with the rapamycin bioavailability, or with outcomes rapamycin. So we did see a little bit of a difference with certain measures by gender, but then somewhere early on in the study, someone raised a point to us that said like, “Oh, you’re using compounded rapamycin do you know if it’s as bioavailable and as effective as the generic version that most people take?” And so the team said, “No, we don’t, actually. Great call out, let’s check it.” So we paused this trial altogether and went and did a separate trial about the bioavailability of the two different formulations. And there also, we couldn’t find any correlation between things you would expect like height, weight, overall BMI, gender, self-reported activity, nothing correlated with how much rapamycin was in your blood.
We did fortunately find out that both formulations get into your blood on some level. So there’s just like the compounded has about a third less of the availability in your system as the generics. You have to take three times as much, which at that ratio, I don’t know if it’s really that cost-effective anymore, which is usually why people use the compounded formulation, but it does seem to work. So once we had that knowledge, we checked again a little, to whatever extent we could for our PEARL study participants, and certainly the ones that stayed with us after the study was over as customers and patients through our platform, and they had more regular blood work after that, and we didn’t see any correlation with these things. So that was one thing that I was actually really surprised about, that I’m intrigued about and would love to study more in the future as we continue to build our knowledge base.
Well, that’s great. That’s a great segue into what’s next for this. Is there a continuation? What are the next steps? There’s always something next when it comes to scientific investigations.
I think we have a lot of questions about a couple of things. One is the validity of the self-reports for activity. If you say like, “Oh, are you active?” Somebody might say, “Yes,” and active means they walk a mile a day, whereas for another person, it might mean you run five miles a day, and those are not the same levels of activity. “Do I eat a healthy diet?” Yes, but is one maybe pescatarian, is another vegetarian, is one keto, is one paleo? All of those are relatively healthy, but do they impact how the rapamycin processes in your body? Yes. Or potentially, I mean. We don’t really know for sure.
And so those are things that I would love to dive into a little bit further to see … Because the next question that burns in my mind, if we were to summarize it, is what makes the difference in how well rapamycin works for you and how much of it stays in your bloodstream? And then also, these results were cool, but they were just, some of the samples were so small they were not powered for efficacy. So I would love to do a bigger study that is powered to evaluate efficacy and see, if we controlled a few parameters of the study better in a future effort, if we could get clearer answers about a few key elements.
Awesome. Great. Anything else you want to acknowledge? We’ve got a great team here at Ageless, but we had some partners on this study as well.
Yeah, we had a lot of partners on this study, and I think it took us a long time to do this trial, to analyze the data. We spent a long time reviewing and revising the data after it came out, especially because the outcomes weren’t super cut and dry and clear. So there were just so many wonderful people in the longevity space that contributed to this project, whether it was formally or informally or just in reading through it and saying, “You have a giant gap in your work here. Go do better.” Amazing. Amazing group to work with at Ageless and with many of our collaborators. The Lifespan.io team deserves a special shout out because they helped us raise money for this and did a lot of the outreach to help people even know that it was a thing that we could do.
Awesome. Thank you so much. I think we’re just about out of time. So thank you, Stefanie, for sharing all the great information about the PEARL trial.
Awesome. Thank you so much.
Click here to read the full study published by Aging (Aging-US).
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