Below is a transcript of the ~90-minute webinar, hosted by AgelessRx on August 27, 2024, in which the study leaders and organizers presented the primary findings from the PEARL trial, with a Q&A session with viewers in the latter half of the presentation. The following has been edited for clarity and may read differently than the speakers’ spoken words; the content has not been altered otherwise.
Moderator:
Hello everyone, thank you for joining this exciting webinar! We have a great group of panelists here today. We’ll start by going through our slides and then have a Q&A session after the presentation. Please feel free to submit your questions using the Q&A function at the bottom of your screen.
With that, Dr. Z, would you like to kick us off?
Dr. Z:
Thank you! My name is Dr. Sajad Zalzala, Chief Medical Officer and Co-founder of AgelessRx, and I’m also the clinical investigator on the PEARL trial. Today, we’re going to be presenting the results and having a discussion about them.
I’ll be driving the slides as we cover the following: introductions, background, rationale, study design, methodology, key findings, implications, conclusions, acknowledgements, and, most importantly, the Q&A. Hopefully, many of you are here for that, so please have your questions ready!
Oliver, would you like to start with an introduction?
Oliver Medvedik:
Sure! Welcome everyone to this webinar on the PEARL trial: Participatory Evaluation of Aging with Rapamycin for Longevity. We have a fantastic panel of experts joining us today.
First, we have Dr. Matt Kaeberlein, Co-Founder and CEO of OptiSpan Health. He’s also the Founder and Co-Director of the Dog Aging Project, current CEO of the American Aging Association, and has served on the Board of Directors for the Federation of American Societies for Experimental Biology (FASEB), among other prestigious organizations.
Next, we have Dr. Sajad Zalzala, also known as Dr. Z, Co-Founder and Chief Medical Officer of AgelessRx. He’s on the board of the International College of Integrative Medicine and has chaired two of their international conferences. Dr. Z has also been involved in several successful healthcare startups, including Pill Club, Jack Health, For Hims, and Modern Fertility.
Joining us from Lifespan.io is Keith Comito, and I’m Oliver Medvedik from Lifespan.io as well.
Dr. Z:
On the AgelessRx team, we have Girish Harinath, who is currently overseas at ARDD in Denmark, and Stephanie Morgan, a recent addition to our team who leads our research efforts in the Applied Science team. Stephanie spearheaded the data analysis, so you may hear from her during the Q&A as well.
Let’s jump right into the presentation. So, just to give a bit of background, targeting the biology of aging is the key to longevity. Aging is by far the biggest risk factor for chronic diseases and mortality, and the rate of biological aging determines both lifespan and healthspan, both of which are thought to be modifiable through various interventions. The good news is that it’s thought to be modifiable through various interventions.
In recent years, Rapamycin has emerged as a promising gerotherapeutic agent, particularly in low-dose, intermittent applications. It has shown potential to mitigate age-related decline, extending both healthspan and possibly lifespan.
I’ll pass this over to Matt to discuss rapamycin in more detail, as he’s the world expert on this topic.
Dr. Matt Kaeberlein:
Thanks, Dr. Z. I’ve been studying rapamycin for a long time, and it really is the gold standard for pharmacological interventions that can positively modulate the biology of aging. Across virtually every model organism tested in laboratories, we’ve seen that rapamycin increases lifespan and broadly delays the onset and progression of age-related declines at the functional, tissue, organ, and molecular levels.
However, the big question—and the focus of the PEARL trial—is: How effective will Rapamycin be in positively modulating the biology of aging in the real world?
I’ve been involved with a clinical trial of rapamycin in pet dogs as part of the Dog Aging Project, and the PEARL trial is designed to assess its impact in humans.
There have been a few small clinical trials with Rapamycin, but the strongest evidence for functional improvements in humans comes from trials led by Joan Mannick with a derivative of Rapamycin called everolimus. They showed that six weeks of everolimus treatment in healthy older people boosted their immune response to the flu vaccine with minimal side effects. This once-weekly dosing schedule has helped guide the design of the PEARL trial.
However, broader understanding of gender-specific effects and optimal longevity dosing for Rapamycin is still absolutely needed. We really don’t have much in the way of evidence for what’s the best or most effective strategy for dosing Rapamycin in humans to ensure that patients get the longevity benefits without getting much of the side effects, which we know can occur in organ transplant patients when taking Rapamycin at higher doses. But we can come back to this later in the discussion.
Dr. Z:
Absolutely. There’s still much to learn, especially about the optimal dosing of Rapamycin for longevity in humans and the potential sex-specific effects. But these open questions are what brought us to the PEARL trial.
The PEARL trial was conceived about five years ago, just before the pandemic. There was a growing interest in the longevity community around prescribing Rapamycin, but, as Matt mentioned, there weren’t many studies supporting the dosing guidelines, and there were concerns about safety.
The goal of the PEARL trial was to explore dosing for Rapamycin and assess safety markers. It’s designed as a safety and efficacy trial, with the aim to be one of the largest and longest studies of Rapamycin in humans. Most human studies so far have been short and narrow in focus. This is also one of the first crowdfunded human randomized controlled trials (RCTs), and thanks to Lifespan.io for helping us host this today.
Our study looked at a broad range of healthspan metrics in aging individuals who are generally healthy and free of major diseases, with the hope to collect real-world evidence as opposed to testing mice in labs. We’re hoping this will be the first of many larger trials.
Oliver:
What are some of the key questions you’re aiming to answer with this trial?
Dr. Z:
Great question. Some of the key questions we’re looking to answer include:
- How safe and well-tolerated is Rapamycin?
- What is the optimal dose for longevity?
- Are there sex-specific differences in responses to Rapamycin?
- Does Rapamycin show potential as an effective healthspan-enhancing intervention in normal, aging adults?
This is a mouthful, but these are the big questions driving our study.
The study design changed a bit over time, but we ended up enrolling 115 healthy individuals aged 50–85, aiming for a trial that could look at safety, biomarker changes, and healthspan metrics over a 12-month period.
Initially, we looked at 5mg and 10mg doses of Rapamycin, which we decided based on discussions with experts in the field. Our primary objective was to establish a long-term safety profile for a single dose of Rapamycin administered weekly in a healthy adult population. The secondary objective was to assess the long-term efficacy of Rapamycin in altering the clinical signs and physiological endpoints of aging in healthy older adults.
For clinical endpoints, we chose visceral adipose tissue (VAT) reduction based on a smaller Rapamycin trial by a group called Better Humans. Although their study wasn’t published, they observed improvements in visceral fat, which we felt would be a useful endpoint to evaluate.
We also looked at adverse effects, metabolic and safety biomarkers, and secondary endpoints like quality of life, joint health, and epigenetic aging clocks. We included the SF-36 and WOMAC for quality of life and joint health surveys.
To set expectations, we should mention that, because this was a decentralized trial and we drew from a highly enthusiastic crowd, our participants had high baseline health. Most of them were already doing everything they could to stay healthy, which we reflected in our health composite score. You’ll see that a majority of the participants scored quite high on this metric at the beginning of the study.We kind of had a little bit of an uphill battle because so many patients were already so healthy.
To provide a baseline health status, we asked patients to complete health surveys, blood work, and DEXA scans. We asked participants to complete more blood tests at 2 and 4 weeks in to continue monitoring, then we repeated the full baseline health
During the pandemic, many organizations shifted to decentralized trials. In many ways, we were ahead of the game. Had we known the pandemic was coming, we might have waited it out, but we didn’t have much to rely on in terms of power and efficacy, so this was very much an exploratory trial.
About a third of the way through trial enrollment, an issue came up with the bioavailability of the non-encapsulated Romy we were using. Although we planned for a 5mg or 10mg dose, it turned out to be closer to 1.5g-3.5g, based on another study we published a couple of weeks ago. If you’re interested in the difference between encapsulated and non-encapsulated forms, there’s another webinar and study that I encourage you to explore.
We also discussed the healthy user bias. When someone is already at their peak, it’s always hard to see improvement. However, I believe we achieved our goal and are now ready to move on to larger, more rigorously designed clinical trials. The data gave us the confidence to expand.
Key Findings
First, regarding safety, we didn’t observe many rapamycin-specific adverse reactions. When looking at adverse reactions overall, there wasn’t any statistical significance between the three groups, as shown in this chart. For COVID-19, there were some clues—though not statistically significant—that Rapamycin could be protective. This was also seen in an observational registry trial conducted by the University of Washington, which we helped participate in.
For side effects, there didn’t seem to be any that were Rapamycin specific, but keep in mind that this was a trial that was run during the pandemic. So we had several waves of COVID come through during our trial, which was more difficult to tell what was causing the side effects. Luckily, no major side effects were seen during the trial that were thought to be caused by Rapamycin
Interestingly, the most common side effect was gastrointestinal upset. That could be because of the lower bioavailability of the dose we used, but it could also just be noise. Otherwise, there didn’t seem to be any differences between the groups.
DEXA scans revealed positive benefits in body composition for Rapamycin users. Because the study ended up smaller than we’d liked, there weren’t any statistically significant differences in DEXA scans. But the 10mg group had the most consistent benefits relative to placebo, while the 5mg group showed improvement across 2 of the 3 measures. Lean tissue mass had the most robust improvement relative to placebo. But I want to emphasize that the limitations of the design make it more difficult to tell.
You can see from looking at the graphs that, as expected, VAT would go up while lean tissue goes down for every year that passes. This is especially true for this age group because, once you hit 50, signs of aging start accelerating.
Bone mineral content and bone marrow density were accelerated for males taking the 10mg dose, though there were also several decreases noticed for both genders and both doses, so it’s hard to say if this metric is just noise. Not all males had a bone mineral content increase, and not all females had a bone mineral content decrease; one female patient reported a 15% increase in bone mineral content after 2 years on Rapamycin. Again, the age range may affect these results. In order to determine if these higher results aren’t just a one-off, we need to conduct more rigorous trials, which we hope will come as a result of PEARL.
In terms of lean muscle tissue (LTM), this is where we saw the most robust data, especially in female participants at the 10mg group. Unfortunately, though these results were statistically significant, we did not enroll as many female patients as we would have liked, so we cannot determine how statistically significant these results are truly. Nonetheless, all 6 female participants in the 10mg group displayed LTM improvements.
And Stefanie could you tell us a little more about this next section? I know you put together the next graph, if you want to tell us a little about why you put this chart together for us.
Dr. Stefanie Morgan:
Yeah! Happy to. We found, as we were looking through the data, that we had these differences in response, and while we didn’t want to make big claims about these differences, we did want to understand what was different. We saw that if we looked into the data a different way, there were patients who did really well on Rapamycin, while there were others who didn’t have much of a response. Nobody really seemed to have any detrimental effects, so we made a graph of who improved and who declined given each DEXA metric during the trial.
Dr. Z:
Among the 10mg users, you can see that more participants improved than declined. Though we’re not trying to stretch the results, we are definitely trying to make the best of a limited data set. We’re confident this will inspire others to run with this data and expand in larger trials.
Dr. Stefanie Morgan:
We also had some interesting data from our foreign partner. Similarly, we were trying to take the data we have available, and identify areas for expansion and questions for future research. Our study was not powered in the beginning to find significant effects/benefits, it was really more to evaluate whether these doses were safe. But as we went along, we took those people that improved or declined just to see if we could identify any markers that would suggest there was some kind of loop that we should pay attention to in the future.
We had some data from our partners about measurements to our gut health and gut microbiome. Those who did well overall on Rapamycin often had healthy benefits to their gut microbiota. Those in the 10mg saw improvements to their LDL, but health, and immune readiness, with the most improvements to LDL. By contrast, the placebo group saw gut health and immune response get much worse, while LDL improved slightly but not as much as in the 10mg group. Of course, doing this during a global pandemic is worth noting.
These are just interesting facets of the data that we as curious scientists identified as questions that we personally would want answered, so we wanted to provide these as jumping off points for others to explore in future research. However, there is no directional information here; we don’t know if these changes are caused by Rapamycin, or if they’re potentially caused by some other change in diet or lifestyle habits, or if Rapamycin drove this. So, we don’t want to imply that these results are in any way causative, as they’re only correlative for now. We kept getting questions about what’s next after this study, and this is our response to that!
Dr. Z:
It’s interesting that we saw a drop in LDL. There’s been some concerns that Rapamycin may increase lipid levels, but here we saw the opposite: a near 20% drop in LDL. That’s reassuring to us that we’re not disturbing lipid metabolism. We do have a larger dataset through AgelessRx patients and user metrics that we plan to review in the future, that may give us more clues as to how Rapamycin improves various different biomarkers.
Moving on, we also surveyed quality of life metrics on Rapamycin using the SF-36. Again, we started with really high baseline QOL scores, but we still noticed that all groups improved in QOL metrics over the trial period. The female group really led results; for males, results were hit or miss.
For patient WOMAC scores (a survey that measures osteoarthritis and joint health metrics), females also dominated the improvements. Female users saw general positive improvements across measures of frailty. This was especially true for the 10mg female group. Of the men who saw improvements in their WOMAC scores, the 5mg saw the most improvement.
Conclusions and Next Steps
So where does that leave us, and what can we take away from this?
- No significant differences in adverse reactions or events, and no concerning biomarkers in healthy adults taking Rapamycin for 48 weeks. So at least within this limited timeline, we saw no reason to be concerned about patient safety.
- It also seems like the low dose weekly Rapamycin, at least when taken over the course of a year, has more improvements in the health domains that we looked at over the control groups, with the 10mg group showing the most benefits/improvements.
- Benefits for Rapamycin seem to be more pronounced in women for men, suggesting that men may need a higher dose to achieve similar results
- Variability in response to Rapamycin underscores the importance of personalized dose tailoring and routine efficacy monitoring
I suspect that if you find the right dose for the right individual, they’ll most likely respond to Rapamycin as we suspect, but there are likely some patients that won’t respond to Rapamycin at any dose. These are just my clinical suspicions, but definitely topics to be followed up on in future research.
For next steps, AgelessRx is looking to expand on this and our data on blood Sirolimus levels to create larger trials.
We now have hundreds of Sirolimus blood levels from patients as a result of our previous trial, which we’ll be looking to follow up on by putting together graphs and charts so we can derive further insights from these data. We should specify that Sirolimus levels are not the key: we don’t know that the levels of Sirolimus in your blood controls how much benefits a patient receives. It’s possible that, for 2 patients with the same levels of Sirolimus in their blood, 1 patient experiences benefits while the other doesn’t notice any benefits. We’re also hoping to collect more longitudinal data on patients from the PEARL trial, who have largely been enrolled in a continuing prescription for Rapamycin through AgelessRx.
In the future we’d also like to improve our Rapamycin biobanking efforts. We did have some patients biobank their samples, but it wasn’t enough to provide significant analysis. We’d like more biobank samples in future efforts to evaluate changes in biomarkers of aging and determine other predictive signatures of clinical effectiveness.
Finally, we aim to evaluate Rapamycin for weight loss benefits. One of the reasons I personally got interested in Rapamycin is because I’d heard from several patients and prescribers that Rapamycin can cause some weight loss, if not at least maintain weight. We’d like to evaluate specifically whether Rapamycin helps to maintain weight loss results for those who are weaning off Semaglutide. This could open the gates to evaluating Rapamycin in combination with other weight loss treatments down the road.
I’d also like to thank everyone who came together to make this project possible. From the patients, to volunteers, researchers, lab technicians, pharmacy partners, Lifespan.io, Matt Kaeberlein, there are too many people to thank!
Okay! Let’s open it up for Q&A!
Q&A
Girish:
Fantastic, first I’ll go through some of the questions we have, and I think the best way to do this is just go around the panel and get everyone’s responses. Of course, if you’d liek to comment on some of the trial data before moving into the questions, that’s totally fine too.
I’ll start with the following: Why was Compounded Rapamycin chosen when going into this trial? Given the results at hand, do you think there are any advantages to Compounded Rapamycin, either logistically or biologically?
Dr. Z:
Going back 5 years, compounding medications tends to be a favorite among longevity doctors. That was the first reason why, because it seems to be a trend. We also wanted this study to be as practical as possible, so the practical applicability is part of what drove that decision.
Commercially available Rapamycin normally comes in .5mg, 1mg, or 2mg doses. For Compounded Rapamycin, you can adjust to just about whatever dose you want. This would also set the stage for customizable doses and personalized treatment. Again, another practicability consideration.
The other reason which I think is underappreciated is regarding placebos. If anyone’s seen generic Rapamycin, they have this weird pyramid shape with a particular coating on it. Finding a placebo to match that was nearly impossible; doing so would’ve dwarfed our budget unnecessarily.
We did not understand that there were differences in bioavailability until we were partially through enrollment and had already designed the study. We realized that generic Rapamycin is encapsulated to improve its bioavailability, then we also found out the ITP also had trouble with absorption. Then we completed our bioavailability study that seemed to indicate there was a 1:3 ratio of absorption for compounded Rapamycin. We decided to continue and hope that the lower bioavailability gave us results.
It’s possible that a lower bioavailability means that more medication gets into the gut. This could be an added benefit, but we don’t know, so it’s currently speculative.
Dr. Matt Kaeberlein:
It’s possible, but I’m guessing it’s probably not the case, given that Rapamycin is unstable at gastric pH, so I’m guessing that we probably just have less get into the small intestine. However, the honest answer is that we simply don’t know.
But to get back to this issue of compounding: I think this points out one of the challenges of doing clinical trials in general, and particularly these kinds of clinical trials, which is that you have to take your best guess and live with it for a variety of reasons. These are driven by a combination of the scientific knowledge of the study designers, and understanding of what regulatory bodies will allow you to do, so they come from both a scientific and a practical standpoint. I don’t think there’s any reason to be critical of the team on this compounding question: it was the best decision at the time, and we got some really solid results out of it.
Regarding any advantages to Compounded Rapamycin, I think it’s best if I provide my own takeaways from this study. First of all, Dr. Z, I want to applaud you for presenting this in a very balanced way, without overstating the results. I think the strong conclusions we can draw are pretty limited, but there are a few things we can say.
I think the big takeaway is that Rapamycin, across a pretty wide dose range, can be used safely in otherwise healthy people. So outside of the context of organ transplant patients who are taking other immunosuppressants and taking high doses of Rapamycin, usually daily, I think we’re seeing that Rapamycin is pretty safe when taken at the doses that people usually take for off-label prescription. So this is additional safety evidence that adds to a longer body of evidence, which I think is always good to have.
I think the one piece of data that jumps out to me is the change in lean mass. These results look real to me. They’re at least statistically significant in women of this study. This also fits, at least anecdotally, with what my experience has been on Rapamycin and what I’ve heard from others. I’ve heard just about the same thing from the same groups of people as Dr. Z about Rapamycin and weight loss, so I think there’s real biology there, and I think we can even point to potential mechanisms based on the existing literature.
The last thing I’ll say is that I know a lot of people will be frustrated by the fact that we’re saying it’s limited what we can interpret from this study and more studies are needed. I don’t know what else I can say other than deal with it. If the people who can and should fund the larger trials for efficacy would get off their asses and step up and do it, then we’d be able to answer these questions definitively. There’s no point in complaining about the studies we do have in the meantime, not until somebody steps up and funds definitive clinical trials, as this is an ongoing source of frustration for us all.
Oliver:
To piggyback on what Matt said earlier about budgeting, we ran a campaign on Lifespan.io back in 2020 to raise funding for this study. This project was by far the largest amount we raised via crowdfunding, with over $200,000 raised and some additional funding that came in from parallel investors. I think this creates this alternative model for raising money and keeping the target audience and general public informed. This could also stimulate larger funders. Now that we agree with the results of this, it will be easier to get out in the public and say that this issue is worth raising larger funds for. I’m very optimistic that if we had larger funding we’d be able to more definitively answer these questions.
Dr. Z:
One thing I think will praise interest in these types of therapies is the X prize. I wouldn’t be surprised if multiple teams for this competition included Rapamycin in their presentation. AgelessRx hasn’t decided if we’ll be throwing our hot into this ring just yet, but we’re definitely interested. I think Rapamycin seems to hit 2-3 of the domains they’re testing. This could be the catalyst we need.
Girish:
Knowing what we know now following the results of this study, how would we redesign the next study concerning endpoints, biomarkers, or dosing?
Dr. Matt Kaeberlein:
It’s worth mentioning that in the survey-based study we published in 2023, reduced chronic pain was one of the things we noticed in Rapamycin users, versus non-Rapamycin users. Rapamycin users are more likely to self-report lower levels of chronic pain.
With that in mind, Rapamycin is interesting because you kind of have your pick of endpoints to choose from. There’s a lot of different stuff that goes wrong with aging, and Rapamycin seems to address a wide variety of them. Based on this study, I’d be more inclined to include a body composition analysis, maybe paired with resistance training.
Regarding dosing, this study is valuable in a sense because everybody assumes the dose was too low. We didn’t know that going in. Everybody’s assuming that 6mg once a week is exactly the right dose based on next to no data. So we’d probably want to start with at least 6mg once a week, but we could go higher than that even.
But the value in this study is that these doses are sub-optimal. You may also want to design a study that has a lower dose for females than for males.
So body composition tests for sure, and if you know my research you know I’m a big proponent of oral health. We see improvements in the oral health of rodents on Rapamycin, there’s a small study for periodontal disease going on now as well.
Menopause is also interesting, there’s also a clinical trial out of Columbia analyzing post-menopausal effects. There’s also a study of peri-menopausal women taking Rapamycin experiencing interesting effects. I would think about looking in that population and looking at hormone levels, symptoms of menopause, things like that.
There’s also cognitive function, tons of data in animal studies focused on age-related cognitive decline and dementia. Measurements of senescence in skin may be a good focus, there’s plenty of studies looking at whether cellular senescence in skin goes down with Rapamycin treatment, which is pretty easy in a clinical trial.
But this is one of the challenges: you have so many interesting endpoints that you kind of just have to pick. Almost all the gerotherapeutic trials designed today do not focus on efficacy. People don’t recognize this: you look at all the senescence trials, they’re all safety trials. We need to start moving towards efficacy and stop doing underpowered trials that show limited efficacy and call that a win.
Keith Comito:
Have there been any studies investigating the potential effects of Rapamycin on those with musculoskeletal issues? Remediation of musculoskeletal pain seems to be a result coming from data like this, but is work already underway to confirm that?
Dr. Z:
There’s a study going on in New Zealand by Brad Stanfield that’s looking at muscle function, and actually Lifespan.io helped to crowdfund that study. I don’t think he’s looking at pain, but I don’t think it would be unreasonable to add this as an endpoint. It would be interesting to evaluate what kind of pain potentially responds to Rapamycin. For example, could it be bone-on-bone osteoarthritis pain? Itises like tendonitis? Fibromyalgia type pain, like neuron-specific, sensory-motor-pathway-type pain? These are all really good questions worth exploring, though I personally haven’t seen any formal data on it.
We are looking at larger, observational, longitudinal, datapoints through our telehealth platform with our patient data, so we could have different results for you in about a year.
Dr. Matt Kaeberlein:
I always hesitate to say there’s never been a study on something, but there aren’t any that I’m aware of. But there’s quite a bit of anecdotal evidence out there and people using Rapamycin in combination with ketamine for severe chronic pain and depression, so there are a lot of interesting connections outside of the aging space for having effects on pain. In both of our short-term clinical trials with dogs for the Dog Aging Project—again, double-blind, placebo-controlled—the owners self-reported that these older dogs were suddenly more active, and I think a reasonable interpretation of that is a decline in pain that a lot of older dogs experience. Again, we just need more definitive studies to answer those questions.
Girish:
- How do you explain the push towards measuring Sirolimus blood levels and what value could that bring to clinical trials?
- Are there any robust biomarkers of mTOR activity?
- If we were able to converge on measuring blood levels and biomarkers of mTOR activity, how do you think that could affect clinical outcomes?
Dr. Matt Kaeberlein:
I think we don’t know what these optimal levels are either in terms of dosing or blood levels. What we do know is that there’s a bunch of individual variation, both in the bioavailability of a given dose and the rate at which that was cleared.
That variation really complicates our assessment of an optimal dose, because there’s a multi-variable equation we’re trying to solve for, and we don’t actually know what the endpoint we’re solving for is. This gets to your question of how do we measure mTOR, and it’s going to be different in different tissues, which is part of what makes this so challenging.
Even if we had a really good biochemical assay for measuring mTOR activity in blood, the mTOR activity in the brain is going to be different than it is in the liver, in the kidney, the intestines, than in all the different tissues and organs, so I just don’t think we know what the optimal thing to measure is to get to that optimal dose.
I know that’s not satisfying, but I don’t really have another answer other than: that’s why I think what we really need are the functional endpoints that we can compare to the molecular endpoints, and I think you guys have started to do this a little bit.
I’m very wary of this responder/non-responder analysis, but having said that, I do think we’re trying to figure out whether we correlate microbiome changes or LDL or other blood markers with what we think is a functional signal for a response or non-response to Rapamycin.
Those are the things I think we need to get better data on to be able to try to find an optimal dose. Right now there’s so much speculation in this idea of weekly dosing, knock down mTOR complex 1, don’t affect mTOR complex 2, we don’t even really know how to measure that. I’m just not super confident going down that route to say “You should take 6mg once a week, and this other person should take 12mg once a week.” I just don’t think we know. So we’re just doing the best we can while stumbling around in the dark.
Dr. Z:
It would be really nice if, through the regular biomarkers, there were some changes in some blood markers—let’s say RDW or something like that, or something more anatomical like visceral fat—that would help indicate how to dose.
For example, and this is a hypothetical, it would be helpful to say that you should dose with Rapamycin until you see a drop in your visceral fat. That would be really nice to have, I think that would warrant further studies to see what are these other surrogate markers we can look at.
When we sponsored a Low Dose Naltrexone trial on mice at the University of Washington, the study lead, Jon M, said that weight loss was one of the indicators for the mice. So something like that [for Rapamycin] would be nice to have, where we could say “You know it’s working because…XYZ.”
Canker sores are not a good sign. Some say that canker sores are a sign of when you are or are not on the right dose, but I think only about 20% of patients experience canker sores at all. It could be though, it’s possible. At this point, anything is possible. I have had a couple patients that got up to 6mg of Rapamycin and the canker sores got too intense, so I bumped them down to 4mg and the canker sores seemed to be a lot more manageable. So it’s possible that 6mg might be overshooting. So I’m hopeful we might be able to find something simple like that.
Dr. Matt Kaeberlein:
Getting more data on blood levels will be useful regardless of the fact we can’t necessarily translate that to mTOR inhibition in all the different tissues. I think one reasonable place to start is a hypothesis, and it’s a hypothesis because we don’t have data to support it yet, but if we really believe once weekly dosing is a good strategy, you could think about a strategy where you dose and you make sure you get below the detection limit of the assay before the next dose. You can measure that. For some people it might be 6mg, for some it might be 12mg, for others it might be 20mg. But then you can try to correlate that with side effects like mouth sores or other things you can measure like RDW or other blood-based biomarkers.
Another thing I’ll say is one of the tests we use at Optispan is an immune functional test that we think may give us some predictive capabilities for responders and non-responders to Rapamycin, so I think there are some opportunities to look at immune-based biomarkers for Rapamycin, which are probably going to be the most sensitive to Rapamycin, given what we know about how Rapamycin works.
Dr. Z:
Looking at longitudinal data from our telehealth platform, there is this phenomenon I’m seeing in a few people where the A1C seems to jump up, which does not correspond to an increase in glucose, which may have something to do with the turnover of red blood cells. I’m wondering if that kind of phenomenon needs to be studied more closely to see if there’s some correlation there between these potential bone marrow changes, or something else.
But I’ve seen it multiple times and I’m scratching my head wondering what happens whenever the A1C jumps up by usually .5%, which is big. But you look at their fasting blood sugar and it’s the same as their regular blood sugar, so I’m wondering if that’s potentially influenced by Rapamycin and something we could look at in the future.
Girish:
Those are all great points, and I think Dudley Lamming is organizing a clinical trial where I think A1C is one of the primary endpoints, but there are certainly a lot of different endpoints you could choose from, almost as if you’re throwing darts at a dart board.
Why didn’t we include biological age tests like DNA methylation clocks as an endpoint?
Dr. Z:
Well, we did, or we tried. I don’t think we had enough people perform the TruDiagnostics bioage test, but of the people who did, I’m not sure there were many noticeable changes to speak of.
Dr. Stefanie Morgan:
I can actually speak to that. We only had a fairly small cohort, and a small subset opted in for additional testing, so we didn’t have enough samples to see significant differences. The biggest differences we saw were by gender, which weren’t really surprising. I mean, to say that there are differences in methylation by gender isn’t surprising at all. It’s something that we would love to figure out a way to get more people to participate in the future so we can make stronger conclusions. I think that’s the biggest takeaway message for everything: we would love to have more participation.
Dr. Z:
I’m not optimistic about seeing methylation changes, not with the current clocks anyway. I’ve heard from multiple people, including Steve Horvath, who said “I’ve looked at unpublished data on Rapamycin and the methylation clock and there doesn’t seem to be any signals there.” But that could speak to the severe limitations of methylation clocks, because we know Rapamycin is doing something between the animal trials, human trials, seeing gingivitis getting better on Rapamycin, as well as tendonitis…we know it’s doing something. So it might just be that it’s not doing the right something to show up in these methylation clocks.
Dr. Matt Kaeberlein:
Can I just add, nobody serious would use a biological age clock as a primary endpoint for a clinical trial, they’re just not ready for primetime in that way. I think they’re good research tools, I think you could do it as an exploratory endpoint, and that sounds like what you did, which makes perfect sense.
We use some of the same methylation tests at OptiSpan for exploratory analyses on some of our clients, so I’m not bashing those companies, I’m just saying we don’t know anything about variants, technical replicants, that is all opaque to us. So it is not an appropriate type of data for a rigorous scientific clinical trial without that information.
It’s hard to know how sensitive some of these tests are, you can’t do any statistical power calculation without having that information, and so I feel like it’s fine as an exploratory thing, but I think a lot of the people watching this webinar really don’t understand the limitations with some of these biological age tests as they exist today, and especially using a for-profit commercial company as the vendor for these tests.
Sorry, I know some people from those companies may be listening. Again, not trying to bash those companies, great companies, great people, but there are some limitations to the data that we have on some of those tests.
Dr. Z:
Which highlights that we need multi-omics, we can’t just rely on a methylation clocks, we need data to aggregate the data to come up with a kind of master methylation clock, if there ever could be such a thing. It’s just too early to say, I think.
Girish:
Just to cover a few other ways they’re being used, there’s one trial in Singapore that is using I think DNA methylation tests as a screening tool for inclusion/exclusion. When you look at these biological age clocks, I think we definitely put too much weight on them, but there does seem to be associations that you can make. Are they as good as looking at A1C or other clinical markers? That’s an open question, but I just wanted to put out that there may be other ways to use them that aren’t tied to efficacy. Especially with these omics tools, if you can find patterns, then I wonder if you can use them to predict clinical effectiveness if they’re stable enough, which is the big question—stable across time.
Dr. Matt Kaeberlein:
I think we can, but again, I think we want to be careful about who’s doing the measuring, where’s the measuring being done, and what do we know about the quality control at the locations where these measurements are being done.
There’s no reason to think that a for-profit company can’t do as good or better than an academic lab at doing these assays. I’m sure they can, but we don’t have that information. We don’t have any information about the quality control at all of these companies that are offering these epigenetic tests to consumers, so we just don’t know. Why would you believe it in the absence of that data? As a scientist that’s always the question I have to ask.
Girish:
Up next, one of the questions was regarding sexual dimorphism. Sexual dimorphism and the sex-specific effects in Rapamycin have also been popping up in the literature. With mice you see enhanced lifespan in females, as well as enhanced bioavailability. With marmosets, it’s kind of the inverse relationship where you see that there’s a higher bioavailability in males. But when it comes to standardization, there’s a lot of complexity there. In our bioavailability study, we didn’t see any differences at the 24-hour mark (24 hours after taking Rapamycin) between men and women in blood levels. In the PEARL trial, we do see statistically significant sex-specific, female-specific effects. Can you all talk to or address what you think may be driving some of this based on what we know at hand, and even some hypotheses you may have?
Can we talk to what we think are driving some of the sex-based differences in benefits for Rapamycin?
Dr. Z:
Before I go on to answer that, I know someone brought up why we didn’t check Sirolimus levels. This is maybe a clinical pearl for those who are interested in starting their own trials, but it turns out we couldn’t prevent people from seeing their Sirolimus levels, so we were in danger of unblinding the participants. We had to stop checking Sirolimus levels in our participants, so we purposely stopped. That’s one unfortunate thing we learned after launching the trial.
To answer the question, I think it could be something to do with the immune system. Females in general tend to be much more prone to autoimmune conditions, for example. It could be that Rapamycin is working to improve their immune system that men just don’t have the same issue with. But that’s just pure speculation.
Dr. Matt Kaeberlein:
And just to comment on the mouse data, there’s this misperception that Rapamycin works better in female mice than in male mice. I think the data on the whole don’t support that.
What the data suggests is that, at a given dose, female mice are either more responsive or have greater bioavailability of Rapamycin, so the dose response is shifted. But if you keep pushing the dose higher, eventually the male mice will get the same benefit, but the maximal benefits seem to be in female mice. Again, that hasn’t been completely worked out, but that’s pretty solidly what the data suggests. It’s not that females respond better, it’s a shift in the dose response.
In humans, I don’t think there’s any evidence to suggest that same phenomenon is happening. I think Dr. Z’s speculation makes perfect sense. It could all come down to chronic inflammation and immune-related processes where, in females, those are just more of a burden at a given stage in their lives than with men.
Now, I do wonder if this at all relates to perimenopause and menopause—this has already come up once—given the evidence that Rapamycin can affect ovarian aging, and can potentially affect symptoms of menopause. That may be tied together, those aren’t mutually exclusive and probably some of the inflammatory symptoms are driven by hormonal changes, so I think those are connected and reasonable potential explanations for what we’re seeing here.
Girish:
And just to note, the average age of participants in the PEARL trial was around 60-62. So post-menopausal women. That’s definitely interesting.
Another question that came in: Do we think that Sirolimus is the optimal form of Rapamycin, or are there other forms in the pipeline—like Everolimus—that might be more promising?
I know some of this is contingent on the hypothesis, largely built by Dudley Lamming and crew, that more specific mTOR-1 targeting is going to lead to greater efficacy and reduced side effects. But, interested in both your thoughts on that.
Dr. Z:
I can take a shot at responding to the practical aspect of that, and then Dr Matt Kaeberlein can get into the scientific aspects of it.
Everolimus is incredibly expensive. When I looked it up on GoodRx, I think it’s something like ten times more expensive than Rapamycin/Sirolimus. And Rapamycin itself is not an inexpensive medication, either. So that’s one practical aspect.
From my perspective, I don’t think there are very many animal studies, so I just think we know even less about something like Everolimus than Sirolimus or Rapamycin.
Dr. Matt Kaeberlein:
Yeah, I agree completely. I think right now, Rapamycin or Sirolimus—which, for those of you who aren’t Rapamycin aficionados, are the same thing, two different names—that’s the best we’ve got, given the data we’ve got.
To the extent that I can be 100% certain about anything as a scientist, I’m 100% certain there are better mTOR inhibitors out there in terms of efficacy, we just haven’t looked. And Dr. Z is absolutely correct: there’s a little bit of data out there on Everolimus, and almost nothing about other mTOR inhibitors in the basic literature on longevity. So we just don’t know because nobody’s looked.
I can tell you that a company we spun out of my lab called Aura Biomedical, which is a high-throughput longevity drug discovery company primarily using c. elegans, looked at only a few dozen mTOR inhibitors and found at least one that’s much better than Rapamycin for longevity in c. elegans. So I think if people were to go look, we would absolutely find drugs that target mTOR and have better efficacy than Rapamycin.
Would they be Rapalogs I think is an interesting question. For those of you who aren’t in the weeds, Rapalogs you can just think of as derivatives of Rapamycin that biochemically inhibit mTOR through the same mechanism as Rapamycin. There are other ways to inhibit mTOR biochemically, but no one has really looked at any of these other mTOR inhibitors in any great depth in the context of longevity. I’m pretty confident there are other things out there better than Rapamycin in that context, but nobody has looked. And Rapamycin works pretty well, we think, so I think pragmatically that’s what we should be focusing on right now.
Dr. Z:
Yeah, we can’t get people to fund Rapamycin, so not sure how we’d fund studies on other mTOR inhibitors!
Dr. Matt Kaeberlein:
I do think this question of mTOR complex 1-specific Rapalogs that you mentioned is an interesting hypothesis. It is still a hypothesis—it has not been proven that you can get better effects on longevity or healthspan with a Rapalog that is more specific for mTORC1 than mTORC2.
It sort of gets talked about as if that’s true, but that has not been proven. So, somebody needs to actually show with real data that an mTORC1-specific Rapalog is better than Rapamycin before we get too far down that road in really believing that’s the case.
There are some companies developing these drugs, so hopefully we should get some more data sometime in the near future that supports that hypothesis.
Girish:
Excellent, well here’s a fun question for us that will be totally optimistic and speculative. How large an impact does the panel think Rapamycin could have both in terms of lifespan or healthspan? How do we think Rapamycin compares right now if we could start optimizing protocols moving forward?
Dr. Z:
Well I think Matt is definitely the most qualified to answer that!
Dr. Matt Kaeberlein:
Well, of course it’s speculative so we’re all entitled to our opinions here. I think it depends on who you’re talking about. If you’re talking about someone who’s got the other factors more or less dialed in, doing a reasonably good job on lifestyle factors…you know, I almost hesitate to speculate on this because I know it’s going to end up on X!
I feel like, realistically, for some people, Rapamycin can probably give you a decade of quality healthspan—total speculation. But given what I know and what I have experienced, I think that’s probably a reasonable speculation. It might be more, it could very well be less.
For some people, it will be more in terms of quality of life, because I think particularly people who have a high burden of sterile inflammation, which can have a pretty high impact on quality of life, I think Rapamycin is very effective at knocking that down. That could be a really,really large impact on quality of life for those people that lasts many, many years.
So it could be bigger than that for some people, but I think if you got most of the other stuff dialed in, it’s not going to be 30 years. I hope it is, but I don’t think so. I don’t see anything that’s making me believe that at this point.
Dr. Z:
Yeah, I like to be optimistic about it, and I think that if it is making some fundamental improvements to some of the hallmarks of aging—like inflammation, like microbiome, things like that—you could see a scenario where over time you see a bigger and bigger improvement between the users and the non-users.
How far that will take us? I don’t know. You even cover this on your recent OptiSpan podcast, but even with some of the most sophisticated genetic manipulation in mice, they seem to hit a wall, no matter how well you do on the healthspan aspect.
Humans could be different. We are different in many, many ways, so it is possible that humans could go past that wall. But with Rapamycin alone? Probably not. I think you’d definitely have to add other therapies to rapamycin if you want to have the best shot.
Keith Comito:
Clearly going to defer to the experts here, but I echo Matt’s point. I would be surprised if it went beyond something like 10 years, I think that would be more of an upper limit.
But something I wanted to venture forth on, and something I’m excited about that further testing on Rapamycin could show: one question that I’m not sure has been officially touched upon much is, if you do get life-extension benefits, or healthspan benefits, how much of that is due to some core systemic things that are actually changing versus pain remediation and secondary factors that might help people become more active, and then get benefits that way.
So it seems like Rapamycin has those potential positive side effects. I think, in the future, it will be important in those studies to elaborate on what are the mechanisms of actual healthspan extension. That’s one of the reasons why I’m excited about the results here.
Of course, at the end of the day, we want to get to the root of the things that will be changing something fundamental and core. You don’t want to just have the secondary, tertiary benefits. I think whether this has that as well, I can see this being important in this grand hypothesis testing later. Does that make sense?
Dr. Matt Kaeberlein:
That’s a good point, Keith. I think we already know that Rapamycin is doing more than that, at least based on the animal studies. As Dr. Z alluded to, we can find evidence in the literature that all of the hallmarks of aging are affected by Rapamycin, and we actually know some of the molecular mechanisms there.
I think it is clearly the case, at least in laboratory animals, that Rapamycin is modulating biological aging, as we understand it today. It’s not only improving these things indirectly. It could be doing those things as well, and I agree with you that we need to understand those mechanisms and appreciate what the relative contribution is.
I only say this because sometimes people get confused and say things like “Rapamycin delays cancer.” Well, yes, it delays cancer, but it does much more too. I think we can be sure that it’s not only doing one indirect thing indirectly, and that’s what accounts for all of the various lifespan and healthspan benefits that’ve been seen in laboratory animals.
Of course, people are different, and we don’t know yet in humans.
Girish:
Awesome answer. You know, the oldest woman alive just recently died at 117 years old, and we have case examples of individuals living relatively healthy lives, so extending that healthspan is definitely not beyond the question, even for living a healthy life into our 100s.
Dr. Z:
And I don’t think we should trivialize that, either. I know there’s some pessimism that extending lifespan seems to be beyond our range right now, but hey, I’d take 120 years in good health! That would be a huge accomplishment. So I think we may be far away from figuring out how to extend maximum lifespan, but we have so much work to do even just to improve by 10 or 20 years.
I’m a lot more optimistic that we have good tools like Rapamycin that can get us a good chunk of the way there, but they just need to be explored further.
Dr. Matt Kaeberlein:
I just want to echo that because that’s such a hugely important point. People have been talking about immortality or doubling human lifespan so much in the longevity community bubble that the actual impact of a decade or two of additional high-quality life for most people gets underappreciated.
I mean, think about it: what could you do if you have 10 or 20 years of high-quality life? Think about what you were doing 10 or 20 years ago. That’s really important at an individual level and a population level.
We shouldn’t lose sight of that because I agree with Dr. Z that we’re really, really close to that.
Girish:
I’m going to end with this one last question to kind of tie everything together.
What’s in the future for AgelessRx in terms of following up with these studies on Rapamycin? And, for Matt, what’s the status of the Dog Aging Project?
Dr. Z:
At AgelessRx, we are prescribing Rapamycin to people who we think it’s appropriate for. We do require blood tests so we can monitor patients for safety, but that also provides us very valuable data. We are planning to start initiatives to enroll volunteers for DEXA scans and things like that to look at our telemedicine users on a longitudinal scale.
Like I said before, we’re hoping that provides much larger datasets, even though it’s not in the realm of an RCT. I think the larger longitudinal data will give us much better insights.
We are considering the X prize and enrolling as a team. I think the current available tools can go a long way towards improving function in the three domains they’re looking at. Whether or not we have the resources to compete, we’re still considering. But I’d really like to compete. I think that the work we’ve done with the PEARL trial is impressive.
Another thing we didn’t talk about was that it was also meant to be our engine of research, where we’d start with PEARL, work the bugs out, including who the software partners and pharmacy partners are, and then once we have the infrastructure in place, then that would open the possibilities for a lot of other studies.
If someone came to us with a $1 million or $10 million grant, I think we could quickly spin out the infrastructure to do pretty much whatever trial someone would want us to do within the repurposed drugs arena. That’s the other big thing that I think came out of PEARL for us.
We have a large database of patient data too. We’ve published one trial about it using Low Dose Naltrexone quality-of-life metrics.We have biomarker data and other things like that that we’ll also be digging into. PEARL took up so much of our resources that, now that it’s over, we can start moving on to other initiatives.
So we’re just getting started as far as I’m concerned, and we’re really optimistic about where we’ll be going over the next few years.
Dr. Matt Kaeberlein:
That’s great! So, Dog Aging Project update.
As many of you may know, the Dog Aging Project was largely supported by the NIA and NIH grants that were not refunded. That put us into a very challenging position.
Fortunately, the Dog Aging Project is still alive and well today. My partners and I went out and founded a 501C3 non-profit called the Dog Aging Institute. We’ve raised a little over $1 million to keep the project afloat and resubmit our NIA and NIH grants, one of which is for a Rapamycin project that is also part of the Dog Aging Project.
We got a good score, so I’ve gone from cautious to cautiously optimistic. I think that trial will finish—which is obviously important. It’s been set back a couple of years by this nonsense, but we will get it done.
We are still waiting to see whether this larger longitudinal study on Rapamycin will be funded by the NIA. We’re trying to raise philanthropic funding through the Dog Aging Institute. If anyone is interested in supporting the project, I would be grateful. You can go to dogaginginstitute.org, where we’ll be rolling out a campaign next month, which I believe AgelessRx is going to help us amplify, and I’m thankful for that, as well.
So I think it’s looking better than it was a year ago. I’m very hopeful that the Dog Aging Project will continue to carry out this longitudinal study of aging, which has amassed a really interesting and deep dataset that is being made available to the larger scientific community, and has also engaged more than 50,000 Americans in geroscience research, which probably had a bigger impact on the perception of geroscience research on the greater public than just about any other scientific research out there.
So there are a lot of reasons why we should all be hopeful this project continues.
Dr. Z:
Thank you everyone! Thanks especially to Lifespan.io for organizing this crowdfunding campaign, without which we wouldn’t have been able to complete the trial. Thank you Matt for supporting us along the way, and again, I would like to thank everyone who contributed, participated, and worked on this project. We’re looking forward to many more webinars like this one, which we hope people will find informative!