Rapamycin Dosing and Side Effects for Anti-Aging and Healthspan

Jump To Section

• Organ Transplant Rapamycin Dosing
• Anti-Aging Dosing Regimen
• Common Side Effects of Rapamycin
• Infection Risk and Immune Balance
• Data Gaps and Important Cautions
• Full Transcript

Organ Transplant Rapamycin Dosing

Dr. Matt Kaeberlein, MD, PhD, explains the established clinical use of rapamycin (sirolimus) in organ transplant patients. The typical regimen involves an initial loading dose of 4-10 mg per day. This is followed by a continuous maintenance dose of a couple of milligrams daily. Dosing is often individualized based on desired peak and trough blood levels. Dr. Matt Kaeberlein, MD, notes that organ transplant patients typically take rapamycin every day for life to prevent organ rejection.

Anti-Aging Dosing Regimen

The potential use of rapamycin for healthspan extension involves a completely different dosing strategy. Dr. Matt Kaeberlein, MD, PhD, states that most researchers have settled on a once-weekly oral dosing paradigm. The typical rapamycin anti-aging dose falls in the 4 to 6 milligram range taken once per week. This approach is based on anecdotal reports and data from clinical trials using everolimus, a rapamycin derivative. In a study with healthy older adults, a 5 mg weekly dose of everolimus improved immune response to the influenza vaccine.

Common Side Effects of Rapamycin

Dr. Matt Kaeberlein, MD, PhD, highlights the different side effect profiles between long-term daily use and intermittent weekly use. In organ transplant patients on daily rapamycin, known side effects include hyperlipidemia, mouth sores (canker sores), increased infection risk, gastrointestinal issues, potential wound healing defects, and a pseudo-diabetic state with insulin resistance. For the once-weekly 4-6 mg rapamycin dosing, short-term data over 6-10 weeks shows minimal significant side effects. The most commonly reported issue is the development of mouth sores.

Infection Risk and Immune Balance

A key consideration for rapamycin use is its impact on the immune system. Dr. Matt Kaeberlein, MD, discusses a potential two-fold increased risk of bacterial infections with ongoing use, which aligns with the drug's mechanism of action. He notes this risk appears manageable, as bacterial infections are typically treatable with antibiotics. Interestingly, this risk may be balanced by a corresponding benefit. Rapamycin might provide a potent increase in resistance to viral infections. This is supported by the everolimus trial data showing protection against subsequent viral infections, including coronavirus.

Data Gaps and Important Cautions

Dr. Matt Kaeberlein, MD, PhD, and Dr. Anton Titov, MD, emphasize the critical lack of long-term, double-blind, placebo-controlled clinical trial data for rapamycin in healthy aging. The current once-weekly dosing regimen is based on educated guesswork, not proven efficacy. Dr. Kaeberlein cautions against extrapolating directly from mouse studies to human recommendations, using protein restriction in the elderly as an example of a potentially harmful practice. Anyone considering rapamycin must understand these significant data gaps and consult with a knowledgeable physician.

Full Transcript

Dr. Anton Titov, MD: So, having mentioned that important disclaimer, in general terms, can you highlight the differences in the prescription of rapamycin for its original purpose—for organ transplant—and for anti-aging or other indications, including Alzheimer's disease, for non-transplant patients? What are the differences in frequency, dosages, and observed or expected side effects, just in general terms again? Not giving medical advice is important to mention once again.

Dr. Matt Kaeberlein, MD: Sure. In organ transplant patients, there's a bit of variation in the typical regimen. This is my understanding—I'm not an organ transplant doctor, so this is based on what I've read and from talking to organ transplant doctors. My understanding is that rapamycin, which is called sirolimus in the clinical community, was first approved for kidney transplant rejection. That's probably where there's the most data.

Usually, there's what's called a loading dose, which is a higher dose—maybe four to ten milligrams a day when patients first go on rapamycin. Then there's a maintenance dose, which is typically a couple of milligrams a day. It's daily dosing, oral, usually tablet. That dose is based on desired peak and trough levels in the blood, so there's a little bit of individual dosing that goes on there.

Still, it's typically in the couple of milligrams, maybe even a little bit higher, sometimes everyday paradigm, and it's continuous. If you've had an organ transplant, the reason for taking immunosuppressants—and sometimes rapamycin or other mTOR inhibitors—is to prevent rejection of the transplanted organ. You take your medication every day to prevent rejection, and it's usually continuous for the rest of your life.

Now, organ transplant patients sometimes come on or go off of different medications, including rapamycin, but you're going to be on that immunosuppressive regimen for the rest of your life. That's very different than the context of potentially using rapamycin for health maintenance or disease prevention, which is the way I think about it.

I think most people who are studying rapamycin in this context think about it as really keeping people healthy—it's not to treat a disease. In that context, the first thing to appreciate is it's all guesswork. It's educated guesswork based on data, but there haven't been double-blind, placebo-controlled clinical trials to evaluate what is the best dosing paradigm for rapamycin in this context.

So what most people have settled on is once-weekly dosing—again, oral tablets, usually in the four to six milligrams once a week. There's some variation there; some people do lower than that, some people do higher, but that's kind of the ballpark typical rapamycin dosing regimen right now.

That's really based on anecdotal data from a number of people who are public about their rapamycin use, and from a couple of really nice, relatively good-sized, randomized, placebo-controlled clinical trials with a drug called everolimus, or RAD 001, which is a derivative of rapamycin. It's a rapalog—just a slight chemical modification on rapamycin that changes the bioavailability a little bit.

In those studies, in this dosing range—like five milligrams once a week in healthy, older people—the side effects were essentially no different from placebo in the everolimus group, with a couple of minor exceptions. And it appeared to have efficacy for immune function in the elderly, specifically influenza vaccine response, which is interesting, and subsequent infection with several different viruses, including coronavirus.

Given the world that we live in today, that's also interesting. But I think the take-home here is that it seemed as if the rapamycin derivative was at least partially restoring immune function in healthy older people, allowing them to mount a better vaccine response to a flu vaccine and potentially protecting them against other viral infections in the subsequent year.

So that's the data that I think has really guided this development of a once-weekly dosing paradigm with rapamycin in that four to six-milligram range.

What are the side effects? In organ transplant patients, I can't—it would take a long time to read through the entire list of side effects that are in the box. For many of those, it's unclear whether they're even real side effects in organ transplant patients.

This gets to how manufacturers are required to list side effects on FDA labels. But some of the ones that seem to be pretty clearly caused by rapamycin in that context are hyperlipidemia, increase in mouth sores, a somewhat increased risk of infection—that's what you would expect for organ transplant patients on immune suppressants—gastrointestinal effects, potential defects in wound healing.

And then the other one that I think concerns people in the context of potential use as a preventative is an increased risk of something like a pseudo-diabetic state in organ transplant patients, where there is a decrease in glucose homeostasis and insulin resistance that's seen in people that take daily rapamycin for a long period of time.

There are a few others, but I think those are the ones you would be most concerned about, particularly the increased risk of infection for healthspan-promoting use, and the potential for metabolic defects in glucose homeostasis.

So what has actually been seen? Again, it's important to appreciate there isn't much in the way of double-blind, placebo-controlled data, especially for longer-term. Over the short term—six to ten weeks in humans—at once-weekly rapamycin dosing, there's almost nothing in the way of significant side effects.

Maybe with the exception that some people experience mouth sores—this is really like canker sores in the mouth. Not life-threatening, but maybe not particularly enjoyable. Beyond that, there's really no evidence for significant side effects.

What is a little bit—and this is where there's just an absence of data, and we hope to help address this in the project that I mentioned—is when you get outside of that six to ten-week window, what is the real risk of side effects? Again, this is now just anecdotal.

In my experience talking to people, the one thing that seems probably real is that there is maybe a two-fold increased risk of bacterial infection. Again, that kind of makes sense with what we know about the effect of rapamycin on the immune system.

Not much data to support that, but my intuition is that it is probably a real side effect. It's not a huge increase in risk, and of course, treating bacterial infection is pretty easy with antibiotics. So as long as you are aware of the risk, it's manageable.

The interesting thing—and this comes from conversations mostly with Alan Green—is he very much believes that there is a corresponding benefit. This has to do with the effect of rapamycin on the innate immune system versus the adaptive immune system.

At the same time that you get a slight increase in the risk of bacterial infection, you actually get a pretty potent increase in resistance to viral infection, which fits well with the study that I mentioned with everolimus. So that is highly speculative, I would say, but something that many of us are interested in understanding further.

And again, in the middle of a global viral pandemic, you can easily understand why that would be interesting and important to know—if something like rapamycin could actually have a beneficial effect, especially in the context of the aging immune system, on viral resistance. So I'm sort of interested to see how that data plays out over the next couple of years.

Dr. Anton Titov, MD: Well, thank you for this overview. It's very important to dive into the nuances of side effects. A slight increase in bacterial infections is important to note because it is older adults who need to be vaccinated against pneumococcus. There are specific vaccines that are recommended for older adults, but at the same time, they don't mount a significant response to bacterial pathogens.

So if it's a two-fold increase in, say, meningitis, that can be potentially fatal. That's the source of concern. On the other hand, if it's balanced by a decrease in the risks for other diseases, that's also important. That's a significant worldwide discussion that people have on aspirin, that people have on even alcohol.

There are certain risks that are decreased and certain risks that are increased, and where to find that balance in those and frequency. I guess that applies to both pharmaceuticals and diets.

Dr. Matt Kaeberlein, MD: Remember, as we talked about, diets have biological effects too. So again, I think it's hard to know what the absolute risk-reward is in any of these cases because there's always going to be some lack of data. With something like aspirin, certainly we know a lot more about the potential risks, so you can evaluate that equation maybe a little bit more precisely.

With rapamycin, I think we just don't have the data yet. And with things like protein restriction, people don't even think about it. People don't even really think that there's probably a risk associated with protein restriction, particularly in the elderly.

I think that's a really interesting example because there are people in my field who study protein restriction in mice who are making recommendations to people that they should practice protein restriction. That might be good in a young person, but it's pretty clear, at least from my view from the geriatric literature, that protein restriction in the elderly is probably not a great idea.

But there are people who immediately extrapolate from mouse studies to humans and start making recommendations to humans and never even stop to consider that there may be unanticipated consequences to something like protein restriction.

Dr. Anton Titov, MD: Well, that's certainly true. And that's important because it's a function of the immune system and elderly people—the aging immune system. And that's clear: once you restrict the protein, that could have detrimental effects, as you mentioned.