Rapamycin for Longevity: Clinical Trials, Dosing, and Safety in Anti-Aging Medicine

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• Rapamycin in Aging Clinical Trials
• mTOR Pathway and Lifespan Extension
• Rapamycin Side Effects and Safety
• Intermittent Dosing Protocol
• Challenges in Anti-Aging Trials
• Future of Rapamycin Research
• Full Transcript

Rapamycin in Aging Clinical Trials

Rapamycin is an off-patent drug with significant potential for aging intervention. Dr. Brian Kennedy, MD, notes that most clinical trials have focused on severely ill patients, such as organ transplant recipients or cancer patients. This makes it difficult to extract clear data on rapamycin's effects on aging in healthy populations. However, studies like the one conducted by RestoBio offer promising insights. This trial used rapalogs, different versions of rapamycin, in older, reasonably healthy individuals.

The results suggested a reduction in infection rates among older participants. This outcome is significant because increased susceptibility to infection is a hallmark of aging. Dr. Brian Kennedy, MD, explains to Dr. Anton Titov, MD, that a successful anti-aging intervention should bolster resistance to illnesses like respiratory infections. A phase three trial faced challenges due to a shift in how infections were measured, moving from clinically-defined to self-reported events. This change may have obscured the true treatment effect, highlighting the complexities of trial design in aging research.

mTOR Pathway and Lifespan Extension

Rapamycin works by inhibiting the mTOR pathway, a key cellular signaling network. Dr. Brian Kennedy, MD, emphasizes that inhibiting this pathway is one of the most robust interventions known to extend lifespan. This effect has been consistently demonstrated across a wide range of animal models. The mechanism involves modulating cellular processes related to growth, metabolism, and autophagy.

The connection to neurodegenerative diseases is particularly compelling. There is accumulating data suggesting rapamycin could be protective against conditions like Alzheimer's disease. Dr. Kennedy advocates for clinical trials specifically designed to test if mTOR inhibition can prevent the progression of early-stage Alzheimer's. This approach targets a fundamental aging process rather than just the symptoms of a specific disease.

Rapamycin Side Effects and Safety

Despite its promise, rapamycin is a potent drug with known side effects. At high doses used in transplant rejection, it can cause complications like mouth sores and immune suppression. Dr. Brian Kennedy, MD, provides a crucial disclaimer during his discussion with Dr. Anton Titov, MD. He strongly cautions against individuals self-prescribing rapamycin without medical supervision.

The safety profile differs significantly between high-dose clinical use and potential low-dose longevity applications. The side effects observed in sick patient populations may not directly translate to healthy individuals using it for aging. However, the potential for off-target effects and toxicity exists because it is a synthetic drug that can accumulate in the body. This contrasts with natural metabolites that the body processes and eliminates quickly.

Intermittent Dosing Protocol

A key strategy for improving rapamycin's safety is intermittent dosing. Research indicates that taking the drug once or twice a week, rather than daily, can minimize adverse events. This protocol allows drug levels to return to baseline between doses, reducing the risk of cumulative toxicity. The doses being explored for longevity purposes are also significantly lower than those used in transplant medicine.

Dr. Brian Kennedy, MD, explains that this approach appears to retain the potential benefits while mitigating side effects. He advises that if one were to use rapamycin, starting at a very low dose is essential. The goal is to achieve an impact on aging without inducing complications that diminish quality of life. Finding the optimal balance between efficacy and safety is a primary focus of current research.

Challenges in Anti-Aging Trials

Developing rapamycin as an anti-aging treatment faces major regulatory and commercial hurdles. A central problem is that aging is not classified as a disease by the FDA. Therefore, pharmaceutical companies cannot get reimbursement for a drug that treats "aging" itself. They must target a specific, reimbursable condition, which can misalign with the goal of targeting fundamental aging processes.

Dr. Brian Kennedy, MD, discusses this impediment with Dr. Anton Titov, MD. He draws a parallel to preventative cardiology, where drugs treat risk factors like high cholesterol before overt disease occurs. He argues that aging is the ultimate risk factor for nearly all chronic diseases. Overcoming this regulatory barrier is critical for advancing the field and encouraging private sector investment in genuine anti-aging therapeutics.

Future of Rapamycin Research

The future of rapamycin research lies in rigorous human clinical trials. Dr. Brian Kennedy, MD, is a strong advocate for conducting more studies in healthy older individuals. He emphasizes the need to use biomarkers of aging as primary endpoints in these trials. These biomarkers could provide objective evidence of rapamycin's effect on the biological pace of aging.

Dr. Kennedy remains highly optimistic about targeting the mTOR pathway. He calls it the "gold standard" for slowing aging in animal models. The critical task is translating this success safely to humans. He encourages continued investigation into different rapalogs and dosing regimens to unlock rapamycin's full potential for promoting healthspan and longevity, always under proper clinical guidance.

Full Transcript

Dr. Anton Titov, MD: Rapamycin and human aging-related trials. When will we have reliable data on rapamycin in aging? And how do you determine the aging effects of rapamycin?

Dr. Brian Kennedy, MD: Rapamycin is an off-patent drug. There are many other variants of rapamycin, like everolimus. Most foreign big pharma companies have some version of rapamycin in use for suppressing the immune response in organ transplants. It has been used for cancers and kidney disease. It was found to inhibit the mTOR pathway. Inhibiting that pathway extends lifespan in pretty much all of the animal models that have been tested. This is probably the most robust intervention likely to extend lifespan.

There have been a large number of clinical trials, but most have been done in people who are really sick, getting organ transplants or having cancer. You couldn't learn much about aging. I would say that rapamycin does have side effects. I would caution people to just start going out and taking it.

I think it's important to get more human data in healthy individuals first. But there are suggestions from RestoBio, for instance, that you can administer rapalogs. They use a different version in a way that's healthy. It doesn't cause side effects above background in an older population. The bulk of the data from the studies suggested that rapamycin reduces infection rates in older individuals who are reasonably healthy. That was how they chose to look at aging.

Older people are susceptible to infections. When something is targeting aging and improving longevity, it should make you resistant to respiratory infections. This was before COVID. I think that was quite promising. The phase three trial got derailed a little bit for reasons that we can go into.

We need more studies with rapamycin. I would encourage people to look at biomarkers of aging. People are starting to do that now. In addition, I think there's a lot of data that suggests rapamycin is protective against neurodegenerative disease. An Alzheimer's trial, I think, is called for as well to really look at whether inhibiting mTOR can prevent progression of early-stage Alzheimer's disease. I suspect that there may be good results there.

I'm really just encouraging as many people as possible to test rapamycin in different contexts. It's an important disclaimer that whatever we discuss is purely for informational purposes. It should never be taken as medical advice, and somebody should not act upon it.

I think it's very important to always discuss with a qualified practicing physician before you do anything. That's important.

Dr. Anton Titov, MD: You mentioned that the rapamycin trial got derailed, the phase three trial. What was the reason for that?

Dr. Brian Kennedy, MD: Well, apparently, the regulatory group suggested that they use self-reported respiratory infections as opposed to clinically-defined respiratory infections, which is what had been used in the phase two trials that showed success.

People over 65 often feel like they have some kind of infection. They wake up with a cough and say, "Oh, I've got some virus." If you don't test these things and get clinical validation, you may be missing the signal from all the noise.

I don't know if that's what really happened. They also moved away from everolimus to a different kind of mTOR inhibitor, which changed the equation a little bit, although they had preliminary data that that worked as well.

I think there were hints that it might have worked. But there wasn't a statistically relevant signal that came out of that phase three trial. That's not a sign to give up on things. Phase three trials can fail for a lot of reasons. Respiratory infections may not even be the right way to look at it.

What I really want to see is biomarkers of aging. But if you're a company, you don't get reimbursed for changing a biomarker of aging. You need to have some disease you're treating or some condition that you're preventing. That's part of the challenge with private sector interest in the anti-aging pill.

If they're going to go the traditional pharmaceutical route, they need reimbursement. Aging is not a disease according to the FDA. You can't treat something that doesn't exist and get reimbursed for it. That's been a limitation in this field for a long time. That doesn't necessarily apply as much to supplements or diagnostics.

But in terms of developing new drugs, it's a major impediment. It's really something we need to get around because some of the most effective treatments for cardiovascular disease and diabetes involve treating risk factors. You are treating hypercholesterolemia, hypertriglyceridemia, hyperglycemia before people have a lot of overt disease symptoms.

We know the success that can come from treating risk factors. Aging is the biggest risk factor. You can call it a disease or call it a risk factor—I don't care. But we need to develop some method to target aging effectively because I think that will have a huge positive impact on the health of the population.

Dr. Anton Titov, MD: Rapamycin when tested for essentially longevity purposes—that's a significantly smaller dose. And frequency is also radically different, right?

Dr. Brian Kennedy, MD: Yeah, the bulk of the data suggests that if you take it and let the drug come back down to baseline—so you're not taking it every day—you get reduced side effects and adverse events. To be safe with it, most clinical studies use intermittent dosing once or twice a week at a relatively low amount. Some of the people with organ transplants are taking much higher doses.

I just think we have to be cautious with this drug. It may be that higher doses have a bigger impact on aging. But if you're having mouth sores and other complications, you may not want to live longer. I think it's important to start at relatively low levels with a drug like that.

Rapamycin can have complications. Some of these natural products tend to be safer. That's true, but that doesn't mean they're always safe. It is a little bit misleading. When you're giving metabolites, the body knows what to do with them. They don't accumulate typically, like alpha-ketoglutarate—it goes up and it goes down really quick.

It's really hard to overdose on that. The benefits you get from it are the reactions that you're driving probably in cells. When you take a drug that's not easily metabolized, that's been made in a chemistry lab, then you have a bigger chance for toxicity because it can accumulate. It can have off-target effects at high doses. It can have unpredictable effects.

There's a legitimate reason to be more careful with drugs than with natural products, although we should apply some caution to both. Having said that, I'm really optimistic about targeting the mTOR pathway.

I think rapamycin is the gold standard for slowing aging. If I were a mouse, I'd take it for sure. Figuring out a way to deliver this safely in humans is really important.