Rapamycin and human aging-related trials. When will we have reliable data on the rapamycin in aging? And how do you determine the aging effects of rapamycin? Yeah, so rapamycin is an off-patent drug. There are many other variants of rapamycin, like everolimus. But pretty much 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, kidney disease. It was found in that inhibit inhibits the mTOR pathway. And it was found that inhibiting that pathway extends lifespan in pretty much all of the animal models that have been tested. So this is probably the most robust intervention likely to extend lifespan.  Dr. Brian Kennedy. Dr. Anton Titov, MD. There have been a large number of clinical trials, but most of them have been done in people that are really sick, getting organ transplants or having cancer. And so you couldn't learn much about aging. I would say that rapamycin does have side effects. As I would caution people to just start going out and taking it. 

I think it's important to get some more human data and healthy individuals first, but there are suggestions from the RestoBio, for instance, that you can administer Rapalogs. They use the different version, in a way that's healthy. It doesn't cause side effects above background and in older population. And I think the bulk of the data from the studies suggested that rapamycin reduces infection rates in older individuals that are reasonably healthy. So that was how they chose to look at aging. Older people are susceptible to infections. And when something is targeting aging and improving longevity, it should make you resistant to respiratory infections. This was before COVID. And so I think that was quite promising. The phase three trial got derailed a little bit for reasons that we can go into.  Dr. Brian Kennedy. Dr. Anton Titov, MD. But we need more studies with rapamycin and I would encourage people to look at biomarkers of aging. And people are starting to do that now. In addition, I think there's a lot of data that suggests that rapamycin is protective against neurodegenerative disease. And so an Alzheimer's trial, I think, is called for as well to really look at whether inhibiting mTOR and prevent progression of early-stage Alzheimer's disease. I suspect that there may be good results there. And so I'm really just encouraging as many people as possible to test this rapamycin in different contexts. It's an important disclaimer that whatever we discuss is purely for informational purposes. And it should never be taken as a medical advice or, somebody should not act upon it.  Dr. Brian Kennedy. Dr. Anton Titov, MD. I think it's very important to discuss always with the qualified practicing physician before you do anything. So that's important. 

You mentioned that the rapamycin trial got derailed, phase three trial, what was the reason for that? Well, apparently, the regulatory group suggested that they use self-reported respiratory infections as opposed to clinically-defined respiratory infections, which is what we had been used in the phase two trials that showed success. 

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

So, 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 trials I. And that's not a sign to give up on things. Phase three trials can fail for a lot of ways. That may be respiratory infections aren't even 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 presenting. And so that's part of the challenge with private sector interest in the anti-aging pill.  Dr. Brian Kennedy. Dr. Anton Titov, MD. If they're going to go to the traditional pharmaceutical route, they need reimbursement, aging is not a disease according the FDA. And so you can't treat something that doesn't exist and get reimbursed for it. And that's been a limitation in this field for a long time. It's 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, are involved treating risk factors, they're not treating disease, you are treating hypercholesterolemia, hypertriglyceridemia, hyperglycemia, before people have a lot of overt disease symptoms. 

And so we know the success that can come from treating risk factors and aging is the biggest risk factor. So I 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. Rapamycin when tested for essentially longevity purposes, that's a significantly smaller dose. And frequency is also radically different, right? Yeah, and the 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. So if you want 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 the organ transplants are taking much higher doses.  Dr. Brian Kennedy. Dr. Anton Titov, MD. 

And 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. So I think that it's important to start in relatively low levels with a drug like that. Rapamycin can have complications, some of these natural products, or natural products tend to be safer. That's true, that doesn't mean they're always safe. It is a little bit misleading. But, you know, when you're giving metabolites, the body knows what to do with them, you know, they don't accumulate typically, like alpha-ketoglutarate, it goes up and it goes down really quick. 

And so 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 it's much 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. Dr. Brian Kennedy. Dr. Anton Titov, MD. So, there's a legitimate reason to be more careful with drugs than there are with natural products, although we should apply some caution to both. I think, 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. And so the figuring out a way to deliver this safely in humans, I think is really important.