So, for example, if we talk about Alzheimer's disease and billions were spent, you know, on failed medications, they could have been redirected to aging research considering the dismal track record. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And rapamycin is also, as you wrote in your peer-reviewed articles, connected to Alzheimer's disease. So is it time for a clinical trial of rapamycin in timers disease?

Yeah, it was time for a clinical trial for rapamycin and Alzheimer's disease. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Fifteen years ago, when I first started proposing it, it's um, yeah, I mean, look, I to say I'm not frustrated by the lack of the Alzheimer's disease community, paying attention, first of all, to the biology of aging, but second to rapamycin. Specifically, it will be an understatement to say I'm not frustrated by that. I think they should be ashamed of themselves. There's no excuse that rapamycin hasn't been tested in the context of Alzheimer's disease and other dementias right now. It's a failure of the Alzheimer's research community. It's a failure of the Alzheimer's clinical community, in my view. So yes, I think there's a lot of promise there. I think, though, again, taking a step back, the bigger problem is, and this isn't unique to the Alzheimer's research community. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Still, I think it's particularly relevant in that context is, you know, we know that biological aging is the greatest risk factor for Alzheimer's disease, that is crystal clear. And the fact that the Alzheimer's disease research community has not paid attention to that link is embarrassing. In my view. It's still the case that more than half of the National Institute on Aging budget goes specifically to study Alzheimer's disease, without taking into consideration the roll of biological aging and Alzheimer's disease. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And a much smaller fraction of the budget goes to understanding the biology of aging. So I think that's a mistake. I think it should be clear to anyone paying attention that that's been a mistake. And I think that you know, the fact that we now have a drug approved that targets amyloid beta but doesn't help patients, I think should also make it clear to people that it's been a huge mistake to focus all of our efforts on studying amyloid-beta, instead of studying what is creating permissive physiology for Alzheimer's disease, which is the biological aging process. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So I would certainly hope that will change. You know, it takes a long time in biomedicine for paradigms to shift. I feel like that's starting to happen. I feel like people are starting to understand the connection between the biological mechanisms of aging and Alzheimer's disease and other age-related diseases. You know, I think the growth of research on, for example, senescence cells in the Alzheimer's research community, the obesity Community Cancer community, is an indication that finally, finally, the biomedical community is starting to pay attention to what we've been telling them for many years now, which is that these hallmarks of biological aging, certainly create a permissive environment for age-related disease potentially play a causal role in age-related disease. But to some extent, that doesn't matter if we can understand that biology. We can intervene before people get sick and keep them from developing Alzheimer's disease or age related cancers, kidney disease or heart disease, or immune senescence. Right, all of this collection of diseases where biological age is the greatest risk factor, so yeah, I mean, I think, um, you know, frustrating, yes. Optimistic that things are changing. Yes. So I hope that will continue.

Do you think that it's a bit controversial? Still, I spoke London to a very renowned mathematician who played a critical role in determining, for example, you know, the effect of the preventive effect of tamoxifen on breast cancer, Dr. Jack Cusick, and he said that aspirin is the number two, Cancer Prevention step one can take after quitting smoking. And obviously, there's a lot of research going on. Still, aspirin is generic, so that's partly, you know, the pharmaceutical industry cannot make billions and billions on widely available generic drugs. So there is less impetus to conduct, you know, very expensive clinical trials. Rapamycin is generic. Do you think that It has something to do with the reluctance of, you know, major funding for clinical trials of Alzheimer's or other dementias? And rapamycin, even though they are funded not necessarily by the pharmaceutical community, but by public health, you know, bodies. After all, it's the governments around the world who bear a substantial cost of caring for people with Alzheimer's disease. It's not just about the pharmaceutical industry.

Yeah, so it's a good question. I think that's part of it. I don't think that's the primary. That's been the primary challenge. But absolutely, I think the fact that there is not an incentive from a financial and profit perspective to develop rapamycin has contributed to the sort of slow, slow pace. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. But actually, the bigger problem is reputational. And that stems from the fact that rapamycin was first used and FDA approved for use in organ transplant patients. And so it, it got a reputation as an immunosuppressant that has a collection of not terrible, but not great side effects in that patient population. So at high doses given daily in organ transplant patients, there's a long list of side effects that have been, you know, at least somewhat associated with rapamycin and so in the clinical community, because of the way it was developed and used, there is a perception among many physicians that rapamycin has bad side effects. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. 

You know, the data are clear in my mind. I think most people who have read the studies on once-weekly lower dose rapamycin use in Healthy People will agree with this, that in that context, the side effects from rapamycin are very small. And in fact, in most cases, not different from a placebo. But because the reputation is already there, it's difficult I found in the clinical community to overcome a reputation problem. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So I think it's the combination of the lack of profit motive, and maybe even more so the reputation challenge that rapamycin has, a barrier to getting clinical trials funded outside of the pharmaceutical community. And you know, from my personal experience, I can tell you, because I've talked with people at the Alzheimer's Association, and other, you know, potential groups that could fund these kinds of studies, you know, you present them the data showing that in every mouse model of Alzheimer's disease and in, you know, normative aging in mice for dementia and Parkinson's disease, rapamycin works, and it works well. You show them that data, they're enthusiastic about potentially doing a clinical trial. Then they talk to, you know, some physician who doesn't know anything about the data probably has never used rapamycin but is hurt. It's got a lot of side effects, you know, and their expert tells them, oh, yeah, rapamycin has a lot of side effects, and they become less interested in studying for Alzheimer's disease. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So I think that's been a problem. I also don't quite understand why even if rapamycin side effects were comparable to what's seen in organ transplant patients in this context, you know, if I had somebody I loved who had Alzheimer's disease, I'm pretty sure that they and I would be willing to tolerate that level of side effects if you could delay Alzheimer's disease by ten years, or 15 years, or maybe prevent it altogether. So I still don't even quite understand the side effect concern. But it's also not real. And I think it's, it's unfortunate, gradually, that's changing again, you know, I go between being frustrated at how long this has taken to optimism that finally, I feel like you know, there is some momentum where people are starting to actually collect data on side effect on risk and slowly changing the perception in the clinical world about rapamycin. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Still, it's going to be a long road, but I think that's been one of the main things that have prevented, you know, these types of clinical trials for something like Alzheimer's disease.