If we dive into biochemistry on the molecular level, you know, you've done a lot of research, especially on modulating the mTOR pathway in aging and health. And you know, you've written extensively on the connections to the mTOR pathway without autism with epilepsy with polycystic kidney disease. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So, can you briefly summarize this very extensive subject of mTOR in health and aging and disease in humans as it relates to normal aging, but also autism, epilepsy, polycystic kidney disease? Yeah, as you mentioned in your writings,
sure. So this is going to be a generalization because I think, you know, really this subject justice, you would have to do a deep dive would take hours. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. But I mean, I think, you know, maybe one way to appreciate this mTOR is it's a very evolutionarily conserved central hub of detecting the environment and then regulating cellular or tissue organ animal growth based on environmental conditions. And so you know, When nutrient levels in the environment are high, from an evolutionary perspective, that's a signal to grow and reproduce because it only makes sense to grow and reproduce when there's food around. And mTOR is probably the most important player in that decision process. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And so what that means is that mTOR, because it's so fundamental to cellular growth, and division, you know, plays a role in, in almost every biological process that you can think of is that if you perturb mTOR, you can perturb that process. So what we know is that you know, for development, mTOR is essential if you make a mouse that doesn't have mTOR, you get a dead mouse. It can't grow and become an adult. So, almost every developmental process involves the activation of mTOR. What often happens is post developmentally, mTOR activation is maintained at a level that is sub-optimal for health and longevity. So there are many the in the context of aging, you know, there it's been observed that if you inhibit mTOR, with rapamycin post developmentally, you slow aging, some cases reverse functional declines with aging and increased lifespan. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So almost by definition, that tells you that activity activation of mTOR in adulthood is suboptimal for longevity. It might be optimal for reproduction. But it's got a cost in terms of longevity. The consequence of hyperactivation of mTOR during adulthood is the onset of many different pathological conditions. In fact, I would say, a majority of the pathological conditions that go along with aging, there is a role for hyperactivation of mTOR in those processes, which again explains why a drug like rapamycin, which inhibits mTOR, delays or reverses those pathological consequences of aging, I think what you were alluding to is a really interesting other consequence of that the role that mTOR plays as a fundamental promoter of growth, there are a variety of disorders, which at least can start during development, that are caused by over activation of mTOR, beyond the sort of level needed for growth and development. And so that leads at least contributes to things like autism, or certain pediatric cancers, or, you know, certain lifelong autoimmune disorders. Those can be directly traced back to the hyperactivation of mTOR. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And, and I think that's where, you know, you get this collection of disorders that, at least on the surface, you know, aren't obviously connected. It's not obvious why aging would be impacted by the same biological pathway in the same direction as autism. But I think when you think more about the sort of fundamental role that mTOR plays in the development of pretty much every tissue and organ in the body. Then it starts to become easier to understand how if you get hyperactivation of mTOR in one specific tissue, that will lead to a specific disease state, which looks different from hyperactivation of mTOR in a different tissue, or at a different level. And I think that's what contributes to this sort of diversity of pathological conditions, where mTOR hyperactivation seems to play a role. And this drug, rapamycin, seems to have beneficial effects. And so, you know, I'm careful not to, you know, not to try to even come anywhere near saying that rapamycin is a miracle drug, right? In some ways, the fact that it seems to affect all these different diseases makes it sound like a miracle drug. It's not. The biology makes a lot of sense when you understand it. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD.
And I think it's important to appreciate that, you know, just like with caloric restriction, we talked about the risk of side effects. There are risks of side effects from inhibiting mTOR inappropriately, and we know that rapamycin has side effects, especially at higher doses. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. So it's not a perfect drug, but I think it has a lot of potential to be useful for a variety of, you know, sort of interesting and not connected disorders in people. I'm most excited about, you know, the potential utility of rapamycin for age-related disorders. Still, I think it's got the potential for a variety of other types of disorders as well. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. I mean, just to give you an example, you know, I know of a couple of psychiatrists now that are having, you know, sort of remarkable effects from rapamycin for psychiatric disorders in combination with other drugs that are commonly used for psychiatric disorders. So, you know, I think I think we're going to see over the next several years In a sort of emergence of rapamycin used for disorders or for indications that aren't connected to what rapamycin was originally approved by the FDA to be used for which is to prevent organ transplant rejection. So it's a really interesting dragon and a super complicated and interesting area of biology.