Understanding mTOR Pathway in Aging, Autism, and Disease

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• mTOR Biology Fundamentals
• mTOR Role in Development
• mTOR Hyperactivation in Disease
• Rapamycin Therapeutic Potential
• Rapamycin Side Effects
• Future Rapamycin Applications
• Full Transcript

mTOR Biology Fundamentals

Dr. Matt Kaeberlein, MD, PhD, describes mTOR as an evolutionarily conserved central hub. It detects environmental conditions, particularly nutrient levels, and regulates cellular growth accordingly. High nutrient levels signal mTOR to promote growth and reproduction. This fundamental role means mTOR is involved in almost every biological process. Dr. Matt Kaeberlein, MD, explains that perturbing mTOR can significantly alter these processes.

mTOR Role in Development

mTOR is absolutely essential for normal development. Dr. Matt Kaeberlein, MD, PhD, notes that mice without functional mTOR cannot survive to adulthood. Almost every developmental process requires mTOR activation for proper growth. However, maintaining this activation post-developmentally is often suboptimal for long-term health and longevity. This creates a biological trade-off between growth and aging.

mTOR Hyperactivation in Disease

Hyperactivation of mTOR in adulthood is a key driver of many pathological conditions. Dr. Matt Kaeberlein, MD, PhD, states that a majority of age-related diseases involve mTOR overactivity. This includes disorders that begin during development, such as certain forms of autism, pediatric cancers, and autoimmune diseases. The specific disease manifestation depends on which tissue experiences mTOR hyperactivation. This explains the diverse range of conditions linked to this single pathway.

Rapamycin Therapeutic Potential

Rapamycin, an mTOR inhibitor, shows significant therapeutic promise. Dr. Matt Kaeberlein, MD, PhD, explains that inhibiting mTOR post-developmentally can slow aging and even reverse some functional declines. It can increase lifespan in model organisms. The drug's ability to counteract mTOR hyperactivation makes it beneficial for various disorders. Dr. Kaeberlein is careful to note that rapamycin is not a miracle drug, but its effects are grounded in solid biology.

Rapamycin Side Effects

Like any powerful medication, rapamycin carries a risk of side effects. Dr. Matt Kaeberlein, MD, PhD, emphasizes that inhibiting mTOR inappropriately can be harmful. These side effects are especially pronounced at higher doses, similar to the risks associated with caloric restriction. Understanding the balance between benefit and risk is crucial for its clinical application. Dr. Anton Titov, MD, and Dr. Kaeberlein discuss the importance of this cautious approach.

Future Rapamycin Applications

The future of rapamycin extends far beyond its original FDA approval for preventing organ transplant rejection. Dr. Matt Kaeberlein, MD, PhD, is most excited about its potential for age-related disorders. He also highlights emerging off-label uses, including in psychiatry. Some psychiatrists report remarkable effects when combining rapamycin with other psychiatric medications. Dr. Kaeberlein anticipates a significant expansion of rapamycin's clinical indications in the coming years.

Full Transcript

Dr. Anton Titov, MD: If we dive into biochemistry on the molecular level, you've done a lot of research, especially on modulating the mTOR pathway in aging and health. You've written extensively on the connections of the mTOR pathway with autism, epilepsy, and polycystic kidney disease.

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? As you mentioned in your writings—

Dr. Matt Kaeberlein, MD: Sure. This is going to be a generalization because to really do this subject justice, you would have to do a deep dive that would take hours.

One way to appreciate mTOR is that it's a very evolutionarily conserved central hub for detecting the environment and then regulating cellular, tissue, organ, or animal growth based on environmental conditions. When nutrient levels in the environment are high, from an evolutionary perspective, that's a signal to grow and reproduce. 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.

Because mTOR is so fundamental to cellular growth and division, it plays a role in almost every biological process you can think of. If you perturb mTOR, you can perturb that process. 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. Almost every developmental process involves the activation of mTOR.

What often happens is that post-developmentally, mTOR activation is maintained at a level that is suboptimal for health and longevity. In the context of aging, it's been observed that if you inhibit mTOR with rapamycin post-developmentally, you slow aging, in some cases reverse functional declines with aging, and increase lifespan.

By definition, that tells you that 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, a majority of the pathological conditions that go along with aging have a role for hyperactivation of mTOR in those processes. That explains why a drug like rapamycin, which inhibits mTOR, delays or reverses those pathological consequences of aging.

What you were alluding to is a really interesting other consequence of 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 overactivation of mTOR beyond the level needed for growth and development. That leads, or at least contributes, to things like autism, certain pediatric cancers, or certain lifelong autoimmune disorders.

Those can be directly traced back to the hyperactivation of mTOR. That's where you get this collection of disorders that, on the surface, 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 when you think more about the fundamental role that mTOR plays in the development of pretty much every tissue and organ in the body, it starts to become easier to understand. 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.

That contributes to this diversity of pathological conditions where mTOR hyperactivation seems to play a role, and rapamycin seems to have beneficial effects. I'm careful not to try to even come anywhere near saying that rapamycin is a miracle drug. 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.

It's important to appreciate that, just like with caloric restriction, we talked about the risk of side effects. There are risks of side effects from inhibiting mTOR inappropriately. We know that rapamycin has side effects, especially at higher doses.

It's not a perfect drug, but I think it has a lot of potential to be useful for a variety of interesting and not obviously connected disorders in people. I'm most excited about the potential utility of rapamycin for age-related disorders, but I think it's got potential for a variety of other types of disorders as well.

Just to give you an example, I know of a couple of psychiatrists now that are having remarkable effects from rapamycin for psychiatric disorders in combination with other drugs commonly used for psychiatric disorders. I think we're going to see over the next several years an emergence of rapamycin used for disorders or indications that aren't connected to what rapamycin was originally approved by the FDA for, which is to prevent organ transplant rejection. It's a really interesting drug and a super complicated and interesting area of biology.