The Peter Attia Drive - Qualy #46 - Rapamycin’s effects on cancer, cardiovascular disease, and neurodegeneration

Episode Date: October 23, 2019

Today's episode of The Qualys is from podcast #09 – David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR — the nexus of aging and longevity?. The Qualys is a subscriber-exclusive podcast, released Tuesday through Friday, and published exclusively on our private, subscriber-only podcast feed. Qualys is short-hand for “qualifying round,” which are typically the fastest laps driven in a race car—done before the race to determine starting position on the grid for race day. The Qualys are short (i.e., “fast”), typically less than ten minutes, and highlight the best questions, topics, and tactics discussed on The Drive. Occasionally, we will also release an episode on the main podcast feed for non-subscribers, which is what you are listening to now. Learn more: https://peterattiamd.com/podcast/qualys/   Subscribe to receive access to all episodes of The Qualys (and other exclusive subscriber-only content): https://peterattiamd.com/subscribe/  Connect with Peter on Facebook.com/PeterAttiaMD | Twitter.com/PeterAttiaMD | Instagram.com/PeterAttiaMD 

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So without further delay, I hope you enjoy today's quality. So this may be a theoretical question, but when we think about the life-extending properties of rapamycin, do we believe that it is a result of delaying the clinical onset of disease? Let's use a disease where that tends to be more binary like cancer. But obviously cancer spends probably 70 to 80% of its time undetectable, but due to the just the law of growth, it becomes detectable only at the end. So do we think that in as much as, say, taking these agents would allow you to live longer by not dying from cancer at the same period of time?

Does it delay the time it takes for cancer to become clinically detectable and or delay the demise of the animal once it has that cancer? I think it's specific. In the case of cancer, rapamycin is there are some situations where it has some decent activity, but in general, it's not a cytotoxic agent, it's not going to kill a cancer soldier. Once an organism has cancer, do you know if it's doing anything to prevent the development of cancer? We don't know that well.

The only... There actually has been some epidemiological data where people have compared cancer rates in transplant patients. Identical patients who are with and without rape. FGF6 versus rapamycin. It's actually quite interesting because, as you know, immunosuppression in general is associated with higher cancer rates, right? The idea that you have less immune surveillance, that's not seeing a rapmison. So it is seen with FKF6, it's not seeing a rapmison, and the argument has been that rapmison itself

has cancer cell autonomous. In the dependent of the immunosuppression problem. So you're presumably getting less immune surveillance because it's immunosuppressant, although, of course, that's not proven. But you're mitigating that immune surveillance because it's a immunosuppressant, although of course that's not proven. But you're mitigating that by now directly. And they've canceled each other out. And you know the size of the effect from the FK506 cohort. Exactly.

And other immunosuppressant things like this before I have also been looked at that. So my bet would be that in the case of cancer, you're not gonna... You're not gonna cure cancer once you've got it, but you're... But I also don't think you're gonna modulate the incidents, like the mutational frequencies that are giving you cancer, right? So if you think of cancer in a way is easier to think about when it starts, because you say, well, it starts when you have a cell that has all the requisite mutations to be...

To a big detection and... Exactly, it has uncontrolled growth. So if that's the point, it starts, I think we're not gonna affect that. But once that cell exists and now has to start growing and also escaping the immune system, I do think that's probably what you're going to affect. In other diseases, like a couple cardiovascular disease

where you could imagine things like autophagy could be quite modulatory, I think you can imagine that you're also being affecting the incidence, at the exact point at which you'd say, okay, this is an atherosyrotic plaque or not. What do we know about rapamycin and tour in the brain, especially with respect to neurodegeneration?

Yeah, that's a really interesting one. And that probably is a really important question for the future. So we know a topology matters a lot in the brain. If you delete a topology, and really, Mitsushima was the person who kind of made a topology interesting to lots of people. And it was a word of the Nobel Prize. No, no, he wasn't.

He wasn't. He wasn't. He wasn't. He wasn't. He didn't share. He didn't know that much. I think was a bit of an oversight in my view. But anyhow, he basically studied a topology in the brain, made mutations, showed you got neurodegeneration. So that was a bit of an oversight in my view. But, and now he basically studied autophagy in the brain, made mutations, showed you got

neurodegeneration, right? So that was a really important find. Connects up to lysosomal storage diseases, which, you know, autophagy, basically the autofaggers on refuses with a lysosom, so now you have that connection. So I think like in all tissues, it's a bit of a double edged sword. You clearly need M-Trog1 activity to maintain healthy synapses, certainly during brain growth, if you make mutations around boy and growing animal, you basically don't have a cortex. On the other hand, you clearly need to

modulate M-TRIG-1 to have some level of autophagy to keep the system healthy. Now you could debate, is that in neurons, is that in glia, it's probably in both people have made mutants in certainly neurons, we're suggesting it's both, but then some of those promoters a little bit dirty. But the real question in the brain is, what modulates M-torquon? Because it's not probably nutrients. Because they're so constant, you mean, like,

exactly. Your brain, your body, basically. Your brain prioritizes nutrients in the brain over it. If basically protects your body. So if you take an animal and you fast it for two days a mouse, it loses a lot of weight, 25% of its weight. And now you take every single tissue and you weigh it, every tissue has shrunk. Some like the thymus are shrunk ridiculously.

The kidney shrinks, which you wouldn't expect. The heart shrinks, the brain, nothing. Now clearly, probably if you- in the mouse you can't do that extreme of fast. And so the body protects the brain from a nutrient point of view, yet M-trog1 activity is high there. Clearly we know that we have to modulate autophidies or something must be inhibiting M-trog1. By the way, this is my peripheral argument for why, and I'm in the huge minority here. I do not think the brain is really the repetitive center. I think it's the modulator, but for that exact reason,

I think it wouldn't make sense for evolution to put our appetite center in our brain. It should be in the periphery. It should be in the liver, I think. I think the liver should be the... But if people argue that the things of hypothalamus are in the periphery, right? Because they're not protective.

They're a part of your brain like the hypothalamus. And the point is, I think it has to be... Your appetite center needs to be regulated to something that senses very rapid outside of the body. Outside of the body, for sure. Yeah, yeah. And exactly where it is, and you know, in the bottom line is probably. But I never thought of it through the lens that you just explained it, which was the

implication of that for TOR is enormous. So does TOR look different in the brain? Or, I mean, obviously the protein won't, but do the cofactors around it look different? It's really, you know, we keep talking. We have never done frontal biochemistry out of the brain or obviously the protein won't, but do the co-factors around it look differently? You know, we keep talking, we have never done framble biochemistry out of the brain. It's something that would be very interesting to go and do now.

I think now, it's something we talk quite a bit as a lab to do, we haven't quite done it at all, but then what actually regulates, it's very clear that neuronal activity does, but are there, like as you're suggesting, maybe neuronal specific factors are regulated? I think that's a completely open area. I've tried to get some of my students interested in that. My brother's a neuroscientist, he's argued we should really do some work there.

We just haven't. Maybe when we run out of sensors in the periphery, we'll go to the brain. Because that's where I purified M2, it was out of brain. So there's a ton of M2 in the brain. And I did that not because I was like whatever. I basically measured how much there was, and it was clear the brain had the both. I hope you enjoyed today's quality. Now sit tight for that legal disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

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