Qualy #46 - Rapamycin's effects on cancer, cardiovascular disease, and neurodegeneration

**Peter Attia** (0:05)
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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 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?

**David Sabatini** (1:51)
I think specifically 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, right? It's not gonna kill a cancer cell. It's really gonna-

**Peter Attia** (2:02)
Once an organism has cancer, do we know if it's doing anything to prevent the development of cancer?

**David Sabatini** (2:06)
We don't know that well, and the only, there actually has been some epidemiological data where people have compared cancer rates in transplant patients.

**Peter Attia** (2:15)
Identical patients who are with and without rapamycin.

**David Sabatini** (2:17)
FK506 versus rapamycin. And 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 seen in rapamycin.
So it is seen in FK506. It's not seen in rapamycin. And the argument has been that rapamycin itself has cancer cell autonomous effect.

**Peter Attia** (2:37)
Independent of the immune modulation problem.

**David Sabatini** (2:40)
So you're presumably getting less immune surveillance because it's immunosuppressant, although of course that's not proven. But you're mitigating that by now directly targeting.

**Peter Attia** (2:48)
And they've canceled each other out. And you know the size of the effect from the FK506 cohort.

**David Sabatini** (2:53)
Exactly. And other immunosuppressant things, cyclosporine, 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 be.

**Peter Attia** (3:03)
You're not gonna cure cancer once you've got it, but you probably.

**David Sabatini** (3:05)
No, but I also don't think you're gonna modulate the incidence, 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 a cell that.

**Peter Attia** (3:21)
To evade detection and.

**David Sabatini** (3:22)
Exactly, it has uncontrolled growth. So if that's the point it starts, I think we're not going to 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, for example, 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 atherosclerotic plaque or not.

**Peter Attia** (3:53)
What do we know about rapamycin and TOR in the brain, especially with respect to neurodegeneration?

**David Sabatini** (4:00)
Yeah, that's a really interesting one, and that probably is a really important question for the future. So we know autophagy matters a lot in the brain. If you delete autophagy, and really Mitsushima was the person who kind of made autophagy interesting to lots of people.