Qualy #61 - Rapamycin in cancer treatment

**Peter Attia** (0:05)
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And so there's really two different questions. The first would be if you take a patient with cancer and you inhibit mTOR, is it not helpful because the tumor has already evolved so much to be outside of mTOR's purview? Or is it, it's actually harmful?
And that's of course separate from the option that could be helpful.

**Matt Kaeberlein** (1:31)
Right. So my understanding of the clinical and the literature in humans is that for most cancers, once it's reached the point of diagnosis, that rapamycin is disappointing in its effectiveness. It's not particularly effective.
That's not true for all cancers, but for most cancers it has not been as effective as you might expect, given that we know that activation of mTOR is common, when you get high proliferation, and that turning down mTOR should stop that proliferation.

**Peter Attia** (2:04)
Turn off a proliferative cell.

**Matt Kaeberlein** (2:04)
So I think you're probably right that at least part of the story is that one of the steps in the progression to cancer is evolving to ignore the break of turning down mTOR. So rapamycin may not be effective there. I think it's a complicated system though, because the effects of rapamycin on the immune system could have beneficial effects in terms of cancer or detrimental effects. So we know that immune surveillance is probably the most important anti-cancer mechanism, or certainly one of the most important anti-cancer mechanisms. And we know that immune function goes down with age. That's probably one of the reasons why most cancers are age-related. So if you can boost age-related immune function with rapamycin, enhance immune surveillance, that's going to have a potent anti-cancer mechanism.
And again, this is my guess. My guess is that's why we see in the studies in mice that cancers are pushed back during aging by rapamycin.
On the other hand, if the dose of rapamycin is high enough that you're actually inhibiting immune function, that could promote cancers. And there's not a lot of data yet. So we did one study in my lab where we gave mice, I think it's the highest dose that's ever been given in the context of an aging study. This was a daily injection of 8 mg per kilogram.

**Peter Attia** (3:24)
So we call it the party dose.

**Matt Kaeberlein** (3:25)
Yeah, right. And so this was a study where we only gave the mice rapamycin for three months. So this was from 20 to 23 months. And then we stopped the treatment.
And what was interesting there was we got completely different effects in male mice versus female mice. The male mice lived 60% longer after the end of treatment. They had better muscle function. They got less cancer. The female mice had no difference in lifespan. The mice that got rapamycin or didn't get rapamycin. But they died with, I want to say from, but it's hard to say for sure what a mouse dies from. They died with very different types of cancers. So the female mice that had gotten this high dose of rapamycin for three months all had aggressive hematopoietic cancers.
Whereas about, I think it was about 30 or 40% of the vehicle-treated mice. So in Black 6, that's not an uncommon cancer to get. But none of the rapamycin-treated mice had non-hematopoietic cancers.
Whereas like 60% of the mice that didn't get rapamycin.

**Peter Attia** (4:27)
Now, the 2009 study that kicked all this off actually showed a greater survival benefit in the female mice, didn't it?

**Matt Kaeberlein** (4:32)
That's right. So I think, and again, this is a guess, because I don't actually have the data to back it up. My guess is that because we pushed the dose so high, we might have actually taken it too far in the female. So one school of thought is that female mice, at least, we don't know if this is true in any other organism, female mice are more sensitive to rapamycin, and that could either be that they don't clear the drug as quickly or that, for whatever reason, in female mice, the same amount of rapamycin has a greater mTOR inhibitory effect. But that's one school of thought, and I kind of think that's right. So at lower doses of the drug, you see a bigger lifespan benefit in females than in males.