Peter: Okay. So that's the easy story.

Now the hard one, IGF. Okay. So two schools of thought on this, I am in one camp but I will acknowledge the other camp. One camp says IGF-1 is driven exclusively by amino acids. The other camp says, no, it's actually driven by amino acids and carbohydrates. And carbohydrates indirectly via insulin. So...

Rhonda: Why are those mutually exclusive? I mean...

Peter: The way I define it when I'm...there are certain people who I will not name that are prominent in the field who will argue that the carbohydrates play no role, it's virtually all protein.

Rhonda: But there is a role that they do play that's been shown, depending on...

Peter: I believe it has been shown but, I mean, there are wonderfully erudite people in this field who believe it is entirely an amino acid issue. And it is true, methionine has probably been shown to be the most active amino acid in driving IGF pathway. However, as it sounds like you agree, it's pretty clear that as insulin levels go down IGFBP-3 goes up...sorry, as IGF binding protein 3 goes up...maybe it's worth me taking a moment why that matters.

Rhonda: Yeah, probably explain that.

Peter: So most of these things, as maybe the listeners know when you have hormones floating around the body, whether it'd be testosterone, whether it'd be cortisol, whether it be thyroxine, these things, because they're typically hydrophobic, they can't just travel through the bloodstream freely. They have to be bound and carried just as cholesterol does. And so it's these binding proteins that we often don't think about that play an important role in determining how much active or bioavailable hormone is free.

So in the case of IGF-1 it gets trafficked by this IGF binding protein, and most of these binding proteins actually bear an unbelievable relationship to insulin. So sex hormone-binding globulin goes up when insulin goes down. It's very interesting, there's always this complaint that free testosterone levels will drop, all things equal, in someone who restricts carbohydrates. And I remember through hearing that empirically and not really thinking much about it until I started to, one, observe it and, two, understand why. And it's quite obvious because again, all things equal, when insulin goes down, which is usually what happens when you restrict carbohydrates, sex hormone-binding globulin goes up. That means if you have no change in testosterone level or even estradiol level, free testosterone will go down. Less testosterone is around to be unbound to the sex hormone-binding globulin.

So it's for that reason that I think that insulin and carbohydrate do play an important role in the IGF pathway. And I also think empirically, not that I like to refer to ecology or epidemiology, but when you look at ecology and epidemiology of cancer, to my knowledge the content of highly refined carbohydrate and sugar is more predictive of cancer in a society than the variety in protein content. In other words, there are cultures that have consumed larger and lesser amounts of protein that have been without mass amounts of cancer, but the same cannot be said with large amounts of these things.

Now by these things, I mean sugars and high-glycemic-index carbohydrates. The problem with that is, of course, you can't infer cause from that, but the negative to me is suggestive that at the very least, carbohydrate content matters when it comes to IGF-1 signaling.

Rhonda: Absolutely, and the way I like to think about it actually when you're discussing these two things is IGF-1 is not a cancer initiator, like, it's not going to cause the initial damage that can make a normal cell aberrant, a normal cell that acquires whatever problems it acquired to make it turn into a cell that's not cancer. What IGF-1 is really good at doing is taking that cell that's already acquired the damage.

Peter: It's an amplifier, yeah.

Rhonda: Right. And saying, "Here, keep growing. Like, no, don't die. I know there's signals in your body that are trying to kill you, but don't die." You know, whereas the refined carbohydrates, the way I always think about is that leads to a variety, a plethora of physiological processes in your body, inflammatory processes a lot of different pathways that are causing damage, that are initiating the type of damage. So it's like, well, if you have someone that's eating a terrible diet, they're eating refined carbohydrates, they're they're releasing endotoxin in their gut, they've got this some constant inflammatory process going on, they're releasing hypochlorite damage they were damaging mitochondria, damaging DNA, blah, blah, blah. Well, and then so they've acquired all these damaged cells and then they're eating a bunch of protein and activating the IGF-1 pathway, it's like dynamite. It's like, here's the damage cell and here's the signals to, like, keep living and keep growing. So I kind of...

Peter: Yeah. I mean, so you obviously alluded to this and I think many patients when I talk to them are sort of surprised to learn that every one of us has cancer. I mean, at this moment I have millions of cancer cells in my body, as do you. The good thing is virtually all of the time the problem gets eradicated, right? So either we talk about the apoptotic pathways that you describe, but even when those pathways fail our immune system is remarkable. I did my post-doc in immunotherapy so I spent about two and a half years working with T cells specifically regulatory T cells in looking at this problem, and we just take for granted how good the humoral...the cellular immune system is, rather.

So for those, again, maybe not familiar with the immunology you have your B cell system and your T cell system. These T cells, which are the ones that fight viruses, are unbelievable. When you think about how many antibiotics we have in our arsenal to fight bacterial infections, it's remarkable. Think about how many antiviral drugs we have relative to antibiotics. We have very few and we certainly don't have them for the most common viruses we acquire. And yet, virtually all of us recover in the end unharmed from the typical viral infection we get two to three times a year. That's a testament to how amazing our immune system is. And when you unleash it against cancer, it's effective 99.9% of the time. So, yeah, the name of the game is avoid the amplifiers.

Now, the other reason why I think this is an important concept that goes beyond cancer but now gets to the broader aspect of aging is, when you look at the people who live the longest, when you look at these people who live to 100 and beyond, for the most part they die of the exact same diseases as the rest of us schleps. They just get them later. That's really important because I think it offers an insight into longevity that is often overlooked. So if the people who lived to 100, 105 were all dying in car accidents and plane crashes, you might make the argument that there's two classes of citizens, right? There's the people who get chronic disease and then there's people who will never ever, ever get it and eventually they just die of something else. Because remember, the fourth leading cause of death or the fifth leading cause of death starts to become accidental stuff, once you get outside of the chronic stuff, but that's not the case.

The point is we're all, sort of, preprogrammed to go through this process, but if you want to live longer the name of the game is delaying the onset of the big three, the big three being the diseases that will kill 75% of us, so cerebrovascular and cardiovascular, cancer, and neurodegenerative. And so that brings us back to why we've got to have IGF and mTOR in check, because we've got to prevent them from being able to, sort of, amplify that.