Rhonda: So your approach seems to really look at insulin response. It's looking at obviously the IGF-1, mTOR, dietary nutritional factors that are influencing those pathways and then, of course, the rest being fat. For me, I like to think about food as what you're putting in your body not only to activate these pathways or try to keep the pathways from being too active. But also, I like to think about it at the level of the gut because the gut, one, regulates the immune system, big time. I mean that's you've got more immune cells in your gut than you do in any other organ of your body and your gut bacteria, the interaction between your gut bacteria and your gut are also, you know regulating the types of immune cells that you're making, regulatory T cells being put in that.

And also because it's the major source of inflammation, and inflammation,even very recently has been identified to be a driver of the aging process. So eating things that are good for your gut like fiber and avoiding things that are going to cause a lot of gut damage. So I think about those things as well. And then micronutrients which is also a very important. Micronutrients are cofactors for a variety of enzymes and proteins in the body. It makes sure they're functioning proteins that are involved in these processes we're talking about, keeping cancer cells in check. You know, like p53 zinc-dependent proteins, magnesium which is important for repairing damage, things like that. Are those things that you consider at all when you're thinking about the influence of diet on the aging process?

Peter: I don't think about it as much as a lot of people do. And I would hate to use the term I'm a gut skeptic because I think that conjures up a whole bunch of negative images but...so I'm going to be a late adopter on this one, all right? So there are a whole bunch of facts that everybody can rattle off about the gut. A lot of them by the way are kind of BS. So the cells in the gut outnumber the cells in our body 10 to 1, that actually turns out to be false.

Rhonda: So you mean bacterial cells?

Peter: Yeah, sorry, the bacterial cells within our gut. So putting all that stuff aside, there are a whole bunch of really interesting facts. But it reminds me of what a good friend of mine once told me when I was trying to rationalize something I needed to do or thought I needed to do to him. He said, "Why are you doing this?" And I said, "Blah, blah, blah." And he said, "That's a fact, but is it a reason?" And so that's kind of how I feel a little bit about the gut. Like, there's a whole bunch of really interesting stuff but I don't know that it actually matters that much, right?

I'll give you a really idiotic example. The number of ants on this earth outnumber us 10 to 1. I'm making that up. Ergo, we should be doing more to protect the ants by avoiding climate change.

Rhonda: Yeah, but that's irrelevant.

Peter: And I'm saying, "No, that might be true. There might be more ants than us, but we're the species of interest." So that's my first, sort of, kind of, lack of interest. The second is I don't really know what to do with it, right? So I've been through it all, I've gone through all the sequencing, I've done it with patients, and I have found that it's like there's a very crude set of tools that I can use in really obvious cases.

So, all right, a patient that came to me two years ago who had a history of sinusitis, horrible history of sinusitis. So she probably had to do an Augmentin course six times a year because of recurrent sinusitis. She had three surgical procedures, just couldn't get better. So I started working with her. It became pretty clear to me that there was something in her diet that was creating an inflammatory environment that wasn't a structural problem. So we made a lot of dietary changes, things got better, but in parallel to that I sort of suspected that 10 years of 6 cycles of Augmentin probably altered her gut.

And so, yeah, she's an example of someone where I would do a sequence and can be like, "Lo and behold, you're all yeast." Right? Not surprisingly, and disproportionate bacterial overgrowth. Okay, so she's an example of someone in whom the signal was so big that I felt like there was an intervention I could make which was both fixing her diet but also utilizing agents that could alter that. But for the most part, I don't have a clue what to do. And all the people I see who claimed to know what they do, like, they can't convince me that they're knowing what they're doing.

Now, that doesn't mean that you can't...I mean I'm talking outside of a couple of really amazing examples. So we're familiar with how C. diff colitis works and the reversal of C. diff with stool transplants. So those are remarkable examples, but some of the other stuff I'm still not clear of. So I guess what I'm saying is I'm happy to be convinced but I'm not convinced yet that this is a reason and not just a fact.

Rhonda: So I think that focusing on the gut microbiome and the number of bacterial cells that supposedly outnumber our human cells and all that, I don't think that's the important point. You know, so I've become very interested in the gut mostly because of a colleague of mine, Mark Shigenaga, who has been working doing gut research at Children's Hospital in Oakland, and is brilliant. He's been showing me data and I've just been convinced more and more that gut health, making sure that you're keeping the mucin which your gut goblet cells are producing that disgustingly slimy mucus-like material that's keeping and separating the immune cells in your gut from all the microorganism in your gut. And that's very important because when that starts to break down, the immune cells recognize bacteria and they start [crosstalk]...

Peter: Is there...and I'm not asking this rhetorically, I just don't know. Is there an effective way to diagnose that in patients?

Rhonda: So the problem is that endotoxin released into the blood system would be the way to measure it and to diagnose...

Peter: I see, so you could measure it through the lack of barrier basically.

Rhonda: You can measure the endotoxin levels in someone's blood which is a marker, a proxy, if that helps.

Peter: Yeah, like the throughput, yeah.

Rhonda: But the problem is that there's also a lot of false positives. So that's the only concern until that test, the diagnostic test can be defined...

Peter: Because it seems to be a stool test would be a more effective way to measure that.

Rhonda: Mucin?

Peter: Mucin.

Rhonda: Yeah, there might be. There might be a way to do that, to measure it in a stool. That would be an interesting thing to explore because the...so what I'm getting at here is I'm a scientist, obviously, you're a scientist and like to understand the mechanism and see solid data before you think something is true. And I've become more convinced that the endotoxin released from the gut which is a constant...I mean, really the major source of inflammation in the body is coming from the...

Peter: And to be clear Rhonda, I'm not disputing that. So to be clear, I bought that thesis actually when I was a surgical resident because we would see endotoxemia, right? A surgical procedure gone bad endotoxemia, ICU, death. I know what that looks like in its most extreme state. What I think I'm more of a skeptic of, and again, a skeptic waiting to be convinced, is that I can make that diagnosis in a non-catastrophic case which is basically the chronic case and make an intervention either through some alteration in the microbiome itself or meaning directly or indirectly through diet or other variables. And I think that it would be very interesting, sort of, path to go down but, again, there's so many things I don't know at the moment, I'm just trying to focus on the ones that I do know.

Rhonda: Yeah. There is some interesting work coming out of, like, Justin and Erica Sonnenburg Lab over at Stanford. I recently had a discussion with them on looking at the role of fiber and certain types of fiber in fueling different species of bacteria in the gut and how those are generating short-chain fatty acids and other signaling molecules which are regulating hematopoiesis, they're regulating the number of Tregs that we're making. So it is very interesting that feeding our gut certain types of fiber which are present in vegetables and a variety of fruits even, do have a positive effect on the immune system via the signaling molecules that are being made in the gut.

So that's very interesting, and it is one thing that I consider when I'm thinking about the effects of diet on longevity.