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episode #214

Episode 214 – Interview with Dr. Dom D’Agostino and Jay Feldman (Part 2): Fat vs Carbs as a Fuel Source, Fructose, Fatty Liver, and PUFAs!

December 26, 2022 in Podcast


This week I welcome you to join me for the final segment of this 2-part show with keto researcher and professor Dr. Dom D'Agostino and health coach and bioenergetic researcher Jay Feldman!

This was a friendly debate full of wonderful insights, including:
  • Fat vs. carbs as a fuel source
  • Autophagy
  • Is Fructose to Blame for Fatty Liver Disease
  • Does Higher Omega 3's Increase Lifespan?
  • Problems with Oxidized PUFA
and Are Carbs Beneficial for Our Physiology?

Enjoy the show!

Brian (0s):

Coming up on the Get Lean EAN podcast in the keto state, like you have these ketones and those are great for producing energy. But when you're using fatty acids for energy, it's not ideal. It's not as efficient for a TP production, and it comes at a cost. And you have lower N A D, which is a, the N A D 10 a d H ratio is one of the central regulators of how well we're producing energy in the mitochondria. And so this is my biggest concern when it comes to the, a ketogenic diet, especially in a non, in a state where it's not necessary. A situation where it's not genetically necessary or something like that, is that because we have to shift into this largely fat-burning state. And because that fat oxidation is less efficient than the Carboid station, it leads to greater reactive oxygen species production, a lower N A D 10 a D H ratio, which leads to all the hormetic effects, all of those adaptations.

Brian (50s):

But because of that difference, my, that's one of my central concerns with a ketogenic diet is, is that difference. Hello and welcome to the Get Lean e klean podcast. I'm Brian Grn and I'm here to give you actionable tips to get your body back to what it once was, five, 10, even 15 years ago. Each week I'll give you an in-depth interview with a health expert from around the world to cut through the fluff and get you long-term sustainable results. This week I interviewed keto researcher and professor Dr. Dobb, Diego Augustino, along with health coach and bio-energetic researcher Jay Feldman. For the second time around, this was a friendly debate in which we discussed all about Fats First.

Brian (1m 32s):

Carbs as a fuel source along with autophagy is fructose to blame for fatty liver disease. Does higher omega-3 S increase lifespan problems with oxidized pfas and are carbs beneficial for our physiology? I really enjoyed my interview with Dr. Dom and Jay. This was the second time we've done it and I think there was great points on both ends of the spectrum. Thanks so much for listening and enjoy the show. All right, welcome to the Get Lean E Clean podcast. My name is Brian grn and I have Dr. Adam Dom, Dino, and Jay Feldman on for part two. Welcome guys. Thanks for having me,

Dom (2m 10s):

Brian. Hi Jay. Great

Brian (2m 11s):

To see you guys again. Hey guys. Yeah, I'm excited. This is part two. If you haven't listened to part one, definitely check that out. That was done a couple months ago and we're gonna touch on all different topics today. And I was just thinking before the conversation started how, how these conversations are I think are healthy and these discussions around nutrition and brain health and things that we're gonna get into today. So I was definitely looking forward to doing this again. And, and I know we were cut short a little bit last time, so, but we're gonna just jump right in and I guess we could start in many different places. Maybe why don't we just touch a little bit on some of the things that we talked about last time regarding, and Don maybe you'll touch on like the ketogenic diet.

Brian (2m 58s):

I know we talked about different applications of, you know, brain health. What are you, what are you working on now? And, and maybe I know you wanted to touch on some things regarding that. So,

Dom (3m 8s):

Yeah, well we have a study that we haven't published yet in as far as a peer reviewed publication, but we've presented it at about a half dozen conferences. And that's taking people who are non-diabetic, non-obese, and we're using continuous glucose monitoring, in this case the Abbott Libre device with the levels software application. And we are looking at glycemic variability as a monitoring glycemic variability as a means to alter behavior around eating and creating metabolic awareness in regards to food selection and, and the amount of food.

Dom (3m 54s):

But in, in our case, we're actually using a low carb diet, a ketogenic diet. So we have a massive data set from that. You could, we have a group wearing CGMs and a group wearing, not wearing CGMs. And the bottom line is that there may be some benefit to wearing a CGM in, in regard people like it, other, you know, above pricking their finger. That group seems to have a better reduction in non-alcoholic fatty liver disease. Interestingly, we saw like 60 to 70% of the people who are like, you know, normal people had non-alcoholic fatty liver disease or hepatic steatosis, the precursor to that.

Dom (4m 34s):

And then actually some of the psychological measures, we used the GAD seven tests, PHQ nine, we'd look at sleep, there's a wellness score mood and things like that. They trended better in people that had continuous glucose monitor, but interesting. You know, but the main cardiometabolic biomarkers really weren't much different. But, but I think people do like the idea they ga they gamify a C CGM device and all the benefits seem to happen in the first six weeks and then it kind of levels off. And a lot of people just stop even looking at opening up the app to look at their continuous glucose monitor.

Dom (5m 14s):

And you know, I I, I'm wearing one now. I got Dexcom on and I, I've, I've wore a Dexcom on one side and, and the Abbott on the other, and then I compare the two.

Brian (5m 26s):

Oh, interesting.

Dom (5m 27s):

And, and so I've done that and then, you know, working with different companies that are developing continuous keto monitor, I'm, I'm excited about using these things for metabolic management of epilepsy and neurometabolic disorders. So, so there's that on the clinical front, we're doing a lot on the space research front. I don't wanna go down that path cuz that's like a whole nother podcast, but, but we're looking at ketones as epigenetic regulators. So my student, my PhD student did C Q E and passed and we're looking at the metabolic control of epigenetic regulation. So ketones impacting something called beta hydroxylation.

Dom (6m 11s):

So beta hydroxybutyrate can interact directly with the histone and cause modifications. And then changing in gene expression, we're specifically looking at disorders like kabuki syndrome and pump pump syndrome, which is glycogen syntase disorder type two. Like some of the things that your listeners may not have heard about, but in, in many cases the ketogenic diet is very therapeutic for inborn errors of metabolism and, and also in cases of genetic diseases. So there could be a persistent molecular pathology. You're not changing the the disease state, but you are symptomatically managing the disease, the, the symptoms associated with a genetic disorder.

Dom (6m 59s):

So even in the presence of a persistent molecular pathology, a ketogenic diet can be used to manage that. Or in the case we're actually using ketones supplementation in the form of various ketogenic agents and that that's a PhD dissertation. We're looking at autophagy, we're using lc three. So you can't measure auto. A lot of people talk about autophagy becomes a big discussion and a lot of people talk about many different things, but they don't actually measure it. And so measuring these things is quite tricky. It's very nuanced. You have to measure the autophagic. So we do lc three and P 62 are some of the, the autohaus zone markers that you measure.

Dom (7m 42s):

So we're looking at

Brian (7m 43s):

Maybe explain to people listening maybe what autophagy is, you know, just give 'em a high level idea what that is. Cuz I know that's coming into light a lot with, with low carb and fasting and things like that.

Dom (7m 57s):

Yeah, it gets talked about a lot, you know, and, and even though we're doing research on it, there's so many things that there's, that we don't understand. But in the, the very basic sense auto Fiji is self eating and it's kind of, you know, in simplistic terms, the housekeeping

Brian (8m 14s):


Dom (8m 15s):

Pathway associated, it's happening all the time. It's happening on a high carb diet, it's happening on a low carb diet. It it, it, it does increase the autophagic flux. So you measure something called autophagic flux when you're measuring autophy and it's the, the ratios of certain things i in the context of an energy deficit. So when you have am PK activated and, and mTOR low, insulin slow and things like that, the flux of autophagy will be higher. And just because you're in more catabolic state and the idea for certain disorders that we're looking at, including glycogen syntase disorder type two, which there's a decrease in auto, we're trying to see if we can enhance autophagic flux to decrease glycogen accumulation and and lysosomal activation, we're gonna do that without necessarily creating a sustained energy deficit, which is not feasible.

Dom (9m 19s):

You know, you, you can't fast, you can't do calorie restriction indefinitely. So we're we're developing protocols that could enhance autophagic flux by suppressing the hormone insulin, maybe actually increasing glucagon a little bit and, and various catabolic pathways for certain disorders. And interesting

Brian (9m 41s):

And sorry to interrupt you and exercise also.

Dom (9m 44s):

Yeah, that's a big one.

Brian (9m 45s):


Dom (9m 46s):

Probably more than anything else actually exercise, especially in the context of an energy deficit will increase it. But even, you know, in a, in a fed individual that does vigorous exercise, you're kicking on autophagy. And I think there are many benefits to that, but autophagy is not really good or bad, it's just part of a, a, a normal process in certain disease states, increasing autophagic flux can enhance the degradation or can can enhance certain processes in the body and make the immune system more vigilant, for example, in being able to recognize cancer cells.

Dom (10m 28s):

So it can increase anti-cancer like immunity. So there's people doing research on that and can augment certain aspects of our physiology that can be beneficial. But you know, we're looking at it mostly from a disease state. And I, and I guess for the normal healthy person, you know, fasting can, can activate autophagy and may, you know, and the people that I communicate with, they talk to me and they have a lot of questions about autophagy and for example, they may have an inflammatory episode or they're trying to manage some kind of chronic autoimmune disorder and they're talking about, hey, how, how can I maximize autophagy?

Dom (11m 11s):

And I don't really know, you know, I I I do have, I can speculate though, I think, and what we like to measure is the glucose keto index. If you lower glucose and elevate ketones sort of in a one-to-one ratio, for example, bring glucose down from five to three millimolar and elevate ketones to three millimolar, that's a glucose keto index of one. And that typically correlates with an insulin that's very low around two to three. And in that particular physiological state would be sort of analogous to what we see in animal models with increasing autophagic flux.

Dom (11m 55s):

So now this is speculation. If we're talking and I'm a basic science animal researcher, you know, and, and cells and, and, and we do, we do human research too, but 80% of what I do is animal research. So if I was to extrapolate kind of what we see in animals, if you can achieve a glucose keto index of one, I would speculate, and I don't know if anyone's done this in humans, that you would be activating and triggering perhaps even maximum autophagy. So, you know, periodically I will put myself into a state of fasting where I achieve a glucose keto index of one. But once I do that and maintain that for 24 hours, I quickly get back to eating again.

Dom (12m 38s):

Because if I do that for a prolonged period of time, it tanks my hormones like testosterone goes down, I think it, it's, you know, it's starting to reduce my metabolism and if you fast for a week, it takes, it takes a week or two to recover from that. So, and we can get into this and it's not really talked about that much. And I think you guys, I think this is a good platform for, for discussing the pros and cons of, of doing some of the stuff I did, you know, years ago that I don't do now. I don't do intermittent fasting now. I mean right now I'm fasted I guess cuz I didn't, didn't have time to eat this morning. But, but generally speaking, if I fast, you know, it might be once a week, maybe twice a week if I have like a heavy morning lecture.

Dom (13m 24s):

But I, I don't think it's like the default, I don't think keto should be the default diet and I don't think intermittent fasting should be done every day for most people.

Brian (13m 36s):

Yeah. And Damman just on that point, like I'm, I'm, I was the same way. I think this, that the way I did things years ago are a little bit different now. We've all changed and evolved and learned. Yeah. So yeah, I hear you. I mean I think, like you said, these are tools and I, I do think that like fasting is a tool. I think it's something that if you've never done it before, I think it's worth like, at least like easing your way into it and just like exploring it because it does give you, what I've learned is for my, my own good cuz I don't do it as much now, like you said Dom, is it just when you know you need to do it or like let's say you're traveling and there's just crappy food and you're like, okay, I don't, I'm good.

Brian (14m 17s):

Like I don't need to rely on anything. I think there's that sort of like confidence and that sort of just gives you that flexibility when you, when you maybe aren't in a situation where you're gonna eat something that's actually halfway decent

Dom (14m 30s):

And it works better as a tool, it works better if you're not doing it all the time. Right? If you do it all the time, then your body adapts to this intermittent fast. And if you go to eating, you know, now I eat like three meals a day, maybe sometimes four, then you'll likely overeat. You may overeat when you do that. So I, I feel that intermittent fasting works best if you don't do it all the time. Same with keto. I mean I'm pretty low carb and I will on many days I'm in acidic keto. I, I mostly just do a low, very low carb ketogenic diet because I'm a researcher and I'm constantly experimenting.

Dom (15m 10s):

Although I've been eating more carbs. Like I, I could see in my, my face is more full cuz I, I I eat quite a bit of fruit and probably about a cup of blueberries every day. Then we have fruit on our property. We have a farm. So I'm trying to think, oh

Brian (15m 26s):

I need, I need, I need a farm.

Dom (15m 27s):

I have dark chocolate every day. I have dark chocolate and I have probably about 50 grams of fruit, carbs worth of fruit per day on average. But, and I wake up, I'm not in ketosis, but by middle of the day the, the latter half of the day, my ketones are about one millimolar and that seems to work good for me, you know, if I was to wanting to gain weight, significant amount of weight or muscle or if I was an athlete. I'm kind of the sedentary guy, although I like to lift weights, but I would titrate carbs back in for

Brian (16m 1s):

Sure. Have you found Dom, just on that point, a difference in, in your body composition or your weight since you've added in some more carbs or Oh, had three, four meals a day as opposed to not Yeah,

Dom (16m 14s):

Yeah. I I actually, this weekend I went through all like my medical records cuz I'm scanning all my blood work back to 1992. I started getting blood work in 1992 cuz I went on a drug for acne. It was called Accutane. Oh yeah. And, and you have to like monitor your liver enzymes. And I noticed my liver enzymes were high, not, they were in range but they were always high when I was eating very high protein. And now my liver enzymes are like in the teens or twenties, but they were typically in the thirties and forties all through my twenties when I was just like eating like 400 grams of protein a day, 500 grand, you know.

Dom (16m 54s):

But my blood work that my blood pressure, glucose and many things have remained stable. So I've actually, I'm scanning all this, I'm graphing it cause I'm, I'm approaching 50 and I want to get a handle of all the, the major, you know, body weight, body composition. When I was eating carbs, I was holding a lot of, a lot more muscle for sure. And I think it, I I think having a little bit of insulin, you know, just through some carb consumption definitely made me bigger and stronger. My hormones are not what they used to be, you know, and, and whether that's because of keto or not, I'm not sure. So adding a little bit of carbs back in, I have been monitoring my, my testosterone and other hormones.

Dom (17m 41s):

My, my, my insulin and my glucagon are well within normal range. So I know we, we talked about that previously before, but my testosterone tends to fluctuate like between around 400 to like, and, and I look back at my blood work when I was in my twenties and even thirties and I was like six, 700 a couple times 800, you know, so I'm almost half that and I don't, I think that's more of an age thing. I don't think it's a keto thing. The highest I've been on, like being strictly keto was 5 76 I think. And I've never been over that on keto. Whereas prior to keto I consistently was like in the six or 700.

Dom (18m 25s):

So it, it's po but I think it's more of the, the decrease in some of my hormones is associated with a decrease in body weight and a decrease in total calorie consumption over time because I lost body weight. But I'm still like, I mean technically I'm like overweight. So

Brian (18m 45s):

When you say technically you're overweight, are you saying just based on like a BMI or something?

Dom (18m 50s):

Yeah, if you don't

Brian (18m 51s):

Look overweight to

Dom (18m 52s):

Me, no. My BMI is like 28 or 20, you know, I had to fast to get, when I got life insurance, I fasted, I think the lowest I got is like 2 0 5 or almost got down to 200 when I had to do like my life insurance cuz I pay higher premium because I'm, I'm overweight, but I, I'm two 17.5 right now and, and I'd like to kind of maintain that, but you know, 20 years ago it was like 2 30, 2 45 even just eating a lot of weight. You know, I was training a lot training with like back with Lane Norton back in 2000 7, 8, 9. I think that's when I achieved some of my highest body weight. But I was eating a ton of food and I do not think that is, that is not optimal for longevity.

Dom (19m 36s):

I had my highest blood pressure, you know, totally correlates with my body weight. So bringing my body weight down, the only thing that looks scary to my doctor and she's urging me to get on a statin is my ldl, my LDL and a o b or I. So that's the main thing that I'm trying to experiment with now to manage. And maybe we could get into a talk little bit of discussion about that, but,

Brian (20m 4s):

Okay, well Jay maybe we should bring you in here.

Dom (20m 7s):

Yeah, sorry, I've been talking. That's

Brian (20m 9s):

Okay. There is a third person not I'm here, I'm here. So Jay maybe what have you been up to since the last time we talked? Are you writing any more blog posts? You got, I know you did a most recent podcast episode on your podcast, which is the energy balance podcast. Anything new come to mind that's since the last time we talked, not too much. I do wanna mention, so last time we had the earthquake, now we have some construction going on, imminent new place in Mexico right on the other wall. And this morning they're drilling, so it's been pretty loud over here. I'm gonna try to stay muted when I'm not talking and hopefully they, it just works out well or when I'm talking they're quiet.

Brian (20m 53s):

Oh, okay. But if they, if they do start, it'll just be a second or two. Really Sorry about that. No problem. But yeah, I would say, you know, since we last talked, not, you know, haven't been experimenting with anything particularly different or exploring any particularly new topics. Yeah. Not too much to Dr. Dr. Pete passed away. Yeah, correct. Yeah, it was very sad. Yeah. Yeah. Heartbreaking news. Yeah. And so with, with that, why don't we, I mean there's a lot of great topics Don, that we already touched on a little bit, but let's touch on like glucose oxidation versus fat oxidation. We'll start with that and dive in there and you know, it's interesting because, I mean, we talked about it last time, like what's the, is there a be, is there a best way to go about that if, if, and is it good to come come in and out and be somewhat flexible from that standpoint?

Brian (21m 54s):

So I don't know, Jay, maybe you want to touch on, on your, I know you are obviously more on, on the glucose, on, on like becoming an efficient glucose oxidator and you're, you, well I'll let you explain why that is as opposed to just eliminating that or at at least eliminating a lot of things that that would, you know, obviously carbs that would have you become maybe better at it. So I'll let you get into that. Yeah, so, so there's a couple things that I would that that come to mind. So one thing I know we talked a lot about last time is that one of the main features of any degenerative state tends to be issues metabolically issues with mitochondrial function and with that normally issues with glucose oxidation.

Brian (22m 36s):

And that's a lot of the situations that a ketogenic diet or supplemental ketones benefits. And I think we talked about this as well where I have less of an issue with, well, so, okay, so first thing is my preference is always to say let's fix that metabolic dysfunction. If in the meantime we maybe need to drop carbs down to feel better or to, you know, create some outcome, then I think that's fine. And again, this is talking about somebody who doesn't have a genetic disorder or something like that. And but so my focus would be to say let's fix that ability to oxidize the glucose. And the reason why I wouldn't say let's just go to a ketogenic diet long term, which I'm not saying that Dom is saying, in fact you're kinda suggesting the opposite last time.

Brian (23m 18s):

And you know, we were talking earlier today, the reason for that is not because of the ketones themselves, as I was saying, I don't have as much of a concern with the ketones, but rather that in order to get into that ketogenic state, a we end up really having to rely entirely on fat other than the ketones we produce. And I think there's a cost to that reliance on fat oxidation. And then the other piece too is the, the fact that we, you know, as, as we discussed, there is a stress involved or it is stressful to get into a ketogenic state. And I think that there's a potential cost to that as well. And so that's something we can dig back into too, and the, the hormonal regulation there. But as far as the glucose versus fat burning, cause I think that that's really the central point here also, is the drilling really bad?

Brian (24m 3s):

Oh, you're fine, you're fine. It's real life. Yeah, that's good. That's good. So I know I kind of phrased it this way and we had both agreed that a ketogenic diet is, or a ketogenic state is something that happens when we're in a starvation state, a famine state, a situation where we're not eating at all, where we're fasting. And as such there are certain, like a, I think our bodies are tuned to respond to that state in a particular way, which involves those hormonal shifts. It's supposed to be stressful and it's supposed to involve turning down our metabolic rates so that we can survive without food for longer. And there are signals on the hormonal side that, that tend to signal that, but also in terms of the bioenergetics, in terms of what's actually going on in the mitochondria and outside the mitochondria between oxidizing glucose and carbohydrate and fat.

Brian (24m 50s):

And so I know we talked, I think very briefly, Dom, you had mentioned Dr. Richard Veach last time, and I know in one of his, his later papers in 2014, he had discussed this and he had said basically that he's more of a fan of using supplemental ketones as opposed to the ketogenic diet. And he was saying that that's because of these negative effects of fat oxidation, of fat burning, which has to happen when we're on a ketogenic diet. And I have a, a real quick quote that I wanted to share if you guys don't mind, that he had, this is from his paper in 2014 titled Keto Esther Effects on Metabolism and Transcription. And he says ketosis induced by starvation or feeding a ketogenic diet has widespread and often co contradictory effects due to the simultaneous elevation of both keto bodies and free fatty acids.

Brian (25m 37s):

The elevation of keto bodies increases the energy of a t p hydrolysis by reducing the mitochondrial and adco and oxidizing the coenzyme Q couple, thus increasing the redox span between site one and site two. In contrast, metabolism of fatty acids leads to a reduction of both mitochondrial line ad and mitochondrial coenzyme Q causing a decrease in the delta G of ATTP hydrolysis. And to kind of, for a listener who's like, that doesn't mean a lot to what he's basically saying is that in the ketosis state, like you have these ketones and those are great for producing energy, but when you're using fatty acids for energy, it's not ideal. It's not as efficient for a t p production and it comes at a cost and you have lower N A D, which is a, the N A D 10 A D ratio is one of the central regulators of how well we're producing energy in the mitochondria.

Brian (26m 25s):

And so this is my biggest concern when it comes to the, a ketogenic diet, especially in a non, in a state where it's not necessary a situation where it's not genetically necessary or something like that, is that because we have to shift into this largely fat burning state. And because that fat oxidation is less efficient than the carb oxidation, it leads to greater reactive oxygen species production, a lower N a D 10 a d H ratio, which leads to all the hormetic effects, all of those adaptations. But because of that difference, my, that's one of my central concerns with a ketogenic diet is, is that difference. And I'm happy to kind of dig into that for listeners if we want to talk in more detail about what exactly happens when we burn glucose versus fatty acids.

Brian (27m 6s):

It's mostly just biochemistry, which might not be that valuable to a listener, but yeah, I, I'm, so I'm curious to know what you think about that, Tom.

Dom (27m 14s):

Yeah, so Dr. Veach, I connected with him in maybe 2008 and we had many conversations on the phone, many emails actually went to Dr. Beach's lab at the nih and he showed me, he walked me through the whole process of making keto Esther and Todd King was the chemist there at the time. I consumed Ke Esther and we did talk, he, the, the papers that he forwarded me about the, the dangers of a ketogenic diet and, and high fat oxidation. He, he, he referenced and sent me a paper that was done at Johns Hopkins, a clinical trial showing elevated triglycerides in kids.

Dom (27m 55s):

So this particular study was, I think it was using ketocal, which was mostly hydrogenated soybean oil. And they, you know, so the, the, the papers he was sending me were ketogenic diets that were clinical and they also had a fatty acid composition that was literally scary. And, but we had a lot, he, he convinced me. So my initial proposal to the Office of Navy Research, which is part of the Department of Defense, he was funded by DAR at the time to develop ketones for war fighter performance. But the, the problems with the ketogenic diet, the clinical ketogenic diet, I thought were, were real and in the context of what I was studying it for, which would be for war fighter resilience against oxygen toxicity, high levels of oxygen.

Dom (28m 45s):

At the time I was studying polyunsaturated fatty acids and showing that a high poof of content in the membrane was elevating malindi aldehyde with a T-bar test. And I also used hyperbaric atomic force microscopy to show that the membrane viel elasticity, fluidity and membrane oxidation was increasing with high polyunsaturated fatty acids, which I think you guys touched on a little bit maybe. So that was my interest. It, you know, and, and the, there was a potential danger of high fat diet there. Long story short, the, the navy did not like the idea of a high fat diet. So I changed my proposal and switched out the ketogenic diet with exogenous ketones, a keto nester.

Dom (29m 32s):

The first keto nester that we tested was 13 butane dial beta hydroxybutyrate mono er. And it did not have any anti-seizure effects. So I started to kind of lose enthusiasm because Dr. Veach was very convincing in that, you know, the delta G of a t p hydrolysis would be, you know, enhance with ketones and things like that. And I really thought it was gonna change brain energy metabolism in a way that would confer resilience against an oxidative challenge. In our case, it was five atmospheres of, of oxygen, which increases brain, brain oxygenation, the P two and the brain increases by like 2000% when you're breathing high pressure oxygen, right, hemoglobin saturated, but the oxygen is actually dissolved into the plasma and that plasma spike up, you know, causes redox stress and then the seizures that, that's what we were studying.

Dom (30m 35s):

So long story short, I connected with another investigator, maybe even like a, a colleague, but maybe a, a, a competing biochemist with Dr. Beach. His name was Anri Brungraber and he, he managed the N NIH sponsored metabolomics core, a case western. And he gave me a recipe to synthesize a different keto nester that was one three butane dial acetyl acetate dier. And I, I, I couldn't find any body in academia to, to make it for me. So I end actually ended up connecting with Patrick Arnold, who created a lot of performance enhancing compounds for different applications.

Dom (31m 18s):

He synthesized it for me. And using this keto esther, elevating acetyl acetate and beta hydroxybutyrate in a way that's redox balanced, when you deliver a big bolus of beta hydroxybutyrate, it shifts the redox at the level of the cell in a way to become more reduced. And it also shifts the, the redox state in the liver. But when you deliver it in a redox balance preparation, which would be beta hydroxybutyrate and acetyl acetate in balanced ratios, then this did a number of different things. In our case, the most important thing is that it had a profound effect, not changing diet at all, just simply giving a keto nester increased the resilience to seizures by 600%, which means that an animal typically seizes in like five to 10 minutes under these extreme environmental conditions.

Dom (32m 14s):

Most of our animals would go to like an hour. So that's elevating be hydroxybutyrate and acetyl acetate. And, but the same thing can happen if you fast the animal 24, a 24 hours of fasting in a rat is like, you know, three or three days of fasting, three to five days of fasting for a human that would dramatically increase resilience, reduce. But if you fasted the animal 36 hours, then it was also remarkable about a 300% increase in the latency to seizure. But a single dose of this particular keto nester prolonged the latency to seizure up to almost 600%.

Dom (32m 58s):

So that actually convinced me that independent of a ketogenic diet, independent of shifting macronutrients, you could deliver ketones with an oral gage. And it's totally shifting metabolic physiology and it's actually increasing fat oxidation too, even at the level the muscle. He, he did some studies showing that, but for some reason beta hydroxybutyrate alone did not have an anti-seizure effect. So I started developing and testing different exogenous ketones formulations, which we got a bunch of patents on things like that. But it gave me an appreciation of ketones as an alternative energy substrate in particular for brain metabolism.

Dom (33m 42s):

And that set me off in 2009, I guess we're talking now, it that actually set the stage for my career to, to study, to study different bioenergetic molecules and with a de-emphasis on the ketogenic diet. But then we came back to the ketogenic diet when we were studying cancer and, and different cancer models are very responsive. And then we started looking at blood glucose lowering, we started looking at inflammatory pathways. We have models where we give l p s lipopolysaccharide, if you injected in animals, you know, in mice you can essentially kill them all.

Dom (34m 24s):

But if they're in a state of, of ketosis with supplemental ketones, you can rescue the animal. So, so, so we did a lot of work outside of the world of epilepsy, which is kind of like my bread and butter so to speak. Everything from Alzheimer's disease to als to, you know, and many different model systems. Ketosis is, is therapeutic. And I believe it's therapeutic because it's enhancing the bioenergetic pathways. Well it's, it's, it's restoring bioenergetic pathways in the context of a deficiency. And I think that's important. It doesn't mean just because you get favorable therapeutic effects in a particular animal model and even in humans under certain disease states does not mean that people should be jumping on a ketogenic diet and especially doing that in a prolonged way.

Dom (35m 19s):

And I don't even follow a ketogenic diet anymore, but I do stay very low carb. But yeah, so that was my, my, I have many Dr Veach stories, but that, that's kind of what he, he actually inspired me to go down this path. So I have to, and, and we had different views. He did believe that high fat diets were dangerous and I did not hold that view completely. I al I also felt not to like in a disparaging way, but, but promoting high fat diets as being something that's potentially dangerous is also a way to promote your exogenous ketones, right?

Dom (36m 2s):

So I, I feel that there was some biased against high fat diets to promote the, to promote the use of ketogenic agents in place of ketogenic diet. But it always confused me because the only clinical application of ketogenic diet was for seizures. And I was like, well if you're developing these ketogenic agents, why would you not just studying them in seizure models, which I was the one that stepped in and started doing this. And we did, you know, the phenol and tetra model model, we have the, the, we have an absence epilepsy model, we have many different models of seizures.

Dom (36m 43s):

The ketogenic diets work, but exogenous ketones also work, certain ones work and certain ones don't. And, and I think we don't fully understand why certain ones don't, but we do know that in the case of you get to get maximum anti-seizure effect, you have to have a ratio of beta hydroxybutyrate to acetyl acetate. It's not just spiking up beta hydroxybutyrate. And, and I think that's important in it for people wanting to just enhance their brain energy metabolism for cognition, for longevity and things like that. And we, we have not done the mechanistic work to understand why that's the case. So it's like a top-down approach. Like we see this observation but we don't fully understand why the, the, so, so sorry, but it comes down to redox biochemistry.

Brian (37m 29s):

Sorry to interrupt Dom. I just, so Jay, I guess I guess the point for Dom is, is that, you know, there's a, this clinical application for using the keto diet obviously, which you've been studying for a long time. But let's perhaps try to talk about like just for the general population, do we think it plays a role? And Jay I know you're, what do you think at any time, like we talked about if an individual's like not insulin sensitive and you know, they have these underlying issues bringing carb and when we talk about bringing carbs down, there's, that's a broad term, right?

Brian (38m 12s):

Like what type of carbs, you know, are we talking mainly grains and processed carbs? Cuz that's a lot different than, than having whole food carbs perhaps. You know, obviously like we talked about fruit and things like that. And we can get into fruit cuz I, it's interesting I just, Dr Ken Buren, I think Jay I sent you, he did a recent post, he did an inter, he did a podcast with Dr. Saladino regarding fructose and honey and, and he was just talking about how fructose can cause this guy perhaps could cause glycation, but that's a whole nother sort of topic. I don't know Jay if you wanna jump in here, did you, did you see the video I sent you that he did?

Brian (38m 55s):

Yeah I did. I saw, I saw that you sent it to me yesterday. I didn't watch the video. I Okay. Looked very briefly at the references. And again, so this is premature cause I haven't looked through all the references, but the only one that it looked like had anything to do with increasing ages in an actual applicable sense where it wasn't just mechanistic but rather saying like we gave, in this case it was rats, fructose and increased ages was the way it was phrased. The only study that I cited that was doing that looked at fructose Sweden beverages versus glucose Wheaton beverages versus, I don't remember if it was sucrose or just free glucose plus free fructose Sweden beverages. In addition, a regular diet and the glucose weand and the Sweden one and the glucose fructose one or the sucrose, whichever one it was, there was no negative effect.

Brian (39m 40s):

It was only in the fructose only sweetened beverage group, which I, I've talked about ad na ad nauseum that that's not relevant to any situation When we would be getting fructose any place in nature where we're getting fructose, it tends to be close to a one-to-one ratio of fructose glucose. There's some variation, but we're always getting some glucose there. And when we get fructose without glucose, we don't absorb it in the intestines. It requires, we need to have some glucose coming in to get some good fructose absorption is kind of part one. And so in a lot of the animal models where they look at fatty liver disease and they look at fructose, what's happening is they're giving pure fructose, the fructose doesn't get absorbed, it feeds bacteria.

Brian (40m 22s):

They produce that lipo polysaccharide that Don was talking about using earlier to which can kill organism and that then causes the fatty liver disease. And if they add something like antibiotics to that situation to prevent the lip polysaccharide production, that effect goes away even with the pure fructose. And so this is something we see with alcohol as well, which again, kind of a another tangent here, but yeah, I think to, to put it as simply as like fructose causes fatty liver disease or fructose increases ages when that's the context is just not not representative of the reality. I would love to come back. I, I know Dom you wanna jump in, so I'll let you jump in, but I did want to come back to the

Dom (41m 3s):

Card. Well I have a, I have a quick fructose just observation because I've literally been scanning like all my blood work for 30 years and, and also looking at my, my diet journals and also my, my food, what I was buying in like 2007, I would, I would have two, I would buy two watermelons, two pineapples and two bags of blueberry and this would all be gone at by the end of the week and I would go shop. I I I had a very high fruit consumption, no grains though. But what I did notice in my blood work when I was eating a lot of fruit that I, that has gotten a lot better now that I still eat fruit every day. But it just, I just didn't, don't eat the massive amounts I used to.

Dom (41m 45s):

My A L T levels are went from like thirties, mid thirties and now they're like, you know, 15 to 20. So, and that's, you know, and talking with Robert Lustig who would probably be a good guy to have on if you haven't had him already, he talks, oh okay, yeah. You know, we were, we had dinner together and we're talking about different markers and I was talking, telling him about some of the observations with hepatic steatosis and non-alcoholic fatty liver that we're seeing in like normal subjects. Like we're not even like reaching out to like people with type two diabetes or obesity in our study.

Dom (42m 27s):

And he said the A L T is really like the early precursor once that starts to climb up. And I was telling him, you know, about my A L t levels were, were trending high until I started dialing back, you know, and I think I was just getting, I think that excess amount of fructose from an excess amount of fruit was driving that a l t up. And I think if you were to do an ultrasound or a ct, you'd probably see the beginnings in a, in a perfectly healthy, you know, 20 exercising 20 year old 30 year old person. I had their, that the, I had the precursor to non-alcoholic fatty liver disease just based on some of my, I didn't get a scan in my liver, but my, my blood work from what I know and talking with him and, and talking with other people, what was showing an early predictor of, of non-alcoholic fatty liver with the high fructose consumption.

Brian (43m 22s):

Yeah, that I, Jay do you have any thoughts on on that? Yeah, yeah, so I mean there's obviously it's tough with UNE equals ones. I know do also mentioned the Accutane was something that had interfered with your lung function and those enzyme

Dom (43m 37s):

It they did, but that was like 1992 to 1993

Brian (43m 41s):

And it renormalize and then came back up.

Dom (43m 44s):

They renormalize in about a year or so, but it was like a fairly light dose of Accutane. But then I, I started getting blood work and I started getting, you know, I was studying biology at the time so I would always ask my doctor for copies of my blood work, which I encourage everybody listening to this who's getting blood work. Well I guess they do it all automatically now, but back in the day they did. But when I would go to the doctor be like, I want a copy of my blood work even in 1992. So it's very interesting to see these trends and because I kept all my journals, diet journals and things like that and my body weight, most of the negative effects I could see is just when my body weight was higher.

Dom (44m 23s):

But I, I'm pretty sure I can basically just look at my, the amount of carbs I was buying on my grocery list and, and look at my body weight and see the changes in my blood work. And a lot of the, the things that were creeping up reversed when I started doing will carb, although, you know, my lipids took, took a different turn in some ways triglycerides are still very low, but my HDL went from like fifties to 95, my HDL did and, but my L D L tripled and has, it's, it's like, it's still elevated now, but, but adding some fruit back in and some carbs back in has, has dropped my d l significantly.

Dom (45m 8s):

So I have blood work scheduled, a very comprehensive blood work scheduled in about three, three to four days. So I'm very interested to see the carbs that I'm eating now that I've added back into my diet, how, how it's gonna impact LDL and APO B and my NMR lip profile. So I'm gonna blog on this soon, so I'll be, I'll be writing that

Brian (45m 29s):

Looking forward to it as just, just to kind of add in some, some more unequals ones I suppose. I, I work with clients who have fatty liver disease and, and I've seen multiple people with significantly elevated liver enzymes beyond, you know, beyond reference range, be able to get those into range. I've had one client in particular who had severe fatty liver disease shown on the scans and everything and had adenomas and we were able to get a completely clear scan with no signs of fatty liver or anything. And this was without any restriction in terms of fruit or fruit juice even, which I think when you, like when you take

Dom (46m 7s):

Some probably dropped their body weight though, right? I mean a

Brian (46m 9s):

Little bit a a little bit but we're talk maybe like a few pounds. It really didn't, it didn't seem to correlate so strongly with, with body weight. But I think to, and I'm not saying you're doing this, but in general the picture painted of fructose equals fatty liver or equals increased uric acid is a, is another one that's circulating now. I mean I have my own blood work too showing very low uric acid despite eating quite a bit of carbohydrate, like part, quite a bit of carbs, quite a bit of fruit, quite a bit of fruit juice. And I think there's like, we see this in population data as well. A lot of, or a handful of the native or indigenous cultures that are very high carb, you know, 70% plus carbon intake that have, again, like this narrative that excess carbs leads to the insulin resistant state or leads to the fatty liver state, I think is just an oversimplified model because you, you see those sorts of populations with the most incredible glucose tolerance, you know, showing really, really great ability to oxidize carbohydrate with very small changes in, in blood sugar.

Brian (47m 12s):

You know, this is the VINs, a couple of cultures in Africa, the, the Bantu and the TKI Centa, which you know, we have the research showing that. And there's also, there's a really great article by Denise Minder titled Indef Defensive Lowfat. And there's a, a subtitle to it. I, it, I don't remember the second part. And she was someone who was also, you know, had very much fallen into the low-carb, high-fat world as what the way that most people marketed not, again, not saying you at all dom, cause you don't do this, but people who marketed as this is the optimal diet for everybody. This is the optimal way to live. This is how we always did. You know, we are tuned to very low carb, very high fat.

Brian (47m 53s):

And she points out some extreme examples on the other end that just i, I think are so in your face so blatant that it's hard to ignore them. So there's like the Walter Keppner diet, which this was maybe like 1950s, 1960s, I don't remember the exact years. But he was putting people who had diabetes, high blood pressure, like all sorts of metabolic syndrome, cardiovascular risk factors. I don't remember if it was people with cardiovascular disease as well on very, very high carbohydrate diets above 500 grams of carbs per day with that were coming from rice, fruit, fruit juice, and large amounts of refined sugar. He basically said between a hundred, well the refined sugar was ad theum.

Brian (48m 35s):

So he basically didn't restrict how much refined sugar someone could have. And we can definitely say that a lot of people would say what you had mentioned Don, which is what about the weight loss? Like some of these people lost a hundred plus pounds. So that's this huge confounding variable. But there was, he was actually able to show that in some of the diabetic patients or people who had diabetes that didn't have the weight loss, they were still able to get off their exogenous insulin. They were still able to see some dramatic improvements in insulin resistance that are sometimes said to be nearly impossible. You know, if you talk to a typical, you know, an average medical doctor who says, you know, who has a patient who has, who's on who has type one diabetes is on insulin because of it. You know, they're not saying that that's something you're gonna get off of.

Brian (49m 17s):

But Walter Keer was doing that with very, very high carb diets, a lot of refined sugar, a lot of fructose intake. And there was a handful of others that Denise Winter points to in that article. There's Roy Swank and, and the Precan diet and a couple others that I think are just some pretty notable examples. And it is something is

Dom (49m 36s):

Just in the published literature, like, like peer reviewed trials or is it in a, in a book? Cause I mean with diabetes management it, I mean it really does come down to carb management type one diabetes. But there are many ways, and I think you're probably getting to this point is to increase insulin sensitivity. And I think maybe that's, that's what they're, I mean people can have great effects just on a, on a potato diet, you know, but typically, and you talked about excess carbs and no alcoholic fatty liver and some of those populations, but those populations are weight stable. So whenever you're getting excess carbohydrates, the, the surplus amount of calories from excess carbohydrates will indefinitely be stored in the liver once glycogen is topped off.

Dom (50m 26s):

And then you'll start seeing you, you know, and I think that comes down to each person lead to titrate the amount of carbohydrates to optimize maximum carbohydrate consumption, but to minimize surplus carbohydrates beyond topping off glycogen because that gets deposited in the liver and we'll through Denovo lipogenesis we'll start creating the fatty liver, right? I mean that's, that's kind of my, my academic understanding of it. Although we had weight stable people in our group, pre low carb that had fatty liver, so, and they were I think pretty much weight stable. So I think these things kind of creep up.

Dom (51m 7s):

And what we don't know, I'd like to hear your thoughts on people who are weight stable, people who are eating a balanced diet that they, they have the precursor to non-alcoholic fatty liver disease, probably just shy of fibrosis. But why this is happening is quite a debate right now. And I don't have answers to it, but I'd like to hear your your thoughts on that.

Brian (51m 32s):

Yeah. And, and another, so another point I would, I'm definitely happy to talk about that cause I think it's a great point that so many people are not metabolically healthy and, and that at least, you know, the assumption is, oh well if your weight's stable at least then you probably are. But I think that as you're saying, we can certainly challenge that assumption or the data challenges that assumption. Yeah. But in fatty liver disease, I've also seen some papers, some really great papers showing that only about 25% of the fat in the fatty liver is from fructose, whereas 60 per, so the rest is coming from fat, about 15% is from the dietary fat, so less than the dietary fructose, but 60% is from our own body fat stores due to the high levels of lipolysis that are going on because of the, the highly stressed state, the the high cortisol and high adrenaline and the dysfunction at the liver so that fat gets taken up and then isn't well exported, it's not being able to be oxidized well and you end up storing it as fat.

Brian (52m 27s):

And I think so, so to your point, yes, fructose can be converted to fat through de novo lipogenesis, that's not going to be its primary pathway. I mean normally we're talking very low percentage of fructose that'll be converted to fat unless there is major dysfunction going on. We have pretty, pretty great capacity for storing glycogen and converting that glucose as well, or fructose to glycogen. We con convert it to glucose, we can convert it to lactate and export it and we'll definitely use those pathways before we're converting any large amount to fructose. And I think most of the suggestion that very large amounts are going to be converted to fad is coming from the rat studies or Rodin studies where we're looking at pure fructose intake or massive amounts of fructose, you know, hundreds and hundreds of, of grams of fructose beyond what anybody is consuming, you know, normally.

Brian (53m 20s):

But again, almost every time it's, it's pure fructose and there's this huge confounding variable of poor absorption and increased endotoxin, increased lipo polysaccharide production in those states. And so I'm not saying a low carb, high fat diet is going to cause fatty liver either, just because, like if we wanna say, all right in fatty liver, 75% of that fat is from fat, not fructose. I'm not saying all right, it's that simple. Just don't eat fat. Not at all. I, I think instead we wanna focus on those actual processes that would lead the liver to be storing fat as opposed to oxidizing the carb and or storing it as glycogen or oxidizing the fat or what's leading to the excess fat circulation, which is something that's correlated with insulin resistance and diabetes.

Brian (54m 3s):


Dom (54m 4s):

I think, Hey Jay, what do you think? Not not to interject, but just quickly Well I, I think an energy balance, you know, surplus calories would contribute to fatty liver, but also this idea of just basically enhancing the liver function. So there are many factors in, in our environment that in impairing liver function and some of the, there are some agents out there that can reverse not too many of them, but, but I think just improving our liver function could be one way to, and that could be, I don't know, alpha lipoic acid or you know, there's some stuff with resveratrol and other drug compounds too that we can talk about that independent of any change in diet you give the compound and you can start to reverse, you know, fatty liver.

Dom (54m 56s):

So I, I think a lot of it too is just maybe just a lot of people are medicated and they're taking drugs that are through first pass metabolism and pairing liver function and, and this is backing up the liver and causing a redox shift in the liver essentially re-energizing the liver and you know, fat oxidation, liver gluconeogenesis, ke ketogenesis in many of these, these processes are very, very energy dependent. And if we're on, if we're consuming alcohol, if we're consuming different drugs, I I I think that this is a contributing factor and maybe not talked about as much as it should be because I've seen people get off drugs and they didn't really change their diet and then, you know, their liver fatty liver reverse too.

Dom (55m 48s):

So I'm just throwing that in there to get, I wanna get your comments on, on that.

Brian (55m 53s):

Yeah, Jay. And, and what did you do with those clients? You know, you mentioned those clients that you helped, you know, get rid of fatty liver without maybe tech technically bringing carbs down. What, what did you do with them? Yeah, and yeah, and I guess that, that's a good question too, Brian. Cause I think they go together. So I totally agree that where we should place our, like at the best place to place our focus, at least the most central place is let's restore that liver function and let's first look at the dysfunction that happens there. So as you said, we think of fatty liver as a, a situation where there's this overflow of energy and so it just gets stored as fat. But what we tend to see is lower ATP levels, a lot of oxidative stress, a lot of reactive oxygen species and impairments in the mitochondrial function.

Brian (56m 36s):

So we're not oxidizing the, the carb or fat well and then it's getting stored and we also see a huge shift toward lipid oxidation. So this is one of those I think really key examples where we see that the carb oxidation tends to be, I would say the more sensitive, where that's going to be blocked first and then we kind of resort to the fat burning. And so we think if we're storing a lot of fat in the liver, we aren't burning a lot of fat. But actually what tend, what we tend to see is way elevated levels of lipid ox lipid oxidation, so fat burning and the lipid storage at the same time, and the elevated stress hormones and the dysfunction and oxidative stress, all those things. Again, not saying this is caused by the fat. And yeah, I think looking at medications that are going to be liver toxic essentially is, is a, a good place to start for sure.

Brian (57m 25s):

And I would be considering other aspects of diet and lifestyle that are going to contribute there as well. So a lot of people point to a lack of movement, a lack of sleep. I think those things are, are going to be central factors. I would be looking at nutrients. So vitamin E, handful of B vitamins are all going to be central to restoring liver function if those are deficient. Torian is another one that has a lot of benefits in fatty liver disease. And some of these, you know, you might, somebody might wanna look to supplementation. But also from the diet, making sure that our nutritional status is good, I think is a, is something that a lot of people are probably lacking. The other thing too, so there's two other, other central pieces here, which tend to be ones that I go on about a lot.

Brian (58m 10s):

Ones that we very briefly touched on when we talked last one is the polyunsaturated fats that I do think are implicated in fatty liver disease. You know, studies, and again we don't have these models in humans, but looking at rats with highly saturated fat intake versus a highly polyunsaturated fat intake and seeing much greater progression of fatty liver disease on the unsaturated fat side or sometimes the saturated fat even being protective against alcohol for example, or other things that would create a fatty liver state. So I think that that is a point that I would argue for is that even in the people who are weight stable, I think the huge increase in polyunsaturated fats, this is the omega six s and omega-3 S, for someone who isn't familiar with those in the diet that we're seeing, especially in the United States, is a huge culprit.

Brian (58m 57s):

I would, I would argue and, and the other would be coming back to the endotoxemia, the lipo polysaccharide where the average person is not septic. But I do think there's good suggestion of low-grade endotoxemia in states of insulin resistance and fatty liver disease. And mechanistically we can see that as a lone way like that on its own can essentially cause a fatty liver state. And so I think that's something that we want to consider is what sorts of foods are we consuming that could be driving an imbalanced or poor, you know, poor balanced microbiome. And I think part of the benefit of a low carb diet and why people see a lot of benefits is they tend to avoid those, those factors or they tend to have some benefits in the gut microbiome.

Brian (59m 44s):

And I think that's probably going to reduce endotoxin. And I would say, and to come back to the example you mentioned Brian, or the example I mentioned is with this client she was dealing with a lot of gut symptoms, a lot of gut symptoms and so removing things that had been major culprits driving that. So in her case, removing the breads and grains gluten was something she was not responding well to and she was dealing with a lot of reflux, which again could come back to already the fatty liver issues because you tend not to produce bile adequately and so that's gonna lead to impaired fat digestion. So shifting the types of fats was, was a factor. And sometimes when people are really sensitive there, I lean more toward monounsaturated fats than even saturated because those tend to be a little bit easier to digest.

Brian (1h 0m 29s):

But I'm also a fan of the saturated fats in most cases. So in her case it was shifting away from the polyunsaturated fats using supplements like B vitamins touring, I believe she was, she might have been on tug cut instead of touring or maybe was just touring plus the udca, the versus oxy coic acid, which is normally given for fatty liver. Don't remember all the other details of the, of the like supplements that might have been used. But I, I know that we were seeing major resolution and gut symptoms, which I think was a, was a huge factor and shifting the, the types of foods to increase the availability of nutrients and you know, some shifts in lifestyle but at, but it wasn't reducing the total carbon take.

Brian (1h 1m 11s):

If anything, I think it stayed the same, maybe even increased, I'd have to look back at the, the food tracking but shifting actually more toward fructose containing carbohydrates more toward fruits and juices over I think over the grains, which I, I think in her case were causing some major issues.

Dom (1h 1m 29s):

Hey Jay, do you, are you using any of these like I have an OMEGA3 index tests. Are you measuring these polyunsaturated fatty acids in people? I mean it's kind of a big part of the research that I actually predates all the keto stuff I was very interested in, in PFAS from a membrane component cuz we'd have artificial membranes and you know, and, and in our model systems we have these chambers, right? And then we increase oxygen from hypoxia to graded levels to like 0, 20, 40, 60, a hundred. And then we go to hyperbaric and we see that membrane lipid peroxidation and we, we've developed different techniques for that directly correlates to membrane PFA levels.

Dom (1h 2m 15s):

So these were a number of grants that I submitted that did not get funded because the reviewers would just point to data saying, hey, you know, polyunsaturated fatty and humans, I, I'd point to my data and some of the animal data, but they would point and say, hey PFA levels, higher PFA levels correlate with longevity as well omega-3 levels. So I mean, so you know, I don't know what your thoughts on, on omega six to omega-3, but many human randomized clinical trials, there's a massive amount of data that omega-3 levels in the blood and in the tissues correlate with longevity about a two, well, depending on what study, 2.2 years of extra life to some studies say five years of extra life, the higher the pfas you have, the higher the omega-3 S you have.

Dom (1h 3m 7s):

So I, I mean that's not talking about omega six s, but what are your thoughts on that? Like I, I mean, because I was almost gonna build a whole research program on kind of like anti pfas, but because our, the lab data shows it, but the human clinical trials basically shows the higher pfas you have, you know, the greater, the better, you know, your health biomarkers improved dramatically the higher, you know, pos you have. So what are your thoughts on that?

Brian (1h 3m 35s):

Yeah, I I I love the the thought process that you were having there and I just, I don't, I've tested, I've done one of the finger prick tests with, I think it was through Genova where they tested

Dom (1h 3m 46s):

Yeah, Genova,

Brian (1h 3m 47s):

Yeah. Yep. I don't, it's not something I use with most clients, but I don't, I don't know if you is that looking at, I would assume it's looking at serum values, which I don't know how well that would correlate.

Dom (1h 3m 57s):

This is, this is a blood spot kit actually I think Rhonda Patrick had mentioned it to me and mine's being analyzed right now.

Brian (1h 4m 8s):

So And is its so they're not looking at the, the composition of the phospholipid? Yeah, yeah,

Dom (1h 4m 13s):

No, actually, so you can, when you submit your sample, they can just give you a comprehensive analysis of the omega three s and omega six s or you can check the box and then they could do a whole lipidomic analysis of it. So I actually checked the box and I'm having extra ana, I, I've had done my own metabolomic profile just taking my own blood, spinning it down and sending it not to a clinical lab, but to like basic science. But yeah, this will do, I'm paying a little bit extra and they're gonna do a whole fatty acid analysis. So I'm, I'm kind of curious because I do eat, I, I'm not a big fan of fish oil supplements unless you're not eating fish.

Dom (1h 4m 58s):

If you don't have any fish in your diet, then I would want to get some omega-3 S in there to just offset the omega omega sixes that are permeate the diet. But, but I do eat a lot of fatty fish and I do, so I, I would expect my omega3 s would be pretty high. And from my understanding, I mean that that's the higher, higher omega-3 s if you go to the human clinical trials, you know, the higher omega-3 content in your blood and tissues, that that confers a significant longevity advantage. I mean just Google like omega-3 S and lifespan and you come up with a lot of legit human clinical trials. But I can tell you from being in the lab that if you're studying oxygen toxicity, you want lower pofa levels like in your, but, but we have not done the human trials on the animal models that we have have done, but experimentally, I mean we see it.

Brian (1h 5m 54s):

Yeah, yeah. And it, I, so a couple confounding variables that come to mind with the human data. I mean, I think if you took in, took the population of, in the states and said if you can, like whoever can look at people and how at their fish consumption, right, or looking at their fish oil consumption as well, even if they're taking fully oxidized omega-3 fish oil from, you know, which has been shown in various studies, a lot of the major products are already oxidized, you know, already having those lipid peroxide products. Even I think even if you looked at the correlation between longevity and a product that was even potentially harmful, I bet there would still be a benefit looking at longevity because of the healthy user bias, right?

Brian (1h 6m 37s):

Like those people who are consuming fish oil, who are eating more fish are I think probably more health conscious, more active, probably lower body weight. I don't know in those studies how much they controlled. I would assume they tried to,

Dom (1h 6m 48s):

I'd like to add, yeah, that, I don't think there was like a particular benefic benefit to fish oil supplementation. So you know, these people that had two or three times higher levels of omega-3 just for eating more fish, they weren't supplementing, which I'm a, I'm a big believer in just getting what you can from food. I mean I eat tons of eggs, liver, oysters, sardines and things like that. And then I've done micronutrient profiled, if I eat a lot of liver, my vitamin A and other things start to get too high. And I think that's equally as bad. But then you become, you know, you have hyper vitamins, which I think is probably not a good thing.

Dom (1h 7m 29s):

But, but yeah, I mean, I mean this idea of just, we wanna jack our omega-3 levels as high as possible because the human data is very clear that the higher it is, it confers a longevity advantage. You, you know, I I have seen some of the opposite stuff in our experimental models with just poof of causing membrane oxidation. But, but I think

Brian (1h 7m 50s):

What's the poof of con, I'm sorry Dom, what's the poof of content in like salmon, wild salmon do we like

Dom (1h 7m 57s):

In wild salmon? Yeah, I guess it's different. You know, I guess it d depends on where you get your source. I eat salmon maybe once or twice a month, but I do eat sardines probably about, you know, I don't know, I have macro in my bag now, so I eat macro or sardines a couple, couple times a week.

Brian (1h 8m 16s):

I do that too sometimes. Yeah, yeah. It's, it's easy. It's, and it's, and people who, it's cost effect, it's not that expensive, right?

Dom (1h 8m 23s):

Yeah, yeah. It's, yeah, canned fish, I mean, some people have things against canned fish, but canned fish is typically frozen immediately. As soon as it's caught, it's just thrown into a freezer and, and then it's, it's, it's cooked and it's has pretty low oxidized omega-3 s I mean, and, and that's the problem I think with polyunsaturated fatty acids, right? Is that when you go to a restaurant and in some restaurants you could literally just smell it. I mean there's a couple restaurants that we have our, our, our business mailing there and I walk by it and you could just smell, I, when you study these things, you kind of understand the smell of certain oxidized fatty acids and, and things like arien and, and you know, when you tinker around these things and you have them in jars and you're work in a lab, you just know that that's, that's a very bad destructive smell.

Dom (1h 9m 21s):

And I think once you stimulate oxidized polyunsaturated fatty acids, it's like a, this futile chain reaction that can cause and, and I, I attribute some of my health problems maybe 15 years ago to eating like higher omega six oils and which I, when I phased out, it reversed some of some symptoms. It could have been other things too, but maybe there's a correlation there. But, but at the problem, my, my my biggest concern with pot and saturated fatty acids, it's not the the, not the products on the shelves per se, but when these things are heated, when these things are heated, then they become, you know, very toxic to the body.

Brian (1h 10m 10s):

Yeah. Because they're, they're in almost everything. Like you go to like the, like the vegetables, you know?

Dom (1h 10m 18s):

Yeah. But they're not oxidized on the shelf. I, I, I don't think I, I, I thought that that was a problem. But if you take these products off the shelf and look at them, they're not oxidized, but you know, people cook with them, then it becomes a problem. Or people reusing, like these restaurants are probably the worst offenders where they're just reusing the oil, cooking things in it, then that becomes a huge problem, I think. But I know there's a big discussion about, you know, polyunsaturated fatty acids and I'm a little bit on the fence about it. I do think it's a problem. I think just if we can reduce the consumption of these things, cuz once they get into the body and incorporate it into membranes, then they, you know, then you're oversaturating the membrane with a higher percentage of a fatty acid that has a greater potential to be oxidized.

Dom (1h 11m 9s):

And I think, I think people who are metabolically healthy, low inflammation, high endogenous antioxidant function, I think they will be okay. But the majority of our population is not metabolically healthy. So if you're saturating our biological membranes with a polyunsaturated fatty acid that has the propensity to be oxidized in a metabolically unhealthy person, then that's like, that's like lighter fluid on the ga on the fire. You know, I think that's a huge problem and I think, I think it's an underrepresented problem that needs to, I know some people are drawing more attention to it. I've talked to Kate Shanahan and, and some other people.

Dom (1h 11m 50s):


Brian (1h 11m 50s):

What are your thoughts on, I know you've talked, you've, you know Yeah, yeah, I, so I, I I'm a, I'm concerned about them even if they're not oxidized. Even if what, so I know for some of the fish oil products there is some of the research looking at them has found that they are already damaged al already. Some of 'em are already oxidized. But even if we took it in from salmon, which I know your question Brian, what about like wild salmon? And I'm sure it varies based on the individual one. I just pulled up the nutrition data for Atlantic wild raw salmon, which is still high fat and and looking at about 40% pfa, which about 80% of that is the omega three s. And to your point, I'm con even if it's fully intact and not oxidized by the time we consume it and by the time it goes through our digest digestive tract, the amount of poof we eat will influence the amount of poof in our membranes.

Brian (1h 12m 40s):

And that's going to leave those more susceptible to damage in that situation. And I would say even if someone's healthy, there's still always going to be some amount of reactive oxygen species, some amount of oxidative stress, whether it's happening in bursts due to exercise or anything else. And I would say those are situations where then every time that's happening, the more unsaturated those membranes are, the more susceptible they are to inf to inflammation, to oxidative stress, to amplifying that signal. And I think that that's concerning to me. I think that I would argue that that's something that would drive someone to become less metabolically healthy. And I know we can't look at human data for this, but because as you were saying, like some of the correlations aren't that clear or, or maybe even suggesting the opposite, but I think there are,

Dom (1h 13m 22s):

Yeah, it's like highly suggested, you know, the more fish and omega-3 s you get like there's multiple like huge studies that just convert of longevity advantage. And so, but I mean there could be a healthy user bias, but I think they account for a lot of that. So I I think it'd be good to, to revisit some of that.

Brian (1h 13m 41s):

Yeah, I think it would be, I would love to, to, I'll have to dive into some of those studies. I'd be curious to know like how much did they account for something like healthy user bias? Cuz I think that that's the first thing in my mind would go to. But when we look, and I know I referenced him last time, AJ Holbert, he has, he's put forth what's called the membrane pacemaker Theory of aging, I believe is is what it's called. And he's basically looked across all, not all species but you know, data across tons of different species and was building upon the oxidative stress theory of aging. The, also the metabo, what's the, not the metabolic theory, but the, the one where they're looking at at total energy expenditure and basically found that the line fits way better when we're looking at the peroxidation in peroxidation index of the membranes and lifespan.

Brian (1h 14m 30s):

And basically that value can account for the differences in lifespan between species and also within species and all of the things that, all of the ones that were outliers before. So various types of birds and naked mole rats, things like that, which have very high metabolic rates relative, or sorry, very high lifespans relative to their metabolic rate relative to their size, which is those are outliers and we're, you know, outliers there as well. They don't become outliers when you account for the oxidation index of the membranes. And he makes the argument that for one, the omega-3 S would be potentially worse. And there's more of an association with D H A because it's more susceptible to the pation than the omega3 s and than the omega six s.

Brian (1h 15m 10s):

But I would say both are concerning to me. And, and I think that data is, is conflicts with, with the apparent the, the omega3 data in humans that would, I would wanna take a look at and see where are they measuring the omega three s and what are those confounding variables. Because in other species, including and looking at the proximation index of human typical, you know, mitochondrial membranes compared to other species, it is able to account for the lifespan where the lower the pation index is basically the more saturated the membranes, the longer lifespan and the slower aging. And you know, he points to a few mechanisms, one of 'em being the susceptibility to oxidation, one of them being the permeability to protons and to ions like sodium, which basically reduce the efficiency of respiration.

Brian (1h 15m 58s):

So we lose the, the proton gradient because of the permeability at the inner mitochondrial membrane due to the poly saturated fats. So we don't produce the ATP as efficiently and then also losing energy essentially due to the permeability of the, of the other ions. And there's a couple other other points he, he suggests as far as why this can account for the difference in lifespan and aging and drive degeneration, but basically the, you know, corroborating exactly what you were finding in the data that you had on, of course the non-human subjects. And I think there would have to be some dramatic reason. Just real quick. Yeah, I, I would just wanna say like there would have to be some dramatic reason why it would be different in humans versus other species and I don't know of any reason that we could point to why that would be the case.

Brian (1h 16m 46s):

And I think that's why I would look more to like something like healthy user bias being a confounding variable as opposed to it just being that we react differently than every other species.

Dom (1h 16m 55s):

Yeah. I mean, well you just gotta point to people who are just eating subsiding only on fatty fish for their subsistence and you know, they tend to do very well. Right? But, but I think there is a couple big st just Google like omega-3 fatty acids and longevity. I remember I have a folder somewhere on my computer, one study was done at Tufts, but there were like multi-site studies that the data was clear. Some say it's a 2.2 years of extra age and some studies say it's greater than five years of longevity, you know, the higher your omega-3 s and you know, just to preface it, we, I I study the membrane levels of omega-3 S in the context of elevated partial pressure of oxygen, right?

Dom (1h 17m 41s):

So basically my project was to look at, you know, membrane lipid peroxidation in the context of metabolic stress. But I think, you know, if we direct this back to the person who's metabolically unhealthy eating copious amounts of salmon or other, or taking fish oil supplements, which is probably a bad thing in the context of, of, you know, maybe drinking alcohol which can oxidize, you know, the omega-3 S in the liver and things like that. I think there's a study on that then I think it becomes a pro, I think it sees the excess consumption of polyunsaturated fatty acids more so omega six, but maybe omega-3 in the context of metabolic dysfunction.

Dom (1h 18m 33s):

And then that if the mitochondria are dysfunctional, they create more reactive oxygen species and then you have the, the, the membrane lipid peroxidation. But you know, you can't, you can't ignore the human studies showing that higher omega3s correlate to greater longevity. So I think it would be good to further deconstruct that. But I know a lot of people are, are working on it, but I, I don't think they're, I don't think people should be worried about consuming omega-3 S in fish. I think they need to be very picky when it comes to picking a fish oil supplement because yeah, some may be oxidized and if they're getting like very low omega three s in the diet, then they may wanna consider supplementing or I mean if you have depression or other neurological disorders have been shown to be responsive to omega-3 therapy.

Dom (1h 19m 25s):

So d h a and, and epa I think for like things like depression, anxiety, you know, there has, there's a clinical benefit there, but I, but I think, you know, I think people just get carried away with omega-3 s omega dosing supplement. I i I don't think that's a, that's a good thing.

Brian (1h 19m 44s):

Yeah. Well and this, go

Dom (1h 19m 46s):

Ahead. I was gonna say, and, and fatty fish tastes better. My, my wife cooked a big cod filet and I was eating it and it was just like, man, this is nothing like the trout or the salmon. It's just a very lean, you know, I, I like eating all sorts of fish, but I would gravitate towards a fatty fish. I don't necessarily buy it from the market that often, it's more of like a, a luxury thing on the weekends or something. But, but I do eat canned fish quite often and I'm very curious to, to see my omega-3 omega six analysis from this test. Cause can't really say, but besides doing metabolomics on myself a couple times, I haven't really done used these tests before.

Dom (1h 20m 32s):

So I'm gonna do this and I'll probably do the Genova test too and see, see what my levels are.

Brian (1h 20m 38s):

Yeah, yeah, I'd be curious to, to hear

Dom (1h 20m 42s):

This test here. No, I don't have any, you know, what's the,

Brian (1h 20m 45s):

What's the, what's the brand on it, on the,

Dom (1h 20m 47s):

It's called Omega Omega. I dunno if that's reversed upside,

Brian (1h 20m 53s):

Whatever. That's good. That's good. Yeah.

Dom (1h 20m 55s):

Yeah. I, I posted about it just because I wanted to get, I, I just posted it on my Twitter and I asked people if they use the test and I got it overwhelming response and a couple private messages saying, you know, here's the analysis and everything. So, and I think it was Rhonda Patrick that maybe had mentioned this to me to look into it cuz I made a note on it. So I want to compare this and I, I, I'm a big fan of Genova testing too, so I'm gonna probably do their test as well and, and just to look at the levels

Brian (1h 21m 23s):

And I was just gonna say, I think, I think in the context of eating fish, I think if someone's coming from a standard American diet and they wanna implement some fish into their diet, you know, again, the sourcing of a fish is a big issue too. That's a whole nother topic Yeah. About where that fish is coming from. I had the owner of Utopia, it's another cool brand if you wanna, if you, if you love like sushi grade dom, you would love this company. They make pretty much sushi grade fish and it's farm raised, but it's actually raised in an environment that they should be eating in, so it's controlled, so you're not dealing with microplastics and things like that. And every fish is tested for heavy metals and things like that.

Brian (1h 22m 3s):

So really cool company and I've been getting their orders probably bimonthly. So

Dom (1h 22m 9s):

Yeah, the heavy metal thing is something, I remember when I was on the Joe Rogan podcast, maybe it was before we jumped on, or maybe during, during the podcast he said he was eating sardines and maybe from my recommendation or something like that, but then his, his arsenic levels and maybe something else was off the charts and you know, I I eat Wild Planet sardines.

Brian (1h 22m 33s):

Yeah. And

Dom (1h 22m 34s):

You know, I have been, you know, I'm gonna maybe plug this company because seasons macro. So I have, I have like an Amazon subscription to this and I've been eating massive amounts of it. And then we were traveling to like Dominican Republic and I had a whole week of just eating massive amounts of fish and I was like, this would be a good time to check my heavy metals. So when I got back, I went to Quest Labs, had a pretty comprehensive, I did a hair analysis and I did the Quest lab analysis and my heavy metals were low and that's eating massive amounts of this. So either, either this has super low heavy metals. I was also eating Wild Planet. So, so if thi if these fish had heavy metals or wild planet had heavy metals, it would definitely show, because I eat a massive amount of, of both.

Dom (1h 23m 22s):

But I came from the Caribbean and you know, I was eating massive amounts of fish and it didn't show up on, I had been, you know, eating these fish for like decades now, but, so that's good. One thing, go ahead. I eat small fish, I eat kind of smaller fish so that I do not eat swordfish. I do not eat a lot of a larger predatory fish, so I don't wanna make a recommendation that people go out and just eat massive amounts of fish. But I'm just telling you from my personal experience and eating very large amounts of fish, I don't think heavy metals are a problem. But I could just have very good detoxification pathways.

Dom (1h 24m 4s):

Right? So, you know, I I cautiously recommend, I, I think there are legitimate benefits to eating fish, but I think people just have to be cautious and have to do testing to, to make sure, because listening to Anthony Robbins said he almost died of, of, if you, I was reading his book Life Force and he said

Brian (1h 24m 25s):

Mercury right,

Dom (1h 24m 26s):

Died of heavy metal poisoning and he was eating, oh, he was eating swordfish or something. And I've been in, people have emailed me with their, their labs showing toxicity to heavy metals eating. I, I don't know exactly what brand of fish or what kind of fish they're eating, but it's a very real problem. But I think you just have to be very selective of the companies and the type of fish you're eating.

Brian (1h 24m 50s):

Jay, anything else you want to add on this? Yeah, I would just, yeah, my only, you know, I still personally would have some caution around the omega three s and I know what you're saying, maybe in the quintessential healthy person who knows that they're fully metabolically healthy and isn't going to be exposed to a lot of oxidative stress. I think, so for one, what I would say is in a lot of, I think Dou alluded to like depression and other, I dunno if it's mental health states are also like neurodegenerative disorders, but in those situations we tend to see, see elevated levels of the oxidized omega-3 s. We tend to see the acro, the, you know, the h ie the melon, the Hyde.

Brian (1h 25m 30s):

And so that would be situations where again, I would be even more hesitant in that state to be exposing myself to elevated levels of omega-3 S knowing, especially, I know we wanted to talk about this coming in. I mean, knowing the associations in depression with mitochondrial dysfunction and with elevated oxidative stress. I mean, I would say these are situations where we wanna be even more careful. And

Dom (1h 25m 52s):

That's a good point. But I wanna add, in many cases, at least the published studies for depression or some other things, they were reversing a deficiency, meaning that they kind of, of came in, they measured and they, they had low levels of omega three s and then through supplementation they elevated them and then saw like the, the, the benefits, you know, the, the behavioral benefits. But these were people probably with horrible diets coming in. And then the, the supplement moved the needle on on that. And I think Andrew Huberman was mentioning some studies that I looked into in a, in a few other studies showing that.

Dom (1h 26m 32s):

But it could just be, you know, in the context of pushing down omega six s in favor of omega-3, is that balance in the body, something like that. So that, that's kind of what I was thinking when I was reading the study, but I'll have to go back and delve into the methodology.

Brian (1h 26m 49s):

Yeah, yeah, possibly. I, I know I've seen also some papers challenging the, the evidence for fish oil supplementation helping with depression, you know, and I know we're just kind of throwing, like I know the study to study, maybe we'll send some over to Brian or or something you can post in the notes, but yeah, yeah, yeah. Any study you want me, you want me to post? Yeah, let me know. I'll,

Dom (1h 27m 10s):

Well, I, I, yeah, for epilepsy, I was the chair of the American Epilepsy Society special interest Group. So AEs is like this huge conference, mostly like drug-based conference, but they kind of marginalized the dietary therapy section. So they put us at like seven in the morning. But we had a speaker that was, he wasn't talking about the ketogenic diet, which most of the speakers do because it's, it's an epilepsy conference. But his, his presentation was just strictly on d h A and e p a and he gave a very compelling presentation that independent of a ketogenic diet that d h A and EPA has anti-seizure effects through a number of different mechanisms and did a very elegant study.

Dom (1h 27m 53s):

So I, I do think that the fatty acid composition of a ketogenic diet when used therapeutically really does need to be taken into account because early studies used very high levels of, of omega six fatty acids. I mean, hydrogenated soybean oil or soybean was like one of the first ingredients in some of these prescription medical foods, which were basically the, the three to one and four to one ratio. But surprisingly, they actually had it, they worked, i i I don't think they worked as, as well as like a whole food formulated ketogenic diet. But, but there were some anomalies in the blood work which are published.

Dom (1h 28m 35s):

And actually it was Dr. Veach who point pointed some of this stuff out to me, but especially with the tri elevated triglycerides. So yeah, I, I think there needs to be a greater appreciation for the fatty acid composition. I'm in favor of saturated fats and monoline saturated fats is basically being your primary fuels for, and I know, I don't know what the current guide guidelines or something like seven to 10% or less of saturated fat, but I think probably 20% is probably a, a good estimate. But with the balance of being a heavy mono one, saturated fat would be your, your fuel.

Dom (1h 29m 15s):

So I get this question a lot, like what should be the primary fatty acid for, for like ketogenic diet? You want to dial back to some extent the saturated fatty, but get a large amount of mon and, and you know, the, your polyunsaturated fatty acids are your essential fatty acids, but you just need to prevent a deficiency of them. You don't need to get, you don't have to like think of them as like your fuel, your macronutrient. Like you don't want to get calories from pfas, you just wanna make sure you're not deficient in it. Because I I, I do believe just based upon the research that we've done, that a high PFA membrane content will, will oxidize in the presence of metabolic arrangement.

Brian (1h 29m 58s):

Yeah. And, and as far as, you know, if we wanna say just enough to prevent any deficiency based, you know, based on what's suggested as possible deficiency there, I mean we're talking very tiny amounts as you were saying, not getting any, even like calories from it really. We're talking, you know, 0.1% of the diet, something like that. And if we're eating, as you said, whole foods, and it's not of super low fat diet, I think it's nearly impossible not to reach that point anyway. If you're eating dairy and, and meat and seafood, even if it's not the fatty fish, even if it's the leaner fish, you know, the mahimahi and cod, which I know you weren't the biggest fan of, or halibut or whatever it is, just

Dom (1h 30m 33s):

Don't taste that good. So I

Brian (1h 30m 35s):

Like, you know, I personally don't like salmon, so Oh wow. But I don't love cod either. I, I really like, you know, like, I like mahimahi and grouper and halibut a lot as far as low fat Yeah. Fish go. But, but anyway, yeah, so I think even if you're getting, or you know, as you mentioned oysters or muscles or shrimp, you know, any of those options are still gonna be overall very, very low in the poly saturated fats and still will will do more than enough as far as meeting the absolute essential needs, assuming that there are some, which yeah, if, if there are, they're very, very low. So I thought maybe we could finish up with, and this is, we could probably talk for another hour, but, we'll, I thought we could maybe finish up, it's interesting, I was just doing a little bit of research before the interview and I was, I just watched a video, you know, on YouTube it's like nowadays you can go down a rabbit hole and find what you want if you really wanna find it, you know, like totally, it was this, this physician he was talking about do we really need carbs?

Brian (1h 31m 35s):

And he was just going through the whole litany of reasonings why, you know, you need proteins, you need fats, you know, for hormonal health, both omega-3 and omega six. And he was like, do we need car? You know, he was like, people make the argument, do we need cards for energy? And he was, and just making this whole argument for also do we need carbs for thyroid function? And I know these are a lot, lot of different topics, but you know, a lot of people will say, well, you know, carbs aren't essential, you know, you can live off, you know, fats and protein. And I know you guys have come from both sides of the spectrum and maybe there's not a perfect answer and everyone's a little bit different perhaps.

Brian (1h 32m 19s):

But I'm just wondering, maybe we can just, Jay maybe just start off as to your reasoning behind, you know, why you shouldn't be too extreme on one end and, and your reasoning behind the reasoning behind carb intake and things like that. So yeah, there's a lot of arguments for or against, as you're saying anything, right? As far as that argument against carbohydrates, I think it's the weakest of them or one of the weakest to suggest that, that because they're not essential, that essential to our diet, that that means that we shouldn't consume them because, so for one, if we look at fat intake, the only essential fats are the polyunsaturated fats. So there's no essentiality as far as monounsaturated or saturated fats.

Brian (1h 33m 2s):

And again, when I say essential, this doesn't mean essential to the, to our physiology, it mean it's essential to our diet. So what that means is that as long as we get our 0.1% of our diet from a little bit of omega six and omega-3, then we don't need any fat. So it's such a small amount, I I would even say, all right, it's fats are barely essential, but that doesn't mean that we don't use fats in a ton of places and they're not necessary for our physiology in the same way that that's the case for carbs. The difference is, or the, I guess the exact same situation in both of those is we can produce fat and carbohydrates endogenously, we just can't produce the omega-3 S and omega six s, although we can't produce omega nine s. So there's even, again, some question as far as, you know, if we produce those are the threes and sixes essential, but again, we're talking about 0.1% anyway.

Brian (1h 33m 45s):

So the point I'm getting at is that what that argument is not saying is that carbs are not essential to our physiology because when we don't consume carbs, we go to great lengths to produce them. We convert, you know, oftentimes it's mostly from amino acids, but we'll also use the glycerol backbones from fat from triglyceride to produce carbs through glucogenesis to a pretty decent amount. And it will reduce when we're on a ketogenic diet. But it's still like, you know, still a pretty decent amount of, of carbs that we have to produce that are absolutely essential. And they're not only essential for the brain, which does need at least a portion of glucose, you know, at least talking about 30% of its fuel needs needing to come from glucose. But if we're not in the extreme state where we're producing ketones, it's gonna be about a hundred or nearly, you know, we talked last time, like lactate and, and other things.

Brian (1h 34m 32s):

There's some minor fuels there. But to suggest that because we don't have to eat them, that means that they aren't beneficial is I think just a very weak argument when we consider that they, they play very necessary roles in our physiology as well. And I sent in a paper in one of the podcast episodes, I'll, I'll just pull up the title now, but it talks about, you know, even just in the brain how necessary glucose is for, for producing certain neurotransmitters and things like that. So it's titled sugar for the brain, the role of glucose in physiological and pathological brain function. Just again, something that points to the, some of the necessary rules of, of carbohydrate even outside of a fuel.

Brian (1h 35m 12s):

But this isn't saying anything about, and anyway, to come back to the, to the basis of the argument, this isn't saying anything about what is ideally healthy or what contributes to health or doesn't contribute to health, but rather just what is absolutely essential in the diet. And I would just say just because we, just because carbs aren't essential in the diet doesn't mean that having some amount of carbs is not ideal or optimal or beneficial. And I think we would've to look to a lot of other lines of evidence and argument in terms of biochemistry, in terms of hormones, in terms of, you know, the effects on muscle mass and you know, talking testosterone, talking about female hormones, talking about thyroid hormones. I, I, I think we would have to, the, the argument has to be a lot more complex and it's nice when we can simplify it and just say, try to make it as simple as like, carbs aren't essential, so you don't, you don't, you shouldn't eat them.

Brian (1h 36m 0s):

But I think it's just a, it's about as weak of an argument as there is. And I think you could really say the same thing about fat, right? Fat isn't essential, so you don't need to eat it, just get your 0.1% of omega six s and omega-3 s. And I don't agree with that either. I think fats also serve a ton of important purposes and we shouldn't avoid them just because mono and saturate mono etat, man monounsaturated and saturated fats are not essential. That's a very weak argument from my view. Yeah. And regarding thyroid, I was doing a little bit of research, you know, with Dr. Steven Finney who's a, a big, you know, low power proponent, and he was just, he, I, I read this line that he wrote, he said, A ketogenic diet seems to result in improved thyroid hormone sensitivity, meaning it takes less hormone to produce the same effect, which if anything puts less of a burden on thyroid hormone T4 production in the thyroid gland and its conversion to three T3 in the liver.

Brian (1h 36m 57s):

And so I'm, I'm curious to know your thoughts on that because I, I think that's a knock sometimes with the ketogenic diet is over the long haul. Perhaps it takes a toll on thyroid health and, but when you, and, and then you hear a different perspective where someone, you know, makes the, a comment like that saying that yes, maybe thyroid gets, you know, downregulated a bit, but he's just saying it, it it it's almost like more efficient or it's more sensitive in a sense. Yeah. So, and this was something I know we didn't get to today, but I did wanna mention is I, I think there are some good papers looking at lower, like decreased t3, especially on ketogenic diets. There's, there's a good handful looking at, you know, three, four weeks in, but even some long-term ones on epi, epi and epileptic patients, patients who have epilepsy, there's one titled changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy to paper from 2017.

Brian (1h 37m 52s):

And they see decreased T3 levels. This was on, it was on 120 patients who were on the ketogenic diet for at least a year. So we're not looking at like short term mechanisms here showing increased incidence of hypothyroidism and, and decreased t3. And I, they weren't suggesting anything as far as improved sensitivity to it. I don't know what that would look like and I'd be interested in seeing some of those papers, but I do think that that's something that's potentially a harmful outcome. And I know we talked about this last time too, this is something that Dom was talking about was that women, and again, I'm just repeating what what you had Dom, but I had written it down that you said that that women on the ketogenic diet for epilepsy are five times more likely to be a manure.

Brian (1h 38m 34s):

I think that that is also saying something as to some of those hormonal effects. And I would be concerned about, you know, for men we, we might not be as sensitive or we might not see those changes as much, but I would be concerned about androgenic hormones for men as well due to some of those parallel mechanisms.

Dom (1h 38m 51s):

Yeah, I'd like to add, you know, most people are not, I mean that's a clinical ketogenic diet. Yeah. A 41 ratio. It's really nothing like, I mean, kind of what most people are calling ketogenic diet. And I think if you equate for protein and get protein sufficient enough, the thyroid issues not that much of an issue. I will say that looking at blood work from the 1990s where my T3 was a little bit always on the high end of normal couple times it was like above normal T T H S and T4 were normal. And then ever since I've been on a ketogenic diet, it almost brought it from high normal to slightly above normal, into normal range. So maybe I was just starting at a higher baseline of t3, but I've done lots of thyroid testing and I've, I've never been below normal or even on the low end of normal, usually just like right smack in the middle.

Dom (1h 39m 40s):

But even when I fasted, yeah, actually my, my thyroid was kinda, I I was expecting it to go down a little bit, but, but I, but I, I do think that certain physiology, especially female physiology, is much more reactionary to low glucose and low insulin. And insulin does play a role in the enzyme that converts T4 to t3, the di d enzyme. So that is regulated in part by just your energetic status, but but just by insulin too. So it's something, it's just something to monitor. I think it's important to monitor and, and like I said, I don't think necessarily a ketogenic diet is like a default diet for lifestyle or longevity, but I do trend towards low carish.

Dom (1h 40m 30s):

So the idea is that titrate the amount of carbohydrates in based on your lifestyle, based on your performance, based on a number of metabolic biomarkers, but probably most importantly titrate the amount of carbohydrates in based upon your body composition and subjectively how you feel. And I think that's the important and and only consider very low carb diets or ketogenic diets or fasting to manage some kind of chronic disorder that you have or, or as a metabolic therapy. But, and, and I think it'll work better if, if you are following a sort of a normal healthy, balanced diet and a problem does arise, then you could, a tool in your tool belt could be to transition to ketosis or you know, use intermittent fasting or whatever as a tool to, to manage that.

Dom (1h 41m 23s):

And some people have periodic in inflammatory states. It could be like shingles, it could be like covid, it could be autoimmune where it may not work as well if you're chronically in this, you know, ketogenic state, it may work better if you just stay low carb, metabolically flexible, but use that tool to manage it when it arises.

Brian (1h 41m 49s):

And, and

Dom (1h 41m 49s):

Like my general thoughts and

Brian (1h 41m 51s):

Yeah, and I'll just say on that point, Don, you've talked a lot today about how you do a lot of sort of self experimentation and you're, you're measuring like you're, even though omega three, omega six tests that you're taking, I mean I think a lot of people don't go to those length to measure these, you know, hair mineral tests and, and I think may, if there's one thing people should take is that they maybe should start taking these measurements and finding out where they're at, where the baseline is and sort of do a self experimentation. Because I know Jay, you've, you were just on Brad's b Brad Kern's podcast again. And, and I've also started implementing carbs whole, you know, fruit mainly as a third meal just to see how it would affect, cuz I got blood work done, this was probably like four months ago and I, and I, and I actually waiting on blood work right now so I'm gonna see how it affect hormonal health and things like that.

Brian (1h 42m 45s):

But I did do a DEXA scan and it's interesting cause I was texting with Brad about what it, you know, from, so eight, so August I did a DEXA scan until now, and between then and now my lifting and everything was the same. You know, I lift like four days a week, you know, and I implemented about 600 more calories and about probably at least 150 grams more of carbs I would say at least. And I was like, I could tell a difference in my body and I, I went up 2% body fat, I went from 9.6 to 11.8, I gained about 10 pounds, I put on five pounds of fat and five pounds of lean muscle and I have no visceral fat from that, which was a good positive, I think it was a somewhat of a positive outcome from all of that.

Brian (1h 43m 40s):

I was, so I put on about five pounds of muscle and five pounds of fat from that and no visceral. So I just thought it was interesting and I know Brad did it and Brad didn't put on any weight. I know Brad implemented and you know, but also Brad's training was different than my training, right? So I think it depends on your goals and where you wanna be. Like I know he's a sprinter, I don't really sprint or he, you know, he, he high jumps and does things. I was simply just resistance training and so I'm waiting on the blood work and so we'll see what that comes back, see how, you know, maybe thyroid is and things like that, if that took an effect or maybe, you know, improved. So I guess my point is who knows, Brad did one thing, I did another thing, we got different results.

Brian (1h 44m 22s):

So I think the, the, the moral of the story is you gotta sort of do some type of self experimentation and do some testing and if you want to implement a certain dietary, you know, dietary protocol, then, then you can sort of see, see what it does. So,

Dom (1h 44m 37s):

And sustainability is a big thing too. You know, you don't wanna push yourself into following a particular dietary paradigm if you're not enjoying it and if it's not sustainable, I mean a big reason that I shifted towards, you know, ketogenic and, and even intermittent fasting is that I could get more work done in the lab and then, you know, not have to stop to prepare a meal, eat a meal, clean up, things like that. So logistically it, it made a lot of sense, you know, in, in academia where you're just that's true. Just going full a hundred percent all the time. But now I've transitioned back towards like three, three meals a day, sometimes even four with a snack.

Dom (1h 45m 17s):

And yeah, but I, but I, I did actually back in the day I was eating six meals a day and I would even wake up in the middle of the night and drink a protein shake. Oh wow. Like I had that crazy, that is hard. Yeah. Yeah. It's just back, you know, back in the day and, and I was actually in, in grad school at the time, so, or, or undergrad, but all I did is basically study and lift and eat. That's all I did. I don't, I didn't have had much less obligations way back then, but that's, I could never go back to that pattern. That's a good point. So people need to embrace and adopt the pattern that they're gonna stick with and that's not screwing up, you know, and they wanna just at, at the very least on a yearly level to do a comprehensive blood work analysis, body composition, I'm telling you.

Dom (1h 46m 5s):

Cuz as you get older you start thinking about how age is affecting you. And I go back and look at this and it motivates me to be like, okay, I gotta stop losing like lean body mass, I gotta maintain my strength, you know, because I know maintaining muscle and maintaining certain metabolic biomarkers are gonna pay big dividends over the next 10 to 20 years for me. And I think right now is when you know you gotta put in the time and effort and work to improve those things. So I'm telling that to like the younger crowd out there to start measuring and start, you know, tracking and, and monitoring your blood work and keeping records of all this stuff. Cause I didn't really think about it like five years ago, but something about, you know, just getting older makes me think about I I need to track these things so I understand where my body's going.

Brian (1h 46m 54s):

Yeah, that's a good point. Yeah. And, and I would just add in as far as doing the tracking in terms of the numerical values, you know, the blood tests and everything, also consider how you're feeling, you know, if Yeah. Whether somebody's on either side of the spectrum as far as carbon take or food intake, whatever it is. Yeah. Evaluate how you're feeling and be open to trying new things and, and seeing how that goes. And I would preface also for somebody who's been low-carb or fasting for a while, there's a couple things I'll consider when if someone's trying to transition to bring more carbs in. So Brian, this might, you know, maybe could pertain more to you, but we a talked about how when you haven't been burning a lot of carbohydrates, the machinery that normally burns those carbohydrates is downregulated.

Brian (1h 47m 34s):

And so there can be an interim period where you're not going to be particularly insulin sensitive and, and that's something to consider. Sure. There's also can be some changes in the blood test as well as far as thyroid activity that can actually make someone think it's worse. So one thing that can happen is if somebody was under a lot of stress that ts H level will get suppressed. So cortisol will suppress that tssh. And something that I do see a lot in the people who are coming to me and have struggled on low carb is I'll see the elevated reverse T3 along with a low TS h and to me that's suggesting a actually suppress thyroid activity. Sometimes there'll be excess cortisol at the same time. So we see the suppressed tssh due to cortisol and impaired T4 to T3 conversion largely also due to cortisol and related mechanisms.

Brian (1h 48m 20s):

And so if you then bring carbs in into your tssh jumps up, let's say it goes from one to four, that I would just caution that that doesn't necessarily mean the decrease in thyroid activity, it can mean a relief from suppression. So that's just, you know, it's important to interpret these things and also recognize that in that transitionary period some things might look off in initially. So that's one thing I would consider. Another thing too is with the change in, in insulin sensitivity, and also you mentioned Brian, you know, bumping up the calories by 600 calories a day or something like that, which when I did this, I bumped up by a lot more than that because I had been also coming from a place of undereating and restriction and had a lot of benefit to bringing those to bring my calories up significantly.

Brian (1h 49m 4s):

But I also gained a decent amount of weight. But that did then come back down, you know, that was, that was a part of, for me, my like, something that was very healing and rejuvenating for me and re you know, led to me feeling a lot better was eating a lot more, including a ton of carbohydrates. And I did gain some weight, but then it came, came back down without intentionally restricting or anything like that to a point where I was, I was very lean still. And I don't necessarily suggest that if somebody is coming from low carb to then go and, and increase your calories a ton or increase your carbs a ton, I think you are more likely to see some effects like weight gain if you do that for some people that's worth it and, and they're okay with that as long as it's a moderate amount and they're careful for other people, maybe it's better to take more measured approach.

Brian (1h 49m 49s):

So just wanted to throw that caveat out there as well when it comes to the experimentation side. Yeah, right. Like you could have that sort of mid period where you might get these results that you might not really want per se, but it's just an ad your body adjusting, which could have essentially for, for my case happened a little bit here. I bet that, you know, in another, if I keep eating the way I'm eating in another four months, it might just level out a little bit and that could have been part of the reason why, you know, but I, I was overall happy. I mean like you doma you mentioned as you get older you gotta maintain lean tissue, muscle mass, right? And so if you could put on five pounds of muscle mass, you know, without, you know, putting on it much visceral fat at all.

Brian (1h 50m 34s):

That's, that's a good step in the right direction.

Dom (1h 50m 36s):

Yeah. And it might not be jump into like three, 400 grams of carbs a day, just titrated in from 75, a hundred or whatever to like one 50, right. Or 200. I'm of the opinion, you know, keeping the fiber content high and then letting like a continuous glucose monitor or your postprandial glucose level not getting above like one 40 or something like that. And, and let that guide you. And, and you know, even if you spike up, it's not all that bad. It's, unless it stays elevated for a long period of time, but if it comes back down, that's normal. But, you know, keep in mind that if you add carbs back in and I remember eating fish and rice just being hungry, like eating and like two other, I would get hungry and then I eat again.

Dom (1h 51m 20s):

That was normal. I mean, that's kind of part of your body growing. But, you know, part of the logistical behavioral advantage of eating low carb is that I pretty much never get hungry. I mean, today's the rare day that I'm like fasting, right? And I'm like, I have abs absolutely no appetite, lots of energy feel great. And, and it's only because I have fasted previously or done low carb. Do I feel great now? You know what I mean? If I went from just high carb to fasting, then my body would have like a, a stress response. So, you know, a adapted body to it. But I think it's, it's beneficial to stay metabolically flexible, you know, to not completely eliminate this macro or that macro, but just to have balance, of course, unless you're using a ketogenic therapy to manage something.

Dom (1h 52m 10s):

And I, I kind of harp on that because that's what we study and, and we do know it has very real world effects. And I think maybe the next frontier is this metabolic psychiatry field that is expanding quite rapidly now and looking at anxiety, looking at bipolar, looking at depression and things like that. So I do think there's a lot of science that needs to be done and a lot of people suffer from a lot of these, these psychiatric conditions. So I think there may be ketogenic therapies maybe be a tool in the toolbox for that too.

Brian (1h 52m 43s):

Yeah, for sure. Well, this was great guys. It went really fast, so Yeah. You know, maybe down the road we'll do a part three. What the hell? Right?

Dom (1h 52m 54s):

I'm up for it. Yeah,

Brian (1h 52m 55s):

Whatever. Yeah, that'd be fun. Of course, of course. And where's the best place? I know, Dom, I know you have some stuff coming up. Where's the best place for people to find if they wanna learn more about your research?

Dom (1h 53m 7s):

Yeah, thanks for keto nutrition org. Keto nutrition.org. We have a newsletter sign up for that. We have a blog. We cover many, many different topics that we discussed. And also ask people to check out Metabolic Health Summit, which is a conference that I helped co-host and, and we're developing a virtual platform for that. So maybe check out the website. There's a YouTube page with many speakers that you guys would be familiar with. Rhonda Patrick was our keynote speaker for the last one. She gave a great talk on intestinal permeability, you know, lipopolysaccharide, all the different things you guys touch on.

Dom (1h 53m 48s):

And I think that's free on YouTube now. You can watch that. So yeah, metabolic Health Summit and keto nutrition.org.

Brian (1h 53m 56s):

Okay. And, and Jay? Yeah, so I always like to point people, I have a, some free content, you know, if, if someone's looking to maybe take some practicals away from, you know, the mechanisms and everything that we're, you know, everything that we're digging into today. I have a free mini course and digs into some of the basics as far, you know, as far as what I would be doing in terms of diet and lifestyle and stress and, and all of that to maximize our, our health from that bioenergetic lens. And so people can find that@jfeldmanwellness.com slash energy. And other than that, I have a podcast called the Energy Balance Podcast and articles and, and also links to the podcast and things like that at my website, which is j feldman wellness.com.

Brian (1h 54m 44s):

Excellent. Well, guys, this was great. Thanks for coming on for part two and I appreciate you, you being on the show. Thanks for having me.

Dom (1h 54m 52s):

Chat me, Brian.

Brian (1h 54m 53s):

Yeah, it was good talking with you, Tom.

Dom (1h 54m 55s):

Yep, you too, Jay. Till we meet again,

Brian (1h 55m 0s):

Thanks for listening to the Get Lean EAN podcast. I understand there are millions of other podcasts out there, and you've chosen to listen to mine and I appreciate that. Check out the show notes@briangrin.com for everything that was mentioned in this episode. Feel free to subscribe to the podcast and share it with a friend or family member that's looking to get their body back to what it once was. Thanks again and have a great day.

Dr. Dom D'Agostino and Jay Feldman

Dominic D’Agostino, Ph.D., has maintained involvement in a vast array of professional, academic and personal endeavors. As an Associate Professor with tenure at the University of South Florida, Dom teaches students of the Morsani College of Medicine and the Department of Molecular Pharmacology and Physiology, with a focus on such topics as neuropharmacology, medical biochemistry, physiology, neuroscience, and neuropharmacology. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC) to assist with their efforts towards optimizing the safety, health and resilience of the warfighter and astronaut.

Jay Feldman is a health coach, independent health researcher, and host of the Energy Balance podcast. He has degrees in neuroscience and exercise physiology and is devoted to using his knowledge and experience to help people heal from all manner of disease, dysfunction, and difficulty losing excess body fat



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