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#01 – Ketogenic Diets: the Good, the Bad and the Genetic with Dr. Aaron Gardner

Are you considering a ketogenic diet? Learn the benefits, potential risks, implications for heart health, how to choose supplements that aid ketosis, how genetics affect the way high fat diets impact different people and whether a ketogenic is a good solution for APOE4 carriers.

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Ok, welcome to the first episode of the Gene Food podcast, a deep dive into the implications of ketogenic and high fat diets for different genotypes. Aaron and I are fascinated by a study that came out last year, called the Retterstol study, which measured biomarkers for 30 healthy adults before and after going on a diet very high in fat and low in carbohydrate. The results confirm what we believe to be true here at Gene Food, which is there is no one size fits all when it comes to nutrition. The rise in LDL-C on the high fat diet prescribed in the study varied between just 5% in some participants to 107% in others! Clearly genetics play a big role in how our bodies respond to high fat diets and that’s what we get in today’s episode.

Because I know many of our listeners will be interested, here is a link to the study Aaron mentioned regarding ketone ester supplements vs. ketone salts. The idea here is that if you are considering supplementing with exogenous ketones, the ester form appears to be far superior to the salts. HVMN is a company that makes a reliable ketone ester backed by testing and is the brand Rhonda Patrick uses.

We also touch on at home lipid testing. Everlywell now offers direct to consumer test kits that will give you your baseline lipids prior to embarking on a high fat diet so you can watch and see what the increase in fat does to your metabolism.

The conversation is a bit on the technical side, but bear with us, this is episode #1, so we are working out the kinks as we go.

This Episode Covers:

  • Are you in ketosis? How to measure ketones and make sure you’re getting the benefits of a ketogenic diet;
  • The protective effect of ketones and the research of Dr. Veech at Harvard [4:00];
  • The GSTP1 gene, glutathione, SOD2 and endogenous antioxidants and ketones as an antioxidant [6:40];
  • Dangers of damaging gut health with excessive keto, cycling in and out of ketosis [7:30];
  • Ketone supplements and exogenous ketones, ester vs salts supplements, MCT oil, VDR genes and high fat diets [11:30];
  • Retterstol study and the variability in responses to high fat diets, including carnivore diet blood work [20:54];
  • LDL receptor, LDL particle saturated fat, cholesterol and the risk for heart disease [27:10];
  • PCSK9, LDLR and LDL-C levels [39:30];
  • PPAR the difficulty of generating ketones and the importance of testing [48:00];
  • FTO the “obesity gene” an high fat diets [53:00];
  • APOE4, Alzheimer’s and ketogenic diets: what is the best diet for APOE4? Vegan vs. high fat / low carb, Rhonda Patrick protocol [57:30];

Genetic Notes:


proprotein convertase subtilisin/kexin type 9

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What it does

Binds to LDL receptor causing the receptor to internalise into the cell, meaning it can’t traffic any more LDL.

If you block PCSK9 function, more DL receptors are present on the cell surface and so more LDL is absorbed. This is the function of PCSK9 inhibitors alirocumab and evolocumab.

Berberine is thought to be a “natural” inhibitor of PCSK9, but the mechanism is unclear, and positive associations are limited to animal models.


rs11206510 – R46L  (C allele is minor and protective)

Minor allele is protective against myocardial infarctions, reduces LDL cholesterol levels by 15%.

Only about 10% of people carry the protective allele, most people don’t.


What it does

Low density lipoprotein receptor (LDLR) binds circulating low density lipoproteins (LDL) and is encoded for by the LDLR gene.

Increased LDLR function is associated with greater clearance and therefore reduced serum LDL.



The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C, and lower risk of CHD.


Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L. This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82).

PPAR alpha

What it does

PPAR-alpha is a transcription factor that increases fat breakdown in the liver by altering the expression of other genes. Importantly PPAR-alpha is activated under conditions of calorie restriction and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.

Results in increase in fatty acid uptake, trafficking etc, also downregulates immune responses.


Rs1800206 – C > G

Associated with higher TG, cholesterol, LDL, apoA1 and apoB

The G allele was associated with greater plasma concentrations of TG and apoC3 in subjects consuming a diet low in PUFAs (<6% of energy), whereas when PUFA intake was high, carriers of the G allele had lower TG and apoC3, indicating a significant dose-response relationship between PUFA intake and serum TG concentrations depending on the genotype . Additionally, dietary fat intake interaction has effects on the peak particle diameter of LDL, a risk factor for cardiovascular diseases. G carriers with higher saturated fat intakes had smaller peak particle diameters of LDL than those with lower intakes.

Furthermore, in healthy white men from Quebec, carriers of the G allele had lower apoA1 concentrations after a high PUFA diet (P = 0.02). In addition, subjects that followed a low-fat diet for 8 wk and then were supplemented daily with 5 g of fish oil for 6 wk showed a significant genotype-diet interaction on the plasma C-reactive protein concentration.

Some evidence in mouse models that G is associated with impaired fasting response, i.e. you don’t go into ketosis.


What it does

See our FTO gene page.


Rs17817449 T > G

Rs1121980 G > A


What it does

See our CETP gene page.


rs708272 – TaqIB

rs2303790 – D442G

Both reduce CETP levels, and activity resulting in higher HDL-C levels ~4.5% increase, and higher apolipoprotein A-I levels. There is a weak association with a beneficial effect protecting against CAD.

For the latter there is a stronger effect, but may just be a study population effect as very rare. Confusing but a meta analysis of all available studies described the weak protective effect.

APOE4, Diet and Alzheimer’s

See our APOE gene page for detail on the APOE4 polymorphism.

The ketogenic diet (also known as keto diet) is a very low-carb, high-fat eating pattern.

There is a lot of research into its effects on brain health, particularly Alzheimer’s.

Our brains use glucose (carbs) as their main fuel source. If glucose is not available, the brain can switch to using ketones.

In Alzheimer’s disease, the ability of the brain to use glucose for energy is impaired. However, its ability to use ketones remains equal to that of a healthy brain (R). This is why a ketogenic diet may aid those already suffering from Alzheimer’s, but be contraindicated as a preventative measure. 

Both animal and human trials have shown ketogenic diets have slight beneficial effects in mild-to-moderate Alzheimer’s disease. Studies that directly supplement ketones in the form of MCT oils (maybe even coconut oil) have also been promising (R)(R)

Unfortunately, early studies indicate that cognitive improvements from MCT supplementation are weaker in those with APOE4 variations. This suggests a ketogenic diet and MCTs may not be as effective in APOE4 carriers (R) (R)

Additionally, it’s especially difficult to adhere to long-term ketogenic diets because they are so restrictive, and it may increase the risk for heart disease in some populations.


John: Welcome to “The GeneFood Podcast.” I’m your host, John O’Connor. Today, our guest is Dr. Aaron Gardner. Aaron holds a masters of research in medical and molecular biosciences as well as a doctorate in immunology from Newcastle University in the UK. Aaron has worked in a number of different medical research labs including Newcastle University in the UK and Columbia University here in New York City. His work is concentrated on understanding the genetics of various fibrodict disorders, including cystic fibrosis. At GeneFood, Aaron is head of research. He has designed the scoring system we use to create custom nutrition plans for clients, as well as the guide to Nutrigenomics we maintain on the website.

We rely on Aaron to help us sift through the mountain of nutrition science out there and give our listeners and readers an unbiased take on what it means for them. In today’s episode, which is the first episode of “The GeneFood Podcast,” we explore ketogenic diets and look at various genetic markers you might wanna be aware of before you venture into the high-fat diet territory. So, Aaron, where are you at, man? Are you in the Lake District still with your folks or?

Aaron: No, so I’m back home in Newcastle, other side of the country, which is just 80 miles, so it’s a very small other side of the country.

John: Not quite as scenic. I’ve actually never been to the Lake District but I’ve heard it’s beautiful.

Aaron: Yeah, it’s really good. It’s really nice.

John: Yeah, so that was a good place to get some fresh air, get out of the city.

Aaron: Yeah. Definitely.

John: Always amazed for me how much that affects me. Like I went out to Long Island just for a couple of days with my girlfriend and I just couldn’t believe, like the stress just melted away. Just not being in the city, it kind of makes you think a little bit but anyway. Okay, so we’re gonna get into a topic today that we get a lot of questions about through our blog and through our nutrition plan customers and that is ketosis, ketogenic diets, the impact of ketogenic diets on apoE4 carriers and other genetic polymorphisms that we’re gonna talk about.

And I figured that even though this is sort of a well-traveled path on the blogosphere and in the podcast world, I thought we would just talk for a minute about what is ketosis. I mean, there’s people that are on ketogenic diets, but they’re not in ketosis and they’re generally getting a benefit in terms of weight loss. But what we wanna talk about today is what do their lipid markers especially look like and how does a ketogenic diet affect different people based on how they clear LDL particle. But starting off ketogenic diet. I mean, what does that mean to you? Do we know? What’s the range of ketone bodies circulating in the blood that would qualify somebody to be in “ketosis?”

Aaron: I mean, that, I don’t think there’s an actual set definite standard of what range you should be. But if you read around a lot and stuff, there’s a generally accepted threshold that your beta-hydroxybutyrate to one of the ketones that’s measured during the blood test should be between about 1 to 4 millimoles per liter, and that’s sort of considered that you’re actually in ketosis at that point.

John: And you know, when I’ve heard guys like Dr. Veatch at Harvard who’s sort of a famous ketone researcher be interviewed, he talks a lot about how you can get into a state of ketosis either through fasting. Basically, as you stop eating, your body burns down its glucose stores and then it burns down the glycogen that’s stored in the muscle, and then you start burning your fat tissue and/or you can essentially eat a diet that’s just giving no real glucose so that your body starts to burn fat. But what he talks about is when you’ve reached this millimole account that you talked about, that these ketones have a protective effect.

And I’ve even heard him say, which I thought was really strange. I mean, I’ve heard him interviewed, I think it was on Bulletproof Radio. He was talking about, you know, using a ketogenic diet as a means for protecting first responders against radiation in the event that there was a dirty bomb that was detonated somewhere in the country. I mean, these ketone bodies, when they’re active and when you’re actually burning fat, they can be super protective. Can you talk a little bit just in terms of mechanism of why switching to a fat adapted state gives you such protection and kind of how that works?

Aaron: Yeah, so I think a lot of the work there is focused on, well, from the early work where they…so the ketogenic diet was really good for people with severe epilepsy and other neurological conditions and they saw that it really improved their health, their quality of life, basically just the general living standards. And then it sort of spins out from there that, well, if it’s having such a dramatic effect on these diseases which are characterized by inflammatory changes, thick changes in the brain, then maybe it can have a beneficial effect in health. And I think there’s been a lot of research looking into the sort of the changes and things like your blood pH, oxidative state that your body goes into when you go switch from a carbohydrate-rich diet, which is what most people are traditionally on, into a diet which encourages you enter ketogenesis.

And then one of the major things is basically, it’s that change in oxidation state in your body and you basically move into an antioxidant sort of environment where your body is…you’re in a more protective environment against the oxidative stresses that you’re sort of commonly exposed to and that’s driven by the changes that the ketones generate in the blood and in the tissues.

John: And that’s funny you say that because as we were preparing for this conversation, I was kind of thinking conceptually, not knowing whether it’s totally accurate but kind of thinking if ketones, when they do reach a certain level as being almost like another form of endogenous antioxidant. So you have, you know, we talked a lot about some of the genes like GSTP1, SOD2 is one I’ve written a lot about, these genes that are coded for basically making antioxidants that work in the body to be protective like and then you have genes that help your body make glutathione. So do you think it’s, conceptually for the listener, a good idea to start thinking of ketones as another endogenous antioxidant, or is it structurally and scientifically so different that that’s a bit of a misnomer?

Aaron: I mean, it’s different. It works in the same way. The way they both achieve it is different, but it has the same beneficial effect if you manage to get yourself into that state of ketosis. The dangerous bit is that if you go too far, then you can start having an even worse effect than if you didn’t have any ketones. Also if you go beyond the upper level of about four, and some people say, about 6 millimoles per liter, then you’re getting into the point where you actually can have a dangerous effect. And most people probably don’t get there on a ketogenic diet, but some of the very extreme ones that you come across could be pushing towards those levels. So it’s kind of if you have to, if you’re going to do it, you have to do it right.

John: Right. And that’s a great point. And you kind of…you just hear that anecdotally out there in the world of ketosis. You have these guys, and you know, guys and girls who go on a ketogenic diet and they get really hardcore about it and they see all glucose as the enemy forever. And then they have, you know, nasty GI issues that develop because they’re not getting any source of like fermentable carbohydrate that can produce short chain fatty acids, butyrate, these essential things to gut health. And I’ve also heard, and maybe you can speak to this a little bit, that if you go into a state of ketosis for too long, it can essentially blunt your ability to use glucose efficiently when it’s then subsequently put into the body. So a lot of these people are, and we’re going to get to this a little bit more in a second, but are cycling in and out of ketosis.

And that seems to be the consensus view of the ketone advocates is that don’t stay in ketosis indefinitely but use ketosis as a metabolic trampoline. Come out of it, eat some carbohydrates, and then go back in and…what’s the you on that in terms of…even in terms of for the listener. Like how long would it take to get into a state of ketosis that was bordering on dangerous even before we talk about lipids, just in terms of…

Aaron: I mean, if you went with a fairly normal ketogenic diet, you know, the sort of fat of about 50% to 60%, and you’re carbohydrates in the 5% to 10%, you’re probably never likely to reach that danger point. It’s the ones where we see people strip out carbohydrates entirely, that you’d be getting to push it towards that point quite quickly. And it’ll be basically, once your body has burned through its supplies of glucose, like you say, the glycogen in the muscle at once, that’s all gone, which could be, depending on individual short as a week, a couple of weeks. If you’re following this absolutely zero carbohydrate diet, then you get into trouble very quickly. But then obviously, we know that there are people out there who seem to do quite well on the zero carbohydrate diet. And that’s something like you say we will get into the individual, the variable response and basically trying to help people figure out where you might sit in that sort of spectrum.

John: Sure. And I think to that point, one of the things I find fascinating about these conversations, just sort of observing them casually on Instagram or people reporting success on a ketogenic diet. I actually saw, there was an article that appeared in one of these, I forgot which blog it was on, talking about Jenna Jameson who’s this, she’s a porn star. And she was talking about how she’d lost a ton of weight and shown these before and after photos. She’s pretty famous out there. And I just think to myself, “That’s fantastic.” I mean, the Retterstøl study that we’re gonna get into in a minute talks about how people, even though they have stuff that can happen to their lipids, it’s not great.

That a good chunk of people lose weight on these diets but you wonder with people like that who are casually doing a ketogenic diet if they are in ketosis and what happens if somebody is following a ketogenic diet but is actually not in ketosis. What’s the metabolic impact then? You’re just eating a high-fat diet but you don’t have the beneficial effect of the ketones circulating. What does that mean?

Aaron: Yeah. I mean in those situations where you’ve got people where they’re following that diet and they’ve had that high fat intake but they’ve maybe not pushed it far enough or their individual genetic makeup makes it more difficult for them to get into that state of ketosis, then it’s exactly like you said. They’re basically eating a high-fat diet and then they’re still gonna be getting the majority of their energy from carbohydrates, so that fat has got to go somewhere. And then it can just depend on the individual’s genetic makeup again, how their lipid profile is gonna look.

You would assume it wouldn’t look good because if that fat is not being used to generate ketone bodies which isn’t being used by the body, it’s just gonna accumulate. So testing that you’re actually in that state of ketosis is a really important step.

John: Yeah, for that. And what about adding exogenous ketones? You know, there’s a lot of…in the supplement world, keto has just become huge. I feel like every single health food store I go to, I’m in the airport, I’m in any different city and guys like Dr. Mercola are coming out with keto fast books and everybody is advocating. There’s a segment of the population. Of course, you have the more plant-based advocates who are on one side who are adamantly opposed to ketogenic diet in any capacity at any time, but it is becoming something that is just very much a part of the consciousness and the supplement industry has followed suit and they’ve created products that will…like you hear MCT oil manufacturers talk about how MCT oil is a precursor to beta-hydroxybutyrate which is a ketone ester, correct? In your research, what’s your take on somebody taking exogenous ketones while not in a state of ketosis? What are the things to look out for, both good and bad, in that science?

Aaron: Because this is sort of as with most things, the U.S. leads the way. So this is kind of just coming over to the UK at the moment. And I’ve been seeing them, like you say, you start to see them and notice them. So I’ve been doing a bit of reading about it as well and there’s basically quite a good study out there that sort of delves into what effect they have on people who take these when they’re not in a state of ketosis. But the most important take-home message from that paper is actually that you should really check out what your drink contains because they say, you know, there’s two broad variants: one that’s gonna contain a ketone salt, and one that contains a ketone ester.

So the salt will be bound with something like sodium and the ester, it’s bound with an alcohol and it’s just to aid in the absorption. And basically, they found that these salt ones, A, you’re getting a mixed population of the BHB molecules, the other half of which that we don’t really know what they do in the body so you’re having a negative effect. And then that they also don’t last that long, those ones that contain a salt. So those ones that kind of pretty much straight away have been shown to not really have any benefit. The ketone ester ones, however, they’re a bit more interesting. So they are more readily absorbed by the body and they actually could measure that you could see these BHB molecules in the individual’s serum for a period of about eight hours.

Well, the bit that they found really interesting was that as soon as you ate any meal that would have any carbohydrates in it, so as soon as you ate your normal meal, you basically stopped that effect. You lost that beneficial effect of the ketones because you’re supplementing your diet again. So they sort of said that well, it has its place if you can fit it in to your existing diet, if you can maybe first thing in the morning where you’ve been fasting overnight, if you have one of these exogenous ketone drinks, you get the benefit from the ketones and then you eat your normal diets throughout the rest of the day. You get that morning boost. But it has to be taken away from carbohydrates and when you’re getting to that point, you might as well be saying, “Well, why don’t I just follow a ketogenic diet anyway,” because you’re avoiding carbs to get the benefit.

John: Right. One of the supplements and you have supplements of that class, like I think of MCT oil, I think of L-Carnitine, I think of CoQ10 to a certain extent, PQQ, some of these supplements that are almost like the buzz supplements. They give you a buzz, they give you energy but what do you really know about kind of what they’re doing over the long haul. I’ve written about taking PQQ and having an amazing result but then over time, kind of having that law of diminishing returns where it sort of goes down. And we had an interesting conversation a couple of years ago about MCTs because I was taking MCTs and like a lot of people, I felt amazing. I mean you can…I can feel the impact on my brain with MCT oil for sure, especially a good-quality MCT oil.

But I did notice over time that I started to have some side effects and I wrote about it. It’s still a blog that’s pretty popular on the GeneFood blog. People will comment on it. We got really into the weeds, thanks to your research, and just to sort of give a disclaimer, this is just a theory that we have. We’re throwing it out as a possible reason why some people could have issues with MCTs but essentially, you made the interesting point that based on certain variants in the vitamin D receptor genes, that certain people will absorb more calcium into their blood because ultimately, vitamin D helps with the absorption of calcium into the blood and that some people with certain VDR genotypes, given such a mega dose of fat, vitamin D being a fat-soluble vitamin, will get hit with this.

If they’re supplementing with vitamin D in high doses at the same time as MCT oil, they’ll get hit with a big rush of calcium in the blood and that can cause different issues. Is that an accurate…you know, correct me where I’m wrong about that but is that an accurate solution?

Aaron: Yeah. So that has never really been studied so it was sort of a theory that we came up with by joining the sort of the dots of what people like yourself and other people have been reporting, that sort of, you know, that feeling of breathlessness. You’re sort of the tachycardia, your heart racing…

John: Yeah. That’s what I got.

Aaron: …when you take the MCT oil and the vitamin D. And it kind of…you can see why it makes sense. It’s never been…there’s no studies out there proving it but it’s sort of…it makes logical sense that you can see the flow through. And that, you sort of hit on a key point there about the quality of the products and the doses that you’re taking them out. So I think the MCT, I think that’s…very specifically, the C8 MCT is supposed to be the one that’s best for getting you into ketosis. Lauric acid is one of the ones where you kind of you wanna avoid taking in too much of it. And that’s why the sort of MCT, mixed MCT oil, maybe isn’t the greatest thing to take in a high dose. And at the same time, give yourself…

John: Sorry, Aaron, to stop you there. So you’re saying, because I know like, for example, like Brain Octane Oil, Dave Asprey’s product, they basically just use nothing but caprylic acid. And some of these other formulations that we’ve written about on the blog, you know, we say, “Hey, if you wanna have some type of antimicrobial effect with your MCT oil, leave in some of the lauric acid because the literature that’s out there on the antimicrobial antifungal benefits of coconut oil really is geared towards the lauric acid count but if you’re looking for ketosis and an energy boost, you want these other fats.”

Aaron: Yeah. So that’s exactly…so the one, the brain boost that’s been…the bulletproof copy that’s been sold, that’s the one.

John: Brain Octane.

Aaron: Brain Octane. That will get you in ketosis. That is its primary function. MCT is derived from coconut. So it’s sort of a mixed bag population. Yeah, it won’t get you into ketosis as quickly. You’d have to take a lot more but then there are all the, like you say, the other benefits of taking a more natural product that has a bit sort of a more heterogeneous mix that you’re getting other benefits from it as well. So it kind of depends what you’re really aiming for and it’s the dose that you take it out as well. So if you wanted to get into ketosis using just MCT, like a mixed heterogeneous MCT, you’re gonna have to take a much higher dose than you would with brain Octane.

John: Sure. And just as an aside with the vitamin D supplementation and the whole calcium issue and the chest discomfort and things like that which is, I know, one of the side effects that some people experience. Really what they experience I think more often is the digestive issues but I think it’s also interesting that the increases in vitamin D can also draw down on magnesium and I think it’d be interesting in the future to look at genes like I think it’s like MUC1, some of these magnesium level genes in that conversation and see how people would do on a high-fat diet taking vitamin D, and then in terms of what’s happening to their magnesium levels because we know that based on modern farming practices, a lot of people are magnesium deficient. So do you have any thoughts on that before we jump into…

Aaron: Yeah. I mean that’s an interest. So the issues with taking vitamin D on people’s digestion, it’s kind of really well known and actually promoting people on to a higher fat diet when they’re taking it for medical reasons is often sort of prescribed because it helps with the absorption. But you know it plays havoc with people’s digestive systems and adding magnesium into that mix as well trying to get…because magnesium can also…if you’re trying to supplement with magnesium and go too high on your doses of magnesium and you’re also gonna have all kinds of digestive issues. So that’s gonna be a really tricky puzzle to sort of unpick and find out an individual’s optimum dosage of each.

And the best way to do it is probably start with the lower doses and work your way up if you’re gonna supplement with these things. Don’t go in at a really high dose because you’ll probably make yourself feel rubbish and then you’ll drop off it straight away because you won’t wanna carry on with it.

John: Absolutely. So that’s getting a little bit on a supplement nerd tangent, but what I wanna dive into now is kind of the meat of this episode which is this study that we both love, the Retterstøl study that was done in Oslo and appeared in a journal called “Atherosclerosis” I believe last year. And that study looked at 30 people. I think it was originally 39 people, correct?

Aaron: Yep.

John: Thirty-nine healthy individuals. This is a very rare controlled trial in the nutritional world. And they looked at…they took people and they had a control group and then they had a group that was fed a low carbohydrate high-fat diet for three weeks. And the chaos that ensued the individual responses are absolutely fascinating. And, you know, I’ve written about this recently. Somebody like Mikhaila Peterson who’s a very famous carnivore dieter and she’s maintaining an LDL particle count which is of in the 600s which is very…it’s incredibly impressive eating nothing but beef and beef fat. And we saw in this study, not that I’m advocating for that diet, I’m saying that in some people, based on what we’re about to get into, they can have a very favorable response to a diet that’s very high in fat.

But others, you know, see huge increases in their LDL cholesterol. And in this case, a lot of them saw big increases in their apo B which is essentially their LDL particle count because you have one apo B protein for every LDL particle as well as uric acid which is a metric that we’ve also written about. It’s basically if you have high uric acid, you can get gout which is kind of nasty. Tell us about Retterstøl. What does it mean to you, this whole study?

Aaron: I mean the reason I love this study is because they show individual patient responses. They show you that variation. So a lot of nutritional studies and other studies, they will show you the sort of the mean, the average of a response from a group and you might see the variation around that but it’s very difficult to see individual responses. And then obviously if you’re looking at multiple things, you can’t see how particular individual’s responses are tied together. So I love this study because they show the individual patient’s response. And like you say, they basically go on to a…go ahead, John.

John: No, go ahead.

Aaron: So they put the people in this trial onto the low carbohydrate high fat diet. So it’s about 5% carbohydrate intake which is towards the lower end of what you would consider like a normal ketogenic diet. And then basically, like you say, you go into the results and you can see these people’s responses. And looking at things like the LDLC, the LDL count, you can see it goes from one person who saw a tiny 5% variation all the way up to someone at the other end who saw a 100% variation. They basically saw a doubling of their LDLC count. And it’s just that not a huge variation across the population and that fits really well with those parts of ethos is that these diet plans might work well for someone but they probably don’t work well for everyone and it’s about finding your optimum response to it.

And I think it’s just a really good study for showing that huge variation across a population of people. And even having a quite small study located in a single country to see that variation, if you imagine extrapolating that out into the whole world, then you’re gonna see much, much more variation.

John: Yeah, and I think that’s right. And even just preliminarily, when you read the top lines, sort of the abstract of the study, they mention right away that nine people either withdrew or dropped out because of illness. I mean, this high-fat diet made some people immediately very ill.

Aaron: Yeah. And there was two even beyond those nine, they’re the ones that were due. There was two where it was quite serious adverse effects. So I think one of them had a cardiomyopathy and I can’t remember what the other person had but these are quite serious things and obviously, they may not be linked to the trial but the sort of all does imply that it was linked to the trial. And then yeah, you could imagine those people having no serious effects. They’re not even included in the analysis. So it’s always important just to make sure that you know what you’re getting into with your diet types.

John: Well, correct me if I’m wrong but I think that the study authors chose people who were “healthy” and I think elevated levels of certain biomarkers and disease states excluded people from participating and these were relatively young participants, weren’t they as well?

Aaron: Yes. I mean all of these nutritional tests will happen in a healthy population. So they won’t take people onto a trial if they’re worried that they’re gonna have directly impact on their health.

John: Fair enough.

Aaron: And most trials tend to happen in younger people because they’re more willing to…well, they’re more keen to get the bit of money that you get for participating in the trials, probably their actual reason. But also, they’re just more willing. So yeah, it’s a young, healthy population and you see these significant effects in this population, imagine what would happen if you tried it in someone who’s unhealthy or a much older population. You can imagine that the results would be more significant still.

John: Sure. And I do wanna say that we want to…we’re not advocating against or for a ketogenic diet. That I wanna be clear. We’re trying to tease out genetic differences in biomarkers that could see some people being successful in a ketogenic diet and other people probably wanting to avoid a ketogenic diet. I listen to a doctor who I think is very sharp, Peter Attia. He has a podcast and he does long-form very technical medical interviews. He’s a very brilliant guy. And he talks all the time about how, you know, he’s one of these guys who’s just anti-glucose. I mean you listen to him and he’s wearing a continuous blood sugar monitor and he’s watching his insulin, his glucose spike after moments of stress in the morning, etc., etc., and he talks about how he goes on a ketogenic diet and he sees no increase in his LDL particle.

And it’s one of these five percenters in this Retterstøl study. And the controls in this study, their LDL cholesterol was unchanged. Then you get these people at the other side of the spectrum who are at this 107% increase and just to reiterate, it’s not just the increase in LDL cholesterol. It’s also the increase in apo B and LDL particle because the LDL cholesterol is only a risk factor for heart disease if it’s concordant with the LDL particle, correct?

Aaron: Yep.

John: So let’s dive into these…to some of the genetics that are mentioned in the study. So I think that’s where the meat of this is. And one of the things that we try to do with our nutrition plans from a simplified sort of 10,000-foot perspective is we’re trying to guess at and then it’s…we’re very clear that we want the clients to then go follow up with testing with their physician obviously, but we’re trying to give people a sort of foundational information in guessing at what their LDL receptor activity is gonna be. Can you tell the audience who may have never heard of an LDL receptor, what is an LDL receptor and why is it important?

Aaron: So LDL receptor, as the name, it’s a low-density lipoprotein receptor. So it’s found on the surface of your cells and what it does is it binds low-density lipoproteins that sort of come past and it then internalizes these particles into the cells. The main function of it is to maintain your plasma level of LDL. So if you have lots of active LDL receptor, your LDL levels are likely to be lower. If you have less of it, then your LDL levels in your serum and your blood are likely to be higher. So the simple sort of way of putting it is that more would be thought of as better. I know there’s a lot of discussion now about whether LDL is actually as bad as we say it is but having more LDL-R function on your cells would be thought of to be better.

John: Sure. And just for the audience as to zoom out from that in terms of LDL clearance, the LDL particle is really the taxi, the traffic’s fats and plant fats throughout the body where they can be used in different ways. And the thinking goes, you know, some of the best lipidologists out there that I follow like Tom Dayspring, I mentioned Peter Attia, they still believe that at the end of the day, if you wanna lower your risk for heart disease, you lower your LDL particle count which is the number of taxis that are on the road. And if you have an enhanced ability through some of the genes, you’re about to talk about, to clear these LDL particles, and I think it’s through the liver mainly?

Aaron: Yeah. The LDL-R is most active in the liver. I think it probably is expressed throughout the body but it’s most active in the liver.

John: Sure. So you have the ability to clear these LDL particles and you get rid of them. And it blows my mind. I’ll talk to friends and they’ll be like, “I’m on a super high-fat diet.” And then they’ll share their blood work with me and then their LDL cholesterol is at like 36 milligrams per deciliter and it just blows my mind. Or I just mentioned Mikhaila Peterson, you know, being on a carnivore diet where she’s eating nothing but beef fat for an entire year and her LDL particle was very low. And so the idea is in…the idea was saturated fat for some people is that it can have an inhibitory effect on the LDL receptor, right?

Aaron: Yeah.

John: Okay. So can you speak to that a little bit in terms of how that’s theorized to work?

Aaron: So it’s not really that well understood how it sort of inhibits the LDL receptor. It could be that it’s internalizing it. You know, it’s causing the…rather than being expressed out on the surface into the blood vessels where it can grab those LDL particles and internalize them. It gets internalized without them being…you know, without anything being bound to them. So they’re on the inside of the cell. They can’t grab anything. That’s one hypothesis as to how it’s happening. The other one is that it actually down-regulates the expression, full stop. So rather than having 100 of these receptors on your cell surface, it gets cut down to 50, you know, 25.

And even though they’re working properly, they’re working as well as they can, you’re just by the very process of having less of those receptors on your cell surface. You’re not gonna get that beneficial effect. But it’s not really all that well understood exactly which of those processes that’s driving it.

John: Yeah. It’s still very much…some of this is still very much a mystery in terms of how it works in different people. And as you mentioned, to give the other side of the story, there are commentators out there and doctors out there who say, “Hey, maybe the elevated LDL, maybe these diets that are higher in fat elevate these lipid markers.” But if you look at actual mortality outcomes, having elevated levels of these lipid markers doesn’t always correlate with higher incidence of mortality. Is that essentially the argument that you hear?

Aaron: Yeah. I mean it’s the sort of probably the major health story of our time is this sort of shift away from all cholesterol, all fat is bad and we’re kind of becoming around to the idea that, well, actually fat in your diet depending on the type of fat can be beneficial and almost certainly is beneficial. And it’s kind of getting there with the LDL particles. I think the majority consensus is still that there is definitely a risk for cardiovascular health by having a higher LDL count. So if you have a higher LDL count, you want to be bringing that down.

But then yeah, there are people, like you say, who are following these extreme diets or what we’d consider an extreme diet where you would think these levels are gonna be through the roof but they’re not. The problem is is if there is someone who tries to follow that diet and they don’t respond as well, then they might be doing themselves some serious harm, if not in the short term, then almost certainly in the long term.

John: Right. I mean but let’s tease that out a little bit because the response to saturated fat in terms of this LDL particle count is not the same as the response to diet, to cholesterol. You know, with the cholesterol, one of the things I think is a real shame is that you get people who advocate for a high-fat diet and there’s a basis in fact for doing that especially in some people but the cholesterol and then saturated fat get lumped into the same category. So you tell me where I’m going wrong here in my thinking. My thinking is that you’re eating a diet, most people are eating dietary cholesterol and there may be some theorized mechanistic problems with that like TMAO, for example, that the choline in an egg will be…well, the microbiome will produce metabolites that are bad for your heart health as a result of that. But in terms of cholesterol levels, they seem to be tightly regulated.

Aaron: Yeah. So they are generally tightly regulated and your actual diet has a relatively small impact on what your cholesterol levels will be but there are subsets of people who will either hyper respond or not respond very strongly at all through their diet. So those people can have quite dramatic changes in their cholesterol and LDL levels based on their sort of diet. For the majority of people, yeah, your diet doesn’t have a major impact but even these sort of small changes around the edge can still have an effect.

John: Sure. The problem is you hear these conversations and the people that are having them are usually super well-informed and they know the research but I feel like the caveats are never listed. So it’s like, “Okay, well, cholesterol is no longer bad. The warnings against dietary cholesterol have been removed. Everybody can go eat as much cholesterol as they want.” Well, there’s 20% of people as you’ve just pointed out who are hyper absorbing cholesterol and that’s like the ABCG8 polymorphisms, right?

Aaron: Yep.

John: And so if they’re hyper-absorbing cholesterol, that’s gonna have an impact on their lipid markers. But most people are probably gonna be just fine. But then, the flip side of that coin is that cholesterol and saturated fat are not the same thing. So nobody is…I don’t think anybody is alleging that cholesterol impedes LDL receptor activity.

Aaron: But it’s about the saturated fat intake. And yeah, and that fits in with going on to these high-fat diets. It’s what proportion of your fats do you bring from each source. So some people will be fine with the saturated fat intake. It might not reduce their LDL receptor count or the LDL receptor activity but there will be a proportion of people who do. So maybe the better advice is that rather than any fats is good for everyone, we set a sort of threshold for saturated fat and say, “Yes, you do need an amount of saturated fat but it may be preferable to switch to monounsaturated fats. So the majority of fats for the majority of people.” That might be a more sort of targeted advice that would be beneficial for everyone rather than just have a free-for-all on whatever type of fat that you want.

John: Yeah, yeah. Especially if you’re flying blind as to your genetics and your labs which most people are. Most people are going on these diets and they don’t have access to their LDL particle count. Most blood tests, I mean we’ve written on the blog about how now this testing has been democratized to a certain point so you can use a company like EverlyWell and you can figure out what your triglycerides are and you can figure out what your LDL cholesterol is but you’re not getting access to your LDL particle and you don’t have access to your genetics. And then you’re going…I mean I was just communicating with a guy on the blog who wrote in and said, “Hey, I’ve been on the carnivore diet. I feel amazing but I’m not getting my bloodwork tested.” And I’m like, “Okay, well, that’s your decision but…”

He’s like, “Well, a lot of the carnivore dieters, their blood looks great so I’m not gonna get mine tested for at least a year.” And I’m like, “Okay.” You know, again, that’s his decision. But the whole point that we’re making here is that his reaction could be very, very different from the people that he is following and I think there’s this misconception out there that everybody is gonna react to these diets in this monolithic way and it’s actually just not the case.

Aaron: No, I think it’s definitely a case of the more you know, the better informed you’ll be. So, you know, knowing your genetics, obviously, getting your blood work done is a bit more involved than getting your genetics assessed, which is a sort of a one-off event. But you really do want to if you’re going to follow a more extreme diet, like a carnivore diet, you really probably do want to be keeping on top of your blood lipids just over an extended period of time just to see how it’s affecting you, just because, yeah, the blogger that you follow that does it and has perfect blood work, that might not be you and you might be doing yourself a lot of damage down the line.

John: Yeah. And she really does. I mean, to be fair to the other side, I mean, of course, we don’t know long-term what the impact of these diets are. I mean, there’s all the theories out there, you know, a guy like Valter Longo, who’s the head of longevity at USC, who’s been very beloved by, you know, the sort of the nutrition world and the science and nutrition world, talking about the inflammatory nature of some of these amino acids that are in animal protein, you know, methionine, tryptophan, the branched chain amino acids, steering clear of mega doses of this.

Who knows what that’s going to do over time? And I think that there’s even a debate that’s raging that, you know, people a lot smarter than me are commenting on, which is essentially, what’s the role of IGF-1 in, you know, cancer and disease? There’s all sorts of different, you know, what triggers it. But at the end of the day, just because somebody else had success doesn’t mean that that you will, as you pointed out. But…

Aaron: Yeah. But it’s also an important step, though, because probably the thing that often gets washed away is that maybe some of these diets aren’t best diet that you could be on individually. But if you’re actively thinking about your diet and you’re actively trying to source better quality food, you know, food that doesn’t contain a lot of processed carbohydrates, a lot of trans fats, you’re trying to avoid those on your diet, you’re still probably eating better than the majority of people in the world. So you’re going…once you to start getting into thinking about, you know, will I do better on a ketogenic diet, paleo diet, a vegan diet, you’re probably doing better than most people already.

John: Yeah, absolutely. I think that’s…

Aaron: Just not picking which one’s best for you.

John: I think that’s an important point to make. The standard American diet is probably not one that is a great idea for anyone. Okay, so we’ve been beating around the bush. And I think we were building to this point where people are probably wondering, “Okay, these genetic differences between us, in part, they’re going to dictate some of these snips we know about, are going to dictate whether somebody has success, whether somebody is kind of set up for failure.” I know one of them, that you’ve mentioned that is discussed in the Retterstøl study is PCSK9, which I in my sort of layperson perspective think of as basically normal PCSK9 activity is like a PACMAN for LDL receptor. It kind of like eats the LDL receptor.

Aaron: Exactly that, yes. So basically, your LDL receptor should be just sitting out on the surface of the cell waiting to pick up those LDL particles. What PCSK9 does is it basically binds to that receptor and then flips it on to the inside of the cell. So it’s a way of regulating LDL levels in your blood. And actually blocking the function of this protein is quite a sort of interest to a lot of people. So it’s been targeted by a couple of therapeutics as a way of bringing people’s LDL levels down. And there’s also some natural inhibitors out there as well. But the really interesting bit for us is because we’re sort of a genetics-focused website or the polymorphous enzyme here. So I don’t know if you want me to go into…

John: Yeah, absolutely. Yeah.

Aaron: Yeah. There’s quite a few snips in PCSK9 of a function that’s related to LDL and how it can link in with different levels in the serum. But the one that has the probably the most dramatic effect is one that’s called rs11206510. And so if you want to follow this at home and check up on it, it’s the C allele, is the minor allele, and this is the protective one. So when you read studies about if you’ve got the C allele, you have a protective effect.

John: And Aaron, just to stop you really quick before you continue on, for the listeners at home, these snips that Aaron is listing are all available on your…they’re not available through the 23andMe interface, but they’re included in your raw data. And the product that we’re going to be putting out here in a few weeks called keto score is going to give people their status for all of these genes that we’re mentioning right now. So, sorry.

Aaron: Yep, exactly. So you’ll be able to check up that RS number that I read out and to see which allele you have, and you should be able to figure out what your sort of risk is based on that. That snip’s really interesting one because the minor allele, the C1 I just talked about is protective against load of things. So a lot of cardiac events. And it’s thought to drive this because it basically reduces LDL cholesterol levels by about 15%. And that also correlates with about a 9.5% reduction in total cholesterol measured in the plasma. So this C allele is great. If you have this, you’re going to have much lower levels of LDL cholesterol, much lower levels of total cholesterol, which, you know, it’s debatable what the health effects of that is. But generally, it’s thought of that to be a beneficial health effect.

The only downside is, is that most people don’t actually carry it. I think it’s only about 10% of the Western population would carry a single copy of that protective allele. The majority of us don’t have that. And that’s actually true for a lot of the PCSK9 snips. It seems that the protective one, the one that has a beneficial effect is actually the rarer version of the allele, a rarer allele. So I’m not entirely sure why that’s occurred. But it’s really important to sort of go into your genome and check these different snips and see what you have because that’ll give you the…PCSK9 is probably the one that has the biggest impact on your LDL cholesterol levels. And that’s why it was the focus of the Retterstøl study. That’s why they looked into it in so much detail as well.

John: Okay. But PCSK9 is part of the story. It’s not the whole story. I know you have LDL-R, you have PPAR-alpha, you have FTO. Can you tell us… And I know this is your approach, Aaron, which I’ve always admired, which is, you know, don’t hyper-focus on any one snip. It’s not about, you know, “Oh, man, I found I have this one snip, so therefore, that’s going to be dispositive of my situation in all…” We don’t know the exact mechanism always and these genetic markers work in concert, but these are the big ones that have the most in the way of research behind them. Is that how you would…

Aaron: Yeah, definitely. It’s something that we’ve talked about a lot previously. Imagine there’s going to be a future in 10, 20 years’ time where every single person is fully sequenced. And we know what every single individual polymorphism does and there’s going to be some fancy AI program that kicks out your perfect diet for you as an individual. You know, that’s going to be the future because we’re going to know all of that information soon. Right now, we’re just sort of playing around at the edges. Really, we know that there’s some polymorphisms. We know which ones have the biggest effect, and they’re the best investigated because, you know, you want to look at the thing that has the biggest effect.

But for something like LDL, they’ll be hundreds if not thousands of polymorphisms. And yeah, the big ones are important because they have the biggest effect, but you know, that might be outweighed by 10 other snips that you have. You know, you might have one bad snip, but you have 10 other good snips. And it’s about taking all of that into account, looking at it sort of from a higher picture and seeing what your sort of overall picture is going to be. I think that’s the definite approach. Never ever focus on a single snip or a single polymorphism. But it’s interesting to do it though, as well.

John: It’s interesting to talk about. I mean, in the Retterstøl study, you know, PCSK9 was just right at the top in terms of their conversation, which I found interesting, especially as, like you said, there’s these new drugs that are targeting PCSK9 and it’s becoming something that’s very much a part of the whole lipid conversation. But what about LDL receptor, PPAR, these genes? I mean, are these basically just functioning in the same way mechanistically as PCSK9 or is there anything to know that is unique about how these genes function in this whole conversation?

Aaron: So LDL-R is very similar with the PCSK9 because, you know, how it’s internalized. And if you lose a bit of function in your LDL-R activity, then you’re going to have a similar effect to change it in your PCSK9. So if you have less receptor, it’s not as active or internalizes more quickly, then you’re going to have alterations in your LDL count in your serum. So there’s a couple of snips that people actually are interested in. So there’s rs6511720. And the minor allele for that snip is associated with a lower level of LDLC and a lower risk of coronary heart disease. So if you have the minor allele for that snip, then you’re going to have a beneficial effect.

And that one’s also commonly taught alongside of there’s another one, which is sort of 2228671. And this one, they’ve gone into a bit more detail and they’ve actually measured the counts a bit more accuracy. So in this snip, the minor allele is T. And for every copy of that T allele that you carry, you see a reduction in your LDLC levels of about not…well, they say accurately, not 0.19 millimoles per liter. And this association is dropping LDLC. Was really sort of strongly associated with a lower risk of coronary artery disease and other cardiovascular diseases with a really strong effect. So it’s not quite as dramatic a change in the levels of LDL that you see with PCSK9 but the effects that it has are sort of similar, that strong reduction in a risk of coronary or cardiac events.

John: Yeah, and I think we can probably say that we humbly believe based on the research that you’ve compiled and are looking at this, that we’re probably in the camp that an increased LDL particle count is probably not a good thing when it comes to heart disease risk.

Aaron: Yeah. I know that that’s sort of in [inaudible 00:47:41] in discussion. But my personal take from doing a lot of reading for the site and for the sort of the genetic guides that we do would still be that a lower LDL count is better.

John: Sure.

Aaron: I know you can go into so you can subdivide it and start talking about particle sizes and things like that and obviously is important. But I think keeping it low for me is still the way to go. And the research would support that.

John: Beautiful. And then one other one that’s been talked about, you know, that’s come up is PPAR.

Aaron: Yeah. So PPAR is a really interesting one because this ties in with the whole ketogenic diet as well and how well you may respond to or how able you might be to enter that state of ketosis. So PPAR-alpha, it’s a transcription factor. So what that means is that it’s protein that’s produced and then it alters the expression of other genes. What we’re trying to do is that by altering other gene expressions, it increases the rate of fat breakdown in the liver. But the really important bit is that this gene, PPAR-alpha, only becomes activated strongly under conditions of calorie restriction. So, you know, starvation, or if you’re attempting to go into a ketogenic diet and enter that state of ketogenesis.

John: Go ahead. Go ahead.

Aaron: So it results in an increase in your fatty acid uptake, trafficking, and then it also down-regulates immune responses. So it can put you into that state of ketosis. And it’s also thought to have a really important role in developing the anti-inflammatory state that people associate with ketosis as well.

John: So the people that have favorable PPAR status are more likely to efficiently use the ketogenic state, the fuel that’s produced in a ketogenic state as they’re better suited to becoming fat adapted essentially?

Aaron: Well, so there’s a snip. It’s rs1800206. And there’s two versions of the gene you can have. You can have the C allele or the G allele. And the G allele is the one that’s most interesting. So there’s some work out there in mouse models. It’s not being shown in people. The people who have the G allele have an impaired fasting response in that they don’t go into ketosis as easily. So even though you might be following a ketogenic diet, if you have that G allele, you know, you might be following a standard ketogenic diet that puts someone else into ketosis.

If you have copies of that G allele, you might not be going into that ketogenic state. You might be just having that high-fat diet and still getting the majority of your energy from the small amount of carbs that you’re eating. So people with that allele need to probably pay specific attention to what their fat intake is and actually measure…try and assess whether they have actually entered that ketogenic state.

John: So PPAR is a gene that is a gateway to ketosis if you have…

Aaron: Yeah. And then it also has impacts on ketosis once you get into it, as well. So it’s really it’s sort of a double whammy gene.

John: So that’s really interesting. So some people really can’t get into ketosis, even in a state where they’re fasting with essentially no food?

Aaron: Yeah. I mean, they’d have to…because it’s not really being carried out in humans and it’d be a very difficult study to do because you’d need huge numbers of people to do it. But you can imagine that whereas I might enter ketosis with a sort of 10% carbohydrate diet, people with those G alleles, especially those who maybe carry two copies, might need to drop that to a really low level of sort of 1% to 2%. And then once you’re getting down to that level, the question is, are you doing more harm to yourself by not having that carbohydrate intake and not getting the beneficial effects of that low intake? So at that point, it’s maybe is it actually worth going into the ketogenic diet for you?

John: Now, those people though, Aaron, they’re still going to have the ability to burn fat, they’re just not going to get their ketones to a level that’s protective, correct? I mean, you know, I’m just envisioning the situation where somebody has the PPAR gene and they’re starving. And, you know, they’re just not eating there. They’re out in the woods, whatever the case. They’re still going to be burning down fat as energy, but it’s just that their ketone levels don’t get to a state that’s protective. Is that accurate?

Aaron: I mean, in that situation, where if you go into full-on starvation mode, then I think everyone is going to go into ketosis because that’s just a sort of a normal part of body’s, you know, the sort of defense mechanism to sort of protect its brain, basically provide energy for your brain so you can live long enough to get you to that next bit of food.

John: Gotcha.

Aaron: So, yeah. If you starve yourself, even with that allele, you’re going to enter ketosis, but that’s not great dietary advice.

John: Right. No, absolutely not.

Aaron: We don’t know exactly the particular time we’re gonna go into ketosis, and they’re not going to be getting the beneficial effects. So even like a 2% carbohydrate diet, they might not be in ketosis. And they’re just basically not getting any of the benefits, but they’re also getting the harm from trying to follow this diet.

John: Right. So this scenario that I think of is the observer of some of these blogs and websites. Like, “Okay, ketosis is great for me. They don’t have their lipids. They don’t have their genetics and they’re not measuring ketones. They’re not measuring the millimole account of their ketones and they’re never in ketosis and they’re on a ketogenic diet, losing weight, but they’re not getting any of the protective effects.” I think that probably happens. Say again, what’s the percent of people is it estimated that will have that difficulty getting into ketosis?

Aaron: For that particular snip, I haven’t got time, I can look it up very quickly though.

John: We can add it to the show notes, too.

Aaron: Yeah, I’ll just have a quick look.

John: Okay. I also want to touch on briefly FTO, which is the fourth sort of major gene that we identified. And then I want to close by talking about apoE4 because that’s one where you just get a ton of…there’s just so much out there in apoE4. People are concerned when they have it. For those listeners that don’t know, apoE4, one or two copies, you know, one copy increases your risk for Alzheimer’s. I think having two copies of that gene increases your risk for Alzheimer’s. Correct me if I’m wrong here. So I think it’s like 19 times more likely. Not to say that you necessarily will get it but it just makes it more likely. And…

Aaron: Yeah, APOE is a really interesting one because it has that…I mean, it’s a very strong link for polymorphism to have such a strong link with the disorder. And it’s why I think it’s been removed from 23andMe because it causes a lot of worry, and people because you see it, and then you think, “Oh, I’ve got this 19 times increased risk of getting Alzheimer’s,” and people take that as, “I’m going to get Alzheimer’s.” It doesn’t actually mean that. There’s a lot of other factors that influence it as well.

John: So FTO just real quick. I wanted to run through our list. You know, that’s one that you have to…you’re kind of coining at the “obesity gene.”

Aaron: Yes. I mean, it’s a really popular gene because it basically has a strong association with developing obesity. So you can imagine in today’s world, it’s going to be the focus of a lot of research on that. So it’s actually called the fat mass and obesity-associated protein. So it’s even named in the sort of the protein name that it has this link with obesity.

John: Yeah, sort of a very blatant naming of that gene. In the notes, I mean, you say that this is a gene that’s associated with putting on weight in response to eating a diet that’s high in saturated fat, correct?

Aaron: Yep. So it’s basically how…when people have actually looked into…when it was first discovered, people thought, “Oh, we found this protein, this gene that’s going to control obesity. It’s going to be amazing. We’ll target this clinically and we’ll be able to, you know, have this amazing diet that will solve the problem of obesity in the West.” Once they started looking into it, they found that actually, it doesn’t really make much sense why FTO would have such a dramatic effect because it didn’t seem to have any direct link with, you know, the sort of accumulation of fat on the body. So there’s a couple of different hypothesis about why it does this. And so one that you sort of linked to that it increases your feeling of hunger. So even when you’re full, you keep on eating and that leads to weight gain. And there’s also another one.

John: Is that like a lactone issue? Is that a hormonal thing or what? Is there a mechanism that they’ve…

Aaron: So that’s the problem. So they don’t really have a mechanism for it. That’s one of the hypothesis and that’s based on just where it sits in the genome, and what are the genes it may interact with. And it was sort of showing that, yeah, basically, after you’ve eaten, it was expressed in the brain after or following dietary restriction. So they’re kind of building this model up around it, but it’s never really been shown from, you know, bench to bedside that they can see this dramatic effect. We know it does have an association, but we don’t really know what’s driving it. And then as well as going with the general fat intake, this effect is actually thought to be worse when you have a high saturated fat content in your diet. So there’s a couple of snips where…so I’ll list. Just rs17817449.

John: And these will be in the show notes, too, for people listening.

Aaron: Yeah. And then G allele of that snip, and then 1121980. If you have the L allele of those snips, you’re likely to respond badly to a fat-heavy diet, and especially if it’s high in saturated fat. So it’s being shown that that effect occurs, but the actual mechanism for why it occurs, we really don’t have a clue about it.

John: Okay. So that sets the table for the final gene that we’re going to discuss which is apoE4. I want to spend a little bit of time on this, get the science perspective from you. I know you’ve dug deep into these studies and tried to come up with a nonpartisan sort of viewpoint on what’s going on here. I will tell you story. You may or may not know this, but when I was in Austin, I was eating a ton at this restaurant called the Casa de Luz, which was a phenomenal place. It’s like sort of a macrobiotic restaurant but the people that hang out there are really cool. Shout out to Casa de Luz. My buddy is there. And, you know, you’d run into people sometimes.

A lot of conversation goes on there. This guy that I would hang out with who is having lunch there all the time with me, he would say, “Well, you know, part of the reason why I’m on this very strict vegan diet is because I’ve discovered that I have apoE4. And I have this increased risk for Alzheimer’s disease as a result.” And so my understanding is that there’s this inflammatory response to saturated fat with those that carry apoE4. And this is how I’m going to change my risk. I’m going to eat, you know, a plant-based diet for my whole life.

Then you have vocal commentators, like people that we really love like Rhonda Patrick at FoundMyFitness who is super smart. And she’s publicly stated how she has one copy of an apoE4 gene and her focus seems to be a little different. Her focus seems to be hitting really hard, very beneficial omega-3 fatty acids. I know she’s a huge fan of…you know, she eats salmon roe all the time. And she’s very into micronutrients. But she’s certainly not eating a vegan diet. She’s certainly not eating a plant-based diet. So give us a tour. I mean, what do we know and what don’t we know about diet in apoE4?

Aaron: So I mean, the first bit is for people to understand what the apoE4 or the APOE type is. If you visit the website, we’ve got an easy way to figure out because it’s actually not just a single snip, it’s driven by two different snips, two different polymorphisms. And so you can go on and figure out what type of APOE you have. And there’s sort of a lot of debate about the various different types and how they interact. So apoE3 is the one that most of us will have. And that’s considered the neutral form. So apoE2 is considered one with an increased risk of cardiovascular issues.

John: Apoe2 is an increased risk of…? I always thought if you had if you had apoE2 you’re going to live forever.

Aaron: Well, because it’s kind of you don’t have the neurological issues, but you have some issues with cardiovascular but it’s in the situation of having a high and a high-fat diet.

John: Okay, I gotcha. Okay.

Aaron: So if you have apoE2, you don’t clear your diet, the fat as well. So you can avoid any issues with that by following your sort of traditional healthy diet and reducing your levels of fat.

John: All fat or…?

Aaron: Probably, I think in the study, the studies I’ve looked into it, it’s probably done at the level of general fat, but I could see it being a saturated fat issue rather than all fats in particular. Because it’s about the generation of blood clots and sort of deposition in your arteries and things. So it fits in with the traditional health story.

John: Right.

Aaron: But I think just by following a traditional healthy diet, or you know, any of these other diets out there, where you’re bringing your fat intake down relative to the general population, you’re going to see a beneficial effect.

John: For APOE…

Aaron: The fourth one or the next one that we get into is apoE4 and that’s the one that causes all the concern. Because if you have this, like John said earlier, you’re at much-increased risk of developing Alzheimer’s. You’re not going to get Alzheimer’s, you just have an increased risk of potentially developing it. And so obviously people see that and they think, “Well, I want to do whatever I can to avoid that happening in my later life.” And that’s where dietary adjustment comes in. And after all, a lot of it, like you said, that there’s basically conflicting dietary advice about that. So some people will go out and say that saturated fat, you want to avoid this because it has an inflammatory effect in your blood vessels and that leads to inflammatory aspects in the brain, and then you’re pushing yourself towards development of Alzheimer’s in that way.

John: Aaron, let me stop just really quick because I want to expand upon that a little bit. You hear all the time people saying an inflammatory response. And what I’ve learned just by doing my own research is that usually, an inflammatory response means an immune system response. Does that mean that you have increased cytokines? I mean, what does that inflammatory response look like in an apoE4 carrier as opposed to somebody who does not carry apoE4 to the extent we’re…?

Aaron: Technically, I guess it is an immune response because the activation of the inflammatory system is an activation of your immune system. It’s not in the same way that if you get an infection or a bug that you get this acute response where your body is really trying to shut this pathogen that’s invaded your body dies. It’s more of a sort of a low-level chronic effect. And things are released into the bloodstream that basically start triggering the immune cells to release these cytokines and chemokines that are normally released in response to an infection. So the levels are much lower, but they’re still present.

And it’s basically thought that if you have a low-level expression of these cytokines and chemokines, things that generate an immune response and inflammatory response over a very extended period of time, so your entire life that you’re going to lead to health effects down the line. So, you know, things that are associated with information. So all sorts of cardiovascular diseases, neurological diseases. Basically, I’ve read things that every disorder is a dysregulation of an inflammatory response in some way that you can tie in various cancers to it. So it’s kind of like a low-level chronic response. It’s not that you’re having these acute inflammatory things that you might associate with a disease. It’s just underlying inflammation occurring in your body at all time.

John: And this is inflammation that’s occurring in these genotypes based on their saturated fat intake as far as we know?

Aaron: Yeah. So saturated fat is one that is thought to be a big driver of this because it has a similar structure to some of the bacterial lipids that are present in bacteria. It’s not exactly the same, but it looks similar and it’s thought that in some way, you know, the immune system, things get a bit confused and triggers a response in relation to that. Unsaturated fat is thought to be particularly bad at that. But all fat to an extent. If you expect all fat even at higher levels will generate an immune response. So even if you take the best quality one on saturated fat that there is, but you take too much of it, you’re going to generate the immune response to it.

John: Especially in these carriers, though, correct?

Aaron: Yeah. Especially in these carriers.

John: Yeah. Because that’s one of the things when I’ve spoken to you and tried to get…lean on your expertise to sort of get a handle on where this conversation sits, you know, you’ll talk about you have one side of the coin that says, “Look, Alzheimer’s is diabetes three. It’s an obstruction to glucose metabolism in the brain. You have these…” I think they’re called beta-amyloid plaques that basically impede the metabolism of glucose in the brain, therefore, this is sort of like an insulin resistance thing.

And then on the flip side of the coin, you have, you know, the plant-based world, which says, “No, no, this is not an insulin resistance thing. This is the cause of endothelial, you know, heart issues over the course of many decades. And, you know, you can’t get proper blood flow to the brain, and therefore the brain can’t utilize glucose because you’ve basically ruined your endothelium, your blood vessels.” And where do you come down? I mean, what’s your take on that in the context of apoE4?

Aaron: So, I mean, the interesting thing is that the ketogenic diet has shown a beneficial effect in people who already have Alzheimer’s or a couple of other neurological disorders. So if you’re already in that stage, you know, maybe at an early stage and you switch onto a ketogenic diet, your decline is slowed quite considerably. You see quite a beneficial effect and a lot of neurological measures and sort of physiological measures. And so that’s why there’s a lot of science that supports the idea that maybe a ketogenic diet would be protective and preventing Alzheimer’s even developing.

But that bit has never been shown, I guess, in part, because we haven’t had the time to follow people through and show that it is protective. And it’s also a very difficult study, too, because it’s a long-term study. But then the counter-argument is that in those studies where they showed that the ketogenic diet was beneficial to people with Alzheimer’s, they didn’t show any difference between the various APOE types. So it didn’t seem to matter whether you had apoE2, 3, or 4. If you had Alzheimer’s, the ketogenic diet was beneficial, but it didn’t matter which type of APOE genotype that you had.

So you can kind of see that there is that argument that ketogenic diet is protective, but it doesn’t fit entirely with the APOE argument, and in that respect, that maybe the saturated fat argument is stronger, that it’s an inflammatory thing. It’s kind of it’s not really that well answered. So I know a lot of people are really into it. And it’s going to get a lot of more research done into it. But I would say for now, we don’t really know. And so making a big decision based on it, personally, I wouldn’t want to make a big decision based on my APOE genotype.

John: Sure. You want to look at the concert. But in the matrix we have in terms of, you know, one of the things that we do and I alluded to earlier in the show is that we’re trying to basically get a sense to then be confirmed by the client working with their physician and all that about what their foundational response is going to be to a diet that’s higher in fat. And I think it’s fair to say and correct me if I’m wrong, but I think it’s fair to say that when we’re dividing people into different diet types based on fat metabolism, apoE4 is going to push them in a direction that’s generally lower in fat in terms of their macros, in terms of our best guess. Yeah. It’s a controversial point and you’re going to get strong opinions on either side. But is it fair to say that that’s where we stand, that a ketogenic diet for an apoE4 genotype probably not maybe the best idea?

Aaron: Yeah, so that’s our take. And it’s based on not so much the beneficial ketogenic studies that have been shown because we didn’t see that association with the genotype. It’s more the other effects that APOE has on other lipid markers on the best. And so in that regard, we would push people towards a lower fat diet, which is also low…

John: Go ahead, sorry. Go ahead.

Aaron: And that lower fat diet would also have a lower proportion of saturated fat as well.

John: And that’s great, I think, point to make, too, which is that, “Look, we have this focus on the implications for Alzheimer’s disease, but you can have just run-of-the-mill cardiovascular issues.” If you’re of the opinion that your LDL particle, increased LDL particle increases risk for heart disease, and an apoE4 carrier is likely to have an increase in LDL particle as a result of eating saturated fat. You could argue that they should be eating a diet that’s lower in saturated fat independent of the issue with their cognitive abilities. Is that what you’re saying?

Aaron: Yeah, definitely. And I know people are going to want to go on. They’re going to read the research and they’re going to still want to go into a ketogenic diet based on that APOE genotype. If you do have that, I think a strong advice would be to switch the type of fats that are in that keto diet. You know, don’t completely avoid but reduce the saturated fat intake if you want to go that way. But we would personally say a ketogenic diet might not be the best option for you.

John: Yeah, and that’s the thing. So trying to get into ketosis without eating saturated fat. I mean, I feel like in that situation, you basically are replacing your morning coffee with a morning glass of olive oil, but it probably varies by individual. Well, I mean, how easy do you think it is to even get in the state of ketosis for most people without resorting to saturated fat?

Aaron: I mean, that’s a difficult question to answer. Saturated fat makes it easier because it’s more palatable. You know, it tastes nice. It’s easier to eat a larger amount of saturated fat than it is to eat the equivalent amount of olive oil. So I think you joked about someone drinking a glass of olive oil for breakfast, but I’ve read a few blog posts about people who weren’t responding to the ketogenic diet. They decided that it was the saturated fat aspect and have basically gone down that route of drinking raw olive oil. And there’s no way that that’s…

John: The truth, things are said and just, you know, as they say. I saw the same stuff and I was literally just mentioning that from conversations I’ve heard physicians who…exactly what you just said, which is, you know, they have patients who are doing a diet that’s high in saturated fat and ketosis, and they love the way they feel in ketosis and they want to stay in ketosis. But when they take out the saturated fat, they see these inflammatory markers go way down. So they literally are drinking olive oil.

Aaron: Yeah. I mean, I personally, I couldn’t follow that diet plan. But if you can and, you know, if you’re seeing the beneficial effects, then more power to you. But I think there’s not many people who could follow that.

John: I think the bottom line here is that if you’re going to be going on ketogenic diet, understand that it works for some people really well. There’s some places clinically where it’s indicated, like you mentioned, like children that have epilepsy. And, you know, there’s a lot of researchers out there seem to think that it’s a great solution for preventing cancer. But I think the bottom line is you just need to be working closely with the physician and having your blood work monitored while you’re on these diets. I mean, is that really the takeaway here? I mean, just test.

Aaron: I mean, for me, the sort of the important bits where if you’re going to consider it and you have any underlying health conditions, talk to your physician. So I know a lot of people are interested in because of the beneficial effects relating to type 2 diabetes. But if you’re on any medication for that, going on to a ketogenic diet, you need to talk to a physician first. And then the important bits are basically, yeah, when you go onto a ketogenic diet, you could probably…saturated fats are the most palatable, but possibly have a negative effect. You know, you don’t have to remove them entirely, but you can reduce them and replace them with mono and saturated fats. It won’t do any harm.

And if you can tolerate it, you’re going to possibly be having a beneficial effect. And then, like you say, the important bit is just to keep an eye out on your blood work as you’re going on to the ketogenic diet. And at least for a couple of months while your body transitions until you get to a sort of steady state. And you can sort of say, “This is what my new blood work looks like.” And then once you’re actually in there, you need to sort of be checking that you’re actually in that ketogenic state as well. And that’s something you don’t necessarily need to do with your physician. You can do that at home. But making sure that you’re in that ketogenic state, it’s really important as well.

John: Yeah, it’s the ketones that are protective. It’s not the weight loss or, you know, eating a diet that’s higher in fat. It’s the fact that your body is generating this, like you called it, an antioxidant from within the body. Well, this has been a great conversation, Aaron. I think, you know, first episode of “The GeneFood Podcast,” I’d call it a success, and I really appreciate your expertise as always, and…

Aaron: Yeah, it’s been a pleasure.

John: It’s been fun. I’m sure we’re going to do it again soon. Enjoy England and I will see you on Slack, my friend.

Aaron: See you later.

John: “The GeneFood Podcast” is our attempt to synthesize the latest developments in the fields of genetics, nutrition, and medicine, and offer you practical tips and stories you can use in your own unique health journey. If you enjoyed this podcast, you can find more information online at

John O'Connor

John O'Connor is the founder of Gene Food, a nutrigenomic startup helping people all over the world personalize nutrition. John is the host of the Gene Food Podcast and a health coach trained at Duke's Integrative Medicine Program. Read his full bio here.

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  1. Fascinating stuff, thank you for the comment Micheal. The parasite / Alzheimer’s protective angle is not one we have researched, but we will add it to the list for a blog post in the near future. Thank you for putting these issues on our radar.

  2. Heather Rae, INHC says:

    Low level chronic inflammation is root cause of cellular dysfunction/illness, a reason to look at ability clear hydroxyl radicals, peroxynitrite, and overall function of detoxification pathways. And … what *is* the role of microbiome, pre/pro-biotics …?

  3. Heather Rae, INHC says:

    Thank you for doing the podcasts. I look forward to more! I am a certified functional genetic analyst, and integrative nutrition coach for which bio-indivduality is the over-arching theme. I live between VietNam and US (northeast) and I am interested in race, geography, sunlight, heat effects on nutri-genomics. I have done a Thermo Fisher (NGRI) DNA test – we load it into analytical software with other test results and sign/symptom questionaire. I have APoE4 (homozygous) … this conversation is personal and professional.

    • Hey Taylor,

      Thanks for listening. We have submitted the feed to iTunes and Google podcasts, just waiting for the show to be approved. So, yes, subscribing via Google podcasts will be possible in short order.

  4. Markus says:

    Years ago when I was eating a low-carb/ketogenic paleo diet, my cholesterol skyrocketed to >400 mg/dl. In addition, I had poor lipid metabolism and mitochondrial function according to a Genova NutrEval-analysis.

    Later on I discovered that I’m APOE4/4, heterozygous FTO and PPARA.

    Now, eating a more plant-based, higher carbohydrate diet, my cholesterol is 150 and my mitochondrial markers have improved significantly.

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