Danny Jones Podcast - #335 - Carnivore MD vs Harvard Heart Doctor: Seed Oils are Actually GOOD For You | Paul Saladino & Nick Norwitz
Aired: 2025-09-26
Duration: 03:31:03


=== Breaking News: Seed Oils Are Good (03:32) ===

[00:00:07]  Breaking news seed oils are good for you.
[00:00:10]  And we're going to talk about that today.
[00:00:12]  So, first of all, why don't you guys, for people who haven't seen your interview and for people that aren't familiar with who you are, Paul, why don't you guys introduce yourselves, give yourself a quick background?
[00:00:19]  You want to go first?
[00:00:20]  Sure.
[00:00:21]  My name is Nick Norwitz.
[00:00:23]  I'm an MD, PhD fresh out of med school, actually, like 10 weeks since graduation at Harvard Med.
[00:00:30]  And And my background is I got into speaking about metabolic health through a personal journey with inflammatory bowel disease at the end of college, in grad school, and before med school, that really got me curious about the distinction between what we do in conventional medicine and what is, quote,
[00:00:56]  evidence based care and what is actually the best care based on human physiology and how we can.
[00:01:06]  Bridge the gap between metabolism, physiology, science, and what's working for people and modern medicine to actually just like help improve population metabolic health, which I don't think is controversial to say is not going in a positive direction right now.
[00:01:22]  And you also did the famous Oreo versus statin thing we talked about.
[00:01:25]  I will never live that down.
[00:01:27]  You did an experiment on yourself where you took statins for 30 days and then Oreos for 30 days, and Oreos dropped your cholesterol.
[00:01:34]  So Oreos, 16 days, statins for six weeks.
[00:01:37]  This is actually like a good case in point because.
[00:01:40]  One of the things that I find quite interesting is what gets talked about and what doesn't.
[00:01:47]  We'll get into some examples of research and what gets suppressed is a strong word, but just what gets amplified and what doesn't based on the incentive structure.
[00:01:54]  So I was doing research in an area around lipids and cholesterol that I thought was fascinating.
[00:02:02]  And I had this new tool at my disposal, social media, which I don't have multi million dollars to do large trials, but I do have.
[00:02:13]  Some tools, which are social media and then useful brands.
[00:02:16]  So, in order to amplify discussion around this area of research, we may or may not get into it.
[00:02:23]  I basically formulated an experiment where I would test the cholesterol lowering potential of Oreo cookies versus standard of care statin therapy.
[00:02:31]  So, it was originally going to be two weeks of Oreo cookies, then a washout period, and then high dose statin therapy.
[00:02:38]  So, 20 MIGs of Crestor.
[00:02:40]  And I know how to dot my I's and cross my T's.
[00:02:41]  So, I got an institutional review board letter exemption from Harvard, have my PCP ordering all my labs into my electronic medical record.
[00:02:49]  Had a career lipidologist, William Cromwell, helping me to design the study and write the paper.
[00:02:56]  And then we executed it.
[00:02:58]  And as predicted a priori, the Oreos lowered my cholesterol by more than twice as much as the statin in about a third the time.
[00:03:07]  And for me, that was a social experiment more than anything because it was clearly engineered to be clickbait, obviously.
[00:03:15]  And it's like, how can I use The tools provided by media and understand incentive destruction of people's emotions to start a discussion around something that actually has a lot of nuance.
[00:03:27]  So, I think people in academia try to be idealistic and stay above engagement tactics and then end up kind of bitter and salty that they don't have a seat at the table and influence.

=== The Unfortunate Residency Experience (03:35) ===

[00:03:39]  And I think in the world we live in now, where there is clearly an uncomfortable collision, incursion event between academia, conventional medicine, And the general public because of access to information and social media.
[00:03:54]  That's something we need to understand and play with practically, just because it's the ecosystem we now live in.
[00:04:05]  And we have to do it responsibly and draw our own lines.
[00:04:07]  But that was me just kind of playing with what kind of reaction can I get and how can I actually leverage this to amplify nuanced discussions and push forward research.
[00:04:17]  I will tell you it's been a success.
[00:04:19]  I want to get off this particular soapbox.
[00:04:21]  We can return to it if you want.
[00:04:22]  But I have reason to believe that it was a success.
[00:04:24]  Yeah, we'll definitely get back to it.
[00:04:26]  But I want to hear Paul's background.
[00:04:29]  I'm a traditionally trained medical doctor.
[00:04:31]  I was a physician assistant in cardiology before medical school.
[00:04:34]  Then I went to medical school at the University of Arizona.
[00:04:36]  Did my residency, unfortunately, at the University of Washington.
[00:04:39]  Not that the University of Washington is unfortunate, but the fact that I did a residency is unfortunate.
[00:04:44]  Why was that unfortunate?
[00:04:46]  You go deeper down the rabbit hole into a medical system that you realize is broken and doesn't really serve people.
[00:04:52]  So when I was in medical school, I really liked internal medicine, but I didn't see it actually getting to the root cause of illness for humans.
[00:05:00]  My dad is an internist.
[00:05:01]  I didn't really want to repeat that.
[00:05:03]  I ended up going into psychiatry because I got really interested in human story, humanity, suicidality, neuroinflammation in the brain, and connections with the things that we eat is very fascinating.
[00:05:13]  And, you know, you realize pretty quickly in your residency in psychiatry that it's all kind of a farce, that the drugs we're using in psychiatry.
[00:05:20]  I never practiced psychiatry.
[00:05:21]  I've since left and don't consider myself in any way associated with psychiatry, but the drugs used in psychiatry are anachronisms.
[00:05:27]  And, you know, psychiatry is kind of like 50 years behind the rest of medicine.
[00:05:30]  So it was an unfortunate thing that I did four years of that, but I suppose it shows you from the inside.
[00:05:36]  In some ways, how medicine is broken with regard to that individual specialty and other specialties.
[00:05:41]  So, more broadly, what's interesting to me, similar to Nick, is human health, how we promote it and how we return to it when we lose it.
[00:05:50]  And I've always been fascinated by food and environment as a really, really powerful lever that gets overlooked by Western medicine.
[00:05:58]  In medical school, I had perhaps 45 minutes in four years and then zero time in four years of residency of nutrition or nutritional biochemistry or any sort of thinking about these things, nothing beyond like a gluten lecture.
[00:06:11]  For formal celiac disease and maybe some nutritional biochemistry around the Krebs cycle.
[00:06:16]  But beyond that, there's nothing taught in most medical schools that I'm aware of.
[00:06:20]  And in my sort of life post medicine, in using my credentials to teach online through social media for the last six plus years, I've seen hundreds, if not thousands, of people improve or reverse diseases that I was consistently shown or taught in Western medicine were incurable.
[00:06:40]  Lots of autoimmune conditions.
[00:06:41]  I mean, Nick had ulcerative colitis, I believe.
[00:06:44]  I've seen.
[00:06:45]  So many people reverse ulcerative colitis with dietary changes, eczema that I had personally.
[00:06:50]  Oh, wow.
[00:06:50]  Yeah, yeah, really severe eczema.
[00:06:52]  I had the whole atopic triad with asthma, eczema, and probably some allergic symptoms.
[00:06:58]  I mean, I've seen people reverse depression and ocular autoimmune conditions, thyroid conditions, inflammatory bowel conditions, arthritis, all kinds of things improve when people do a variety of intentional dietary choices and lifestyle choices.

=== Managing Flares During Commencement (04:18) ===

[00:07:15]  That's powerful, right?
[00:07:17]  That you can be taught in Western medicine.
[00:07:19]  This very clear decision tree.
[00:07:22]  If the patient has X, you give them Y medication, but it's really never this option that you're given, or you're never really challenged in medical school or residency to think, like, what's at the root cause here?
[00:07:31]  And could what someone is putting in their mouth or the way they're living with it from a circadian or light perspective or other lifestyle perspectives affect these things directly?
[00:07:40]  And so that's been really eye opening for me.
[00:07:41]  And it's kind of cool to talk about.
[00:07:42]  I mean, I'm really fortunate that almost every day now when I'm in the United States, I get people that I just meet in life who tell me their story.
[00:07:50]  Yeah.
[00:07:50]  And that means a lot.
[00:07:51]  I mean, I was at the gym yesterday and you hear stories.
[00:07:53]  You know, people come up and they say, oh, just changing my diet really improved their life.
[00:07:58]  That's cool.
[00:07:59]  There hasn't been many things that I've experimented with in my life that have really moved the needle as much as being like really, really diligent about my diet and cutting out carbs and like being super keto.
[00:08:09]  I've done it for long stents and I always feel the best.
[00:08:14]  Like, bar none compared to anything, that is like the thing that makes my body function the best.
[00:08:20]  But like the problem for me is I have three kids.
[00:08:23]  And I gotta like take care of them.
[00:08:25]  And it's almost like for me, it's just so hard to manage my life and maintain that diet and live in a house with my wife and three kids.
[00:08:32]  So I gotta make compromises somewhere.
[00:08:34]  And then, you know, that's why I'm popping nicotine pouches all day.
[00:08:38]  I wanna double click on something Paul said just to kind of give a little bit more form to something I said about incentive structures.
[00:08:46]  So you mentioned I had ulcerative colitis.
[00:08:48]  And I ended up trying a bunch of different diets for it.
[00:08:51]  Ended up at the bottom of my to try list was keto.
[00:08:55]  And then it worked like a charm.
[00:08:56]  Why was keto at the bottom of your to do list?
[00:08:59]  I mean, think about the ecosystem in which I grew up.
[00:09:01]  I had a pretty conventional mindset about what keto was.
[00:09:07]  Let's just say a negative mindset.
[00:09:08]  And when I tried it, it was more, I have nothing left to lose.
[00:09:14]  That was, you know, what would be the harm about trying this next diet?
[00:09:18]  So, what was the first thing you tried?
[00:09:20]  I went, what was it?
[00:09:22]  Like standard Mediterranean.
[00:09:24]  I did like low FODMAP, specific carbohydrate.
[00:09:26]  Those are kind of the two that.
[00:09:28]  Were there any drugs, pharmaceutical drugs that you tried at all?
[00:09:30]  I was on various glucocorticoids.
[00:09:34]  I was on some first line therapies, misalamine, some biologics.
[00:09:43]  Yeah, no, it was not fun.
[00:09:44]  In fact, if you, one of my least favorite pictures, but it circulated quite a lot, is at commencement.
[00:09:50]  So, my college commencement, I was the valedictory speaker, which was fun.
[00:09:55]  But there's this picture that goes around of me at the podium.
[00:09:59]  In front of 11,000 people.
[00:10:00]  And my face is actually Cushingoid.
[00:10:02]  Because I was taking Stewart at the time.
[00:10:03]  Nobody really knew that.
[00:10:04]  But I was actually like an inactive flare.
[00:10:06]  So my life, on the surface, it was nice.
[00:10:09]  I had a lot of nice things on paper, but it was falling apart under the scenes.
[00:10:13]  Actually, like leading up to that commencement, I was in a flare and I wanted to be the speaker because it's a fun opportunity.
[00:10:19]  But I was, pardon the pun, shitting my pants scared that I would actually shit my pants in front of 11,000 people.
[00:10:26]  Because you're going to get like an IBD flare.
[00:10:28]  It's not something you can just like hold in.
[00:10:29]  You will run red.
[00:10:31]  If the time strikes.
[00:10:32]  So, that I think was second to my colonoscopies, my first extended fast with, now I'm going to sound like an idiot, but a college cafeteria coffee enema to make sure I was emptied before the speech.
[00:10:48]  So, even then, I had a little bit of grumble, but I was terrified, anxious.
[00:10:53]  And I raised this because, like, if you were there, everybody says that I was composed, that I didn't show it.
[00:10:59]  But, like, underneath, My life was a wreck.
[00:11:02]  And what I came to find after I tried XYZ with diet and something worked for me, and in this case, a ketogenic diet, just to describe what that was like for me, about within a week of starting it, my energy was back, my flare symptoms had subsided, and then my next colonoscopy, there was no disease activity, like biopsy proven remission.
[00:11:23]  Wow.
[00:11:24]  Which was interesting.
[00:11:25]  And what I came to learn, as Paul pointed out, is that my story was not at all unique.

=== Corporate Narratives vs Physiology (05:39) ===

[00:11:34]  That there's this pattern motif of people struggling and becoming desperate and then trying something that is not within the mainstream and that it works.
[00:11:40]  And then you're left doing a double take, like, well, what's up?
[00:11:42]  So I still can't cite to you a randomized controlled trial explaining why a ketogenic diet would work or showing that it does work.
[00:11:52]  So it can't be recommended as standard of care.
[00:11:55]  And you have to question like, you know, what are the incentive structures that get certain studies done to allow them to become standard of care?
[00:12:03]  It's not that people are being malicious.
[00:12:05]  It's just that who's going to fund the like super rigorous $10 million RCA?
[00:12:08]  Companies that have lots of money to make, right?
[00:12:11]  Well, it's never been done.
[00:12:13]  And so.
[00:12:14]  That's just how our system is built.
[00:12:16]  Again, not pointing fingers at doctors or even pharma.
[00:12:20]  It's just this is the business model.
[00:12:22]  And if this is the business model, there are a lot of solutions that are physiology first and might actually work the best that are not getting explored and the types of studies that are needed to make them standard of care aren't going to be done.
[00:12:34]  And so what you could end up with, hypothetically, turns out to be the reality, is a sick population that gets sicker.
[00:12:42]  Because evidence based care does not mean best care.
[00:12:47]  Did you know that?
[00:12:49]  Food, processed food companies spend $11 billion on research a year in the NIH into nutrition.
[00:12:56]  And the NIH, last I checked, spends about a billion, has about a billion dollar budget.
[00:13:00]  So the food industry, and this is not kale farmers of America or beef farmers of America or egg farmers, this is not unprocessed food.
[00:13:07]  This is processed food companies.
[00:13:09]  10 to 11x what the NIH budget for nutrition studies is.
[00:13:13]  So it's, I mean, yeah.
[00:13:15]  You go down.
[00:13:15]  Not only that, but they're hiring people from the NIH and the FDA to work in their companies.
[00:13:19]  And they have.
[00:13:20]  Yes, they do that after the people leave, right?
[00:13:23]  There is a revolving door.
[00:13:25]  And for 70, 80 years, industry has had its fingers in academia and in policymaking.
[00:13:34]  I mean, you know, the influence of what we think of as healthy or the food pyramid or the whole ethos, the whole zeitgeist of what we've thought of as healthy as westernized Americans, which is kind of the context that we all live in, has been influenced by companies for 80 years.
[00:13:51]  I mean, this is why there is a.
[00:13:54]  Almost indelible mark on our society now that meat and saturated fat, things that Nick and I both eat pretty moderate amounts of, pretty good amounts of, are harmful for you.
[00:14:03]  It's very hard to erase that sort of programming that we've had since Ansel Keyes, since the 1950s.
[00:14:10]  By the 1950s, that's when R.J. Reynolds bought all these food companies, right?
[00:14:15]  Yeah.
[00:14:18]  1.9 billion.
[00:14:19]  NIH spent approximately 1.9 billion on nutrition research in the fiscal year of 2019.
[00:14:24]  That's insane.
[00:14:26]  And that pales in comparison to what private companies will spend.
[00:14:29]  I mean, Coca Cola itself, I believe between 2008 and 2016, funded 379 give or take studies on sort of food.
[00:14:40]  And those studies are generally aimed at advancing the narrative that weight loss is not about the quality of food you eat, it's about how much food you eat.
[00:14:48]  So it's kind of advancing the calories narrative.
[00:14:50]  It's okay to drink soda or eat candy as long as you exercise more or limit calories on the back end.
[00:14:56]  In 2015, there was, I think, an expose in the New York Times about something called the Global Energy Balance Network.
[00:15:02]  Have you heard of this?
[00:15:03]  No.
[00:15:03]  Oh, you've heard of it?
[00:15:05]  It was funded by Coca Cola.
[00:15:06]  So, this term energy balance gets thrown down a lot today by very, I think, preeminent people in the health and nutrition space.
[00:15:14]  They'll say, it doesn't matter what you eat, just get enough protein and be in energy balance.
[00:15:20]  But the global energy balance, I think this is very misleading.
[00:15:23]  It's kind of like food quality doesn't matter, right?
[00:15:25]  Global Energy Balance Network is funded by Coca Cola and they try and advance this notion again.
[00:15:30]  It doesn't matter what you eat as long as you are in energy balance.
[00:15:33]  It's again calories forward without any attention to food quality.
[00:15:37]  Nick's story, my story, the story of thousands of people that I've interacted with personally or hundreds of thousands that have interacted with virtually tell a different story, right?
[00:15:46]  It's all about food quality.
[00:15:48]  You've seen this too, right?
[00:15:48]  It's not just about how many calories you eat.
[00:15:51]  Right.
[00:15:51]  It's about the quality of those calories.
[00:15:53]  But there's something sinister going on beneath the surface.
[00:15:56]  Right.
[00:15:56]  Yeah.
[00:15:56]  Global Energy Balance Network.
[00:15:58]  Hey guys, if you're not already subscribed, please hammer the subscribe button below and hit the like button on the video.
[00:16:03]  Back to the show.
[00:16:04]  I will go a step further and say, oh, Calories don't cause obesity.
[00:16:10]  I agree with you.
[00:16:10]  And I want to unpack that a little bit because I know where people's minds go and they have a visceral reaction.
[00:16:15]  But I'm not saying calories don't matter.
[00:16:18]  I am not saying that.
[00:16:19]  When you take the energy balance equation calories in minus calories out equals weight change, what is that?
[00:16:25]  That is a post hoc description of what happened.
[00:16:27]  It is not in any way, shape, or form a biological explanation for obesity.
[00:16:32]  So I'm not saying calories in, calories out is a wrong model for obesity.
[00:16:35]  I'm saying it's not a model at all.
[00:16:37]  It doesn't give you a physiologic explanation.
[00:16:40]  And The narrative around calories, I think it's one of those things where, with enough exposure, just the mere exposure effect, you start to internalize a message and then thinking gets shut down.
[00:16:52]  Rather than thinking about the complex multifactorial cascade of factors that goes into determining what is ultimately the dependent variable, not the independent variable, the dependent variable, calories, it's easy to sweep it under the rug.
[00:17:09]  I try not to ascribe intention to these things.

=== GLP-1 Trials and Metabolic Impact (15:28) ===

[00:17:13]  Maybe there is intention.
[00:17:14]  I mean, there are incentive structures, but I like to frame it as incentive structures, as like, you know, why is or isn't something getting talked about without implying an individual person is sinister per se?
[00:17:28]  A good example I'll bring up that really I found curious is this I mentioned it to you earlier the statins GLP 1 paper.
[00:17:38]  So the two biggest drugs, probably in history, or to be the biggest drug in history, are statins.
[00:17:47]  You know, trillion dollar market over time, something like 20 billion.
[00:17:49]  When did statins first come on the market?
[00:17:52]  Oh, I don't know.
[00:17:53]  Mid 1900s, probably.
[00:17:55]  Really?
[00:17:55]  Yeah, what was the first one?
[00:17:57]  Was it Steve?
[00:17:58]  This might be a Steve question.
[00:17:59]  I'm not sure.
[00:18:01]  But definitely one of the biggest, most prescribed drugs.
[00:18:03]  I think one in four people over 40 are taking it for like secondary.
[00:18:07]  Yeah, something like that.
[00:18:08]  So actually, that was in the paper I can share the reference.
[00:18:11]  But so anyway, this paper came out in Cell Metabolism last year.
[00:18:15]  Now, let's be clear Cell Metabolism is not a dinky journal.
[00:18:19]  It's a highly regarded scientific journal.
[00:18:21]  1987.
[00:18:22]  With lovastatin, yeah.
[00:18:24]  And this was a human trial where they effectively showed that statins chop GLP 1 levels in humans in half.
[00:18:34]  Okay, what's GLP?
[00:18:35]  So GLP 1 is the hormone that drugs like Ozempic and Wagovi try to mimic.
[00:18:40]  So now there's this huge drug market about not exactly biomimicking GLP 1 because they're given at super physiologic doses.
[00:18:47]  That's true.
[00:18:48]  But GLP 1 is a hormone that is.
[00:18:52]  Depleted in a lot of metabolic health conditions.
[00:18:55]  So, you know, insulin resistance related conditions, diabetes, obesity, PCOS, et cetera, there tends to be a GLP 1 deficiency, has to do with inflammation in the gut, decreased GLP 1 production in the gut.
[00:19:08]  So, the hormones produced in the gut, it's called incremental hormone, and also just inflammatory cells in the gut have their own GLP 1 receptors.
[00:19:14]  So, they'll sop up the GLP 1 and make it less bioavailable.
[00:19:18]  So, long story short, low GLP 1 levels are one of the markers for various metabolic diseases.
[00:19:24]  Right now, we're treating a lot of people with GLP 1 receptor agonists, which are effective for weight loss.
[00:19:29]  And I'm not against these drugs.
[00:19:31]  Let's be clear, I'm not.
[00:19:32]  However.
[00:19:33]  So, Ozempic is a receptor agonist?
[00:19:35]  For GLP 1, yeah.
[00:19:37]  I find it interesting that there are human data in a prominent journal showing that statins, a very common drug, deplete levels of GLP 1, which is a hormone and related to a blockbuster group of drugs.
[00:19:53]  It cuts the levels in half.
[00:19:54]  Steve, if you can bring it up, it'll be saying statin GLP 1 is the image or figure 1H.
[00:20:00]  It's a blue line and a red line.
[00:20:01]  Yeah, that one.
[00:20:02]  So this was from a human trial, a 16 week human trial with, I think it was 20 megs of Torvastatin versus control, if it's popping up.
[00:20:10]  Those are the results.
[00:20:12]  The red line is statin.
[00:20:14]  That's not subtle.
[00:20:16]  It's not subtle at all.
[00:20:19]  What is the blue line?
[00:20:20]  The blue line is the control group.
[00:20:21]  Okay, gotcha.
[00:20:22]  So it was a placebo controlled trial.
[00:20:23]  And basically, it's showing statins chopped GLP 1 levels in half.
[00:20:27]  And this was also associated with worse glycemic control, so an increase in average blood sugar, HbA1c, increase in insulin, and increase in insulin resistance, which are all kind of known effects.
[00:20:38]  But what bothers me about this graph.
[00:20:43]  Is not the effect.
[00:20:45]  I'm not concluding from this, no, you can't take statins or you, you know, GLP 1s are, you know, a hack.
[00:20:53]  I'm just perturbed that this comes out about a year and a half ago in a major journal.
[00:21:00]  And there is not only no headlines featuring it, which, you know, statins cut GLP 1 levels in humans by half should be a headline.
[00:21:07]  I bet you if you replace the word statin with steak, that would have been a headline everywhere.
[00:21:11]  Do you agree?
[00:21:12]  Or butter.
[00:21:13]  I think there's selective reporting.
[00:21:15]  And then not only is it not.
[00:21:17]  Presented in the media, but physicians don't talk about it.
[00:21:20]  After I read this paper the same day, I polled 12 doctors in the area to ask them about this relationship.
[00:21:25]  None of them knew about it.
[00:21:28]  And this was in the Harvard area, presumably some pretty well educated people who are like, why isn't this even in the realm of awareness?
[00:21:37]  I don't think that physicians are hiding this information from people, but at the end of the day, if you're going to start a medication, you deserve to have some informed consent.
[00:21:46]  This is the kind of thing where it's like, I just think the patient should know.
[00:21:50]  In the decision making process, it doesn't mean don't take either medication.
[00:21:53]  Heck, if it works best for you, take both.
[00:21:55]  You should not take it.
[00:21:56]  You should know what's going on.
[00:21:57]  This kind of information should be provided to patients or at least be in the awareness of their physicians.
[00:22:02]  Again, not saying anybody's sinister, but major paper, human trial, this is the result.
[00:22:09]  Like, how is this not talked about?
[00:22:10]  Oh, and I'll add the mechanism they found out, which is quite interesting, is that the statin altered the gut microbiome and altered levels of a bacteria that generates what are called certain secondary bile acids.
[00:22:23]  So, Primary bile acids can be metabolized by bacteria into secondary bile acids, and these have numerous effects throughout the body.
[00:22:32]  So they get into circulation, they can impact the brain, muscles, fat, and one is called UDCA.
[00:22:40]  It actually can be prescribed as a drug.
[00:22:42]  And what they found in humans, again, is just giving back the UDCA basically reversed the effect.
[00:22:49]  So what I'm saying here is like, okay, there's a negative effect, and actually there's a solution that has been demonstrated in humans in a major journal.
[00:22:55]  So you could use this.
[00:22:58]  In your patient population to improve care, maybe attenuate some of the negative effects of statins on GLP 1 and insulin resistance.
[00:23:05]  But because we don't focus on metabolism and physiology, this gets entirely ignored.
[00:23:11]  And that's just one small example about how I think dysfunctional norms and incentive structures lead to worse care.
[00:23:20]  Again, there's a broader context here that I think we should talk about.
[00:23:23]  You mentioned this in the beginning with your Oreo experiment, but I'm not sure everyone knows the whole story.
[00:23:27]  Your LDL went up.
[00:23:30]  Quite high when you went keto.
[00:23:32]  This is part of.
[00:23:32]  That happened to me too, yeah.
[00:23:33]  Right.
[00:23:34]  This is part of common, not always, but commonly in human physiology.
[00:23:39]  It happened to me a lot when I was strict carnivore.
[00:23:40]  Lean, mass, hyper respiratory.
[00:23:41]  I'll just interrupt you for a sec.
[00:23:42]  I was listening to your pod with Gary Brecca this morning, and you said your LDL was 125, right?
[00:23:49]  Now.
[00:23:49]  And he's like, oh, that's high.
[00:23:50]  And you're like, yeah, that's high.
[00:23:51]  You know what mine is?
[00:23:52]  Mine's like 250.
[00:23:53]  Mine was as high as 500.
[00:23:55]  Whoa.
[00:23:55]  574.
[00:23:56]  Yeah.
[00:23:56]  So this is my last.
[00:23:58]  In the setting of.
[00:24:00]  I'm not, to be clear, I'm not saying this is fine for all people.
[00:24:03]  We're dick measuring our LDL levels.
[00:24:04]  We can talk about it later.
[00:24:06]  It's now open information.
[00:24:07]  Actually, it was Mark Hyman and Andrew Huberman talking about my cholesterol when we were at his pause.
[00:24:11]  I'm like, all right, this is how you introduced me to the world.
[00:24:13]  Yeah.
[00:24:13]  But my cholesterol, we can talk about it.
[00:24:14]  There's more nuance there.
[00:24:15]  I'm not, well, let me stop interrupting you.
[00:24:18]  We'll go back to it.
[00:24:19]  Go ahead.
[00:24:19]  It's just interesting because, in this context, and Nick has done a lot of research here, which is really interesting, and we should talk about it later in the podcast.
[00:24:26]  I think we've all experienced this sort of lean mass hyper responder phenotype.
[00:24:29]  And basically, the idea, as I see it, and Nick can add context to this as he sees fit, is that in some individuals, particularly individuals who are lean and fit, when you Move over to fat based metabolism in a ketogenic type context, there are more energy moving molecules in the blood, and that LDL actually moves triglycerides and cholesterol.
[00:24:49]  And so it's not uncommon in human physiology to see LDL go up as a physiologic, perhaps not pathologic response in a ketogenic diet.
[00:24:57]  Whether or not this represents an increase in cardiovascular disease risk is the main question.
[00:25:01]  And the central question here, which is something that I'm thinking of as you're describing this paper and the response to it or lack of response to it in the general sort of media space, is that ApoB and LDL, You know, ApoB containing lipoproteins are, that's a broader term for LDL and other lipoproteins, which are broadly felt to be atherogenic.
[00:25:21]  These are sacrosanct in Western medicine.
[00:25:23]  And anything that challenges that hypothesis, this lipid hypothesis, is just disregarded or is not felt to be valid and is kind of cast out to the side.
[00:25:33]  So it's quite interesting because that's a very central theme.
[00:25:36]  If we talk about, we'll talk about seed oils in this podcast, and it comes back to that same idea in many ways.
[00:25:41]  ApoB, I see as like a linchpin in Western medicine.
[00:25:44]  And, um, Having my LDL go up super high and then having it, I had a similar response to Nick's.
[00:25:51]  I mean, I eat carbohydrates now.
[00:25:53]  I don't eat carbs.
[00:25:54]  When you mentioned that you like fruit, I eat fruit and honey and milk.
[00:25:58]  So, milk has lactose, but you're not eating bowls of cereal.
[00:26:01]  I don't eat bowls of cereal or rice or oats or pasta.
[00:26:04]  And there's different responses to different grains, perhaps based on their processing.
[00:26:08]  So, and processed carbohydrates, processed sugars probably react differently in the human gut than fruits and fruit juice.
[00:26:14]  But so I include carbohydrates in my diet now.
[00:26:17]  I found for myself after a year and a half of long term.
[00:26:21]  Strict carnivore, so meat and organs and fat, that my eczema got better, but my electrolytes did not stay within normal limits.
[00:26:29]  It turns out that there is a need for insulin signaling at the level of the kidney to resorb certain electrolyte molecules.
[00:26:36]  And that a lot of people, not everyone, some people probably do better with long term strict keto than others.
[00:26:42]  I had massive electrolyte imbalances that were resolved when I added carbohydrates back.
[00:26:48]  My immune conditions did not come back with the addition of fruit and squash and honey.
[00:26:52]  But I know that for me, if I include things like tomato, for instance, which is technically a fruit, but within this nightshade family, that I will get a recurrence of eczema.
[00:27:00]  So, some things.
[00:27:01]  Interesting.
[00:27:02]  I mean, this is what's interesting and what I've kind of seen over the years is that for people who have autoimmune conditions, inflammatory bowel diseases, eczema, skin conditions, psoriasis, there are some foods that are widely considered to be healthy that can be triggers for some people.
[00:27:16]  And that's just something that I was never taught in medical school.
[00:27:19]  And it's probably not something that everyone needs to worry about.
[00:27:21]  But if people have unresolved autoimmune conditions, it's something to be aware of.
[00:27:25]  More broadly, I think the LDL conversation is that in Nick's case, and again, I'll let him add context here if I'm leaving anything out, and in my case also, strict keto leads to a lean mass hyper responder, quote, rise in LDL.
[00:27:40]  We can talk about cardiovascular implications for that later in the podcast, but the addition of carbohydrates, whether it's fruit and honey and squash or Oreos, then changes your physiology.
[00:27:49]  You're no longer in ketosis, and the LDL can come down.
[00:27:51]  So that, That just so people understand that that's probably what happened to Nick with his Oreos in the beginning, which is this really sort of viral illustration of the fact that you can lower LDL just by changing your macronutrient ratios.
[00:28:05]  And the bigger point that I just wanted to add here is that I see so many of these health discussions revolve around ApoB containing lipoproteins and LDL, and that that's often where they get stuck because a lot of people that I've experienced the stories of get healthier, right?
[00:28:23]  They make changes.
[00:28:24]  Do meat plus fruit and squash, or they do strict meat, or they do keto, their autoimmune condition resolves.
[00:28:29]  They feel better, less brain fog, better libido, fertility, and they go to their doctor, and the doctor says, Oh, your LDL is sky high.
[00:28:36]  Yes, it's exactly what happened to me.
[00:28:37]  Whatever you're doing, stop it now.
[00:28:38]  And you say, But wait, I just told you that I feel the best I ever have in my life.
[00:28:41]  So, this Apo B sort of linchpin is really critical to unpack, and what we know and don't know and what's been assumed about it is really interesting because.
[00:28:50]  Can I just.
[00:28:51]  Well, I want to say, because it's interesting what you said about electrolytes, because the first time I ever did keto, Was under the guidance of Dom D'Agostino.
[00:29:00]  He was the one who kind of coached me through it all and introduced me to everything.
[00:29:04]  And what I noticed was after the first few weeks of doing it, I would, on a podcast, I would notice I'm like falling asleep an hour into it.
[00:29:12]  Like I had no energy.
[00:29:13]  Like I just couldn't, I just couldn't do it.
[00:29:16]  And he was brought up to me, he's like, How much water and electrolytes are you drinking?
[00:29:20]  I'm like, None.
[00:29:21]  He's like, That's why.
[00:29:22]  He's like, You just start pounding electrolytes.
[00:29:24]  And I started doing that and it like changed the game.
[00:29:27]  I was like, felt way, way better.
[00:29:29]  Like it was total night and day.
[00:29:31]  So it's interesting that I would have never known if it wasn't for Dom that you had to get more electrolytes and more salt in your system and drink way more water if you're not eating carbs.
[00:29:42]  I just want to double click on something that Paul said.
[00:29:47]  I don't know why I said Tom.
[00:29:50]  About this LDL and Applebee boogeyman, because I want to be very careful and say that I'm not condoning that my LDL is safe generally.
[00:30:02]  In fact, in most people, it's probably not.
[00:30:04]  But there's the curiosity that gets peaked or should be peaked when you have a patient who has normal LDL and then their LDL quintuples with a dietary shift.
[00:30:19]  Like, this doesn't happen.
[00:30:21]  This is not known to happen.
[00:30:22]  In fact, familial hypercholesterolemia, which you can tell it's a genetic disease, familial inherited, is now, I believe, diagnosed based on just like a threshold blood lipid level.
[00:30:32]  So, an LDL above 190, they just assume it's genetic and familial.
[00:30:36]  And you can get.
[00:30:36]  You know, diagnosed with FH and then, you know, treatments ensue.
[00:30:42]  Anyway, point being, isn't it interesting, just intellectually, that I and other people like me can manipulate our LDL levels five-fold with dietary shifts more than standard-of-care treatment, multi-billion, maybe trillion-dollar drug industry.
[00:31:00]  Right.
[00:31:00]  And I said earlier that I think the Oreo versus statin had a positive impact.
[00:31:04]  I think it had a positive scientific impact.
[00:31:06]  Actually, we've gotten, you know, funding to do more trials because of this.
[00:31:09]  More partnerships, but even clinically, because it got the word out there.
[00:31:15]  And in the weeks and months, and now more than a year following that experiment, I have heard from dozens, if not hundreds, of clinicians and cardiologists who are like, oh, shit, I have these patients.
[00:31:27]  And I didn't know what they were until now.
[00:31:29]  That paper ended up, the Oreo versus Staten paper, was very widely circulated.
[00:31:33]  I think it had 15 times the media attention score of your average New England Journal paper, which was the highest impact factor.
[00:31:42]  Great marketing stunt.
[00:31:44]  It was a marketing stunt, but to get a word out there and what the clinicians saw.
[00:31:48]  Was now this new phenotype and this new reason for a patient presentation that didn't understand before.
[00:31:55]  And what did that allow them to do?
[00:31:56]  Act on the physiology.
[00:31:58]  So even before the Oreo versus statin, we had worked with clinics where they had patients who had this phenotype but didn't need to be in therapeutic ketosis.
[00:32:06]  So they just titrated back in carbs.
[00:32:08]  And you can use a sweet potato.
[00:32:10]  One patient, like about a sweet potato worth of carbs addition per day, lowered his LDL by 480.
[00:32:17]  No medication can do that.
[00:32:18]  So the point being is, This wasn't, you know, I put no value judgment on LDL or statins in this.
[00:32:25]  This was about interesting physiology that can actually serve people because if you can eat a sweet potato and get a more potent effect than taking, you know, a drug for the rest of your life, a drug that does that, cuts your GLP one and a half, like that is better patient care.

=== Debating the Minnesota Experiment (03:45) ===

[00:32:42]  So we need to understand the physiology and metabolism in order to advance care.
[00:32:46]  And the fact that the field is so myopically focused on like a single marker, in this case, LDL or Applebee.
[00:32:53]  That is the problem.
[00:32:55]  And so it's not that that doesn't matter.
[00:32:58]  In fact, it's not even that that's not, quote, causal.
[00:33:00]  We might want to debate whether or not Applebee is causal, but it's that without further context, you are not serving people.
[00:33:07]  So we'll go through a few studies.
[00:33:09]  One that's been debated recently is a Minnesota coronary experiment.
[00:33:14]  And the reason I bring that up is I was rereading it yesterday.
[00:33:16]  It was a paper by Ramsden et al.
[00:33:17]  Originally, this study was done decades ago, a long term randomized controlled trial.
[00:33:23]  It was on like seed oils and actually not seed corn oil versus a higher saturated fat diet.
[00:33:29]  Turns out the spoiler alert the corn oil diet ended up doing quite poorly.
[00:33:35]  But the conclusions, if you actually read the paper, weren't that omega 6 is terrible, saturated fat is good.
[00:33:43]  No, the researchers just said things like there are different physiological reasons for LDL to change.
[00:33:50]  This matters, this context matters.
[00:33:52]  And I think like the final lines of the paper.
[00:33:56]  Steve, can you bring up there's like a Minnesota end quote?
[00:33:59]  We can actually get into the study.
[00:34:00]  It's the third one down in the top left.
[00:34:03]  Now, you were talking about titrating in carbs to a keto diet.
[00:34:06]  Yeah.
[00:34:07]  I just want to quickly read this quote because I think it's really important to frame our whole discussion and, like, you know, the angle I'm trying to take.
[00:34:13]  This is what the paper ended on.
[00:34:16]  Given the limitations of the current evidence, the best approach might be one of humility, highlighting limitations of current knowledge and setting a high bar for advising intakes beyond what we can provide for a natural diet.
[00:34:25]  So I'll just frame up right now.
[00:34:28]  We may end up debating this, but like, I'm not against omega 6.
[00:34:31]  I don't think walnuts are terrible.
[00:34:32]  But I think by the same token, like, butter, saturated fat rich whole foods are probably also very healthful.
[00:34:38]  I was doodling out, you know, how I think about this.
[00:34:41]  Can you bring up, Steve, a Steve oil, sorry, a seed oil map complex?
[00:34:46]  It's in the top left.
[00:34:48]  That's a simple one.
[00:34:49]  The one above it.
[00:34:50]  The one above it.
[00:34:51]  So I was drawing this doodle on the way to the airport about the way I think about seed oils.
[00:34:56]  We might end up touching on a lot of this.
[00:34:58]  People don't need to understand it.
[00:34:59]  The point I want to make right now.
[00:35:02]  Is I doodle out that and come to the conclusion wow, there's so much we don't know about this.
[00:35:09]  And I think one thing I want to do, this has been a long preamble to get to the seed oil topic, but my mission, I guess, is not to say good or bad, but to wrap context around this and give people like an awe and humility for how interesting and complex the biology is.
[00:35:28]  Because right now we just hear, you know, clickbait taglines and people are very attracted to simplicity.
[00:35:36]  But I really feel that there is.
[00:35:39]  A growing community of people who like hunger for nuance and respond to it.
[00:35:43]  So that little doodle can be a framework we come back to, but I've been on my soapbox for too long.
[00:35:47]  I'll pass it back to you.
[00:35:48]  Nuance doesn't get views.
[00:35:50]  That's the problem.
[00:35:50]  But it can.
[00:35:51]  I think if you can be provocatively reasonable, that's what I try to play with.
[00:35:55]  That's why I'm even like playing with social media in the first place.
[00:35:59]  Is like, oh, yeah, you need an engagement tactic.
[00:36:02]  Harvard scientist eats Oreo cookies, great clickbait.
[00:36:06]  But does the clickbait, is it then followed by something with depth?
[00:36:10]  So, you do need to pay homage to the clickbait gods or whatever.
[00:36:16]  But that doesn't mean you can't use that as a tool to really advance conversations and research.
[00:36:20]  Totally agree with you.
[00:36:22]  I just challenge people to really hear the words that are going to be coming out of our mouths and the rest of this conversation.

=== Beyond LDL: The ApoB Debate (07:42) ===

[00:36:28]  So, before we get to CDOLs, I want to ask though is LDL bad?
[00:36:31]  If you have high LDL, is that bad?
[00:36:32]  See, Nick sort of foreshadowed this.
[00:36:36]  My perspective, Nick can add if he feels differently, is that it's contextual, right?
[00:36:40]  And this is a really, really important question.
[00:36:43]  It's a really important question.
[00:36:44]  As Nick has suggested, the statin industry is potentially a trillion dollar industry.
[00:36:48]  There are a lot of financial zeros on the line here if LDL is not all it seems.
[00:36:57]  The mainstream medical perspective is that LDL and APO B containing the proteins are atherogenic, they are bad.
[00:37:04]  They directly cause atherosclerosis.
[00:37:06]  Yes.
[00:37:07]  I don't agree with that based on what I've seen.
[00:37:09]  I think it's much more nuanced and contextual.
[00:37:12]  Broadly, when I look at the evidence with ApoB and LDL, we can just use one of those terms moving forward.
[00:37:19]  In humans who demonstrate markers suggestive of insulin sensitivity, metabolic health, there is a different effect, cardiovascular sort of correlate for LDL levels than there is in people who are metabolically unwell.
[00:37:36]  If you are a diabetic and you have a high LDL, that does seem to consistently represent a, A significantly increased risk of cardiovascular disease, in some cases, four to 6x, right?
[00:37:48]  Wow.
[00:37:48]  A low LDL.
[00:37:50]  If you are metabolically healthy, which is something that we can really only achieve proxies for, whether it's an HDL or unfortunately, very few studies are done with fasting insulin.
[00:38:01]  I think if studies were done with fasting insulin, that's probably the best marker.
[00:38:04]  Fasting insulin.
[00:38:05]  That's an easily obtainable blood marker.
[00:38:08]  I'm actually not familiar with a single study that's done with fasting insulin, but if you look at things that approximate insulin or you use that as sort of a third variable, anything that approximates insulin sensitivity, you see a markedly attenuated relationship between LDL levels and increased cardiovascular risk.
[00:38:24]  And so I think that there's a question.
[00:38:26]  To me, if something is causal, you get into this sort of semantics of what is causality, right?
[00:38:33]  Is something consistently associated with a process enough to claim causality?
[00:38:40]  My brain is simple in this respect.
[00:38:41]  I think if something causes it, then LDL must be enough to initiate atherosclerosis on its own.
[00:38:46]  And if you're saying LDL causes atherosclerosis, The associated inference is that more LDL is always bad.
[00:38:54]  And that's really the relevant clinical question if you, Danny, go and eat a ketogenic diet and your LDL goes up, does that represent an increased risk of cardiovascular disease for you?
[00:39:03]  Is that something we need to be aware of?
[00:39:04]  Or if you become more metabolically healthy because you're getting rid of garbage foods, if you're getting rid of, quote, carbs, right?
[00:39:12]  Yeah.
[00:39:12]  And you become more metabolically healthy with a higher LDL, right?
[00:39:16]  Is it possible that your cardiovascular risk is the same or lower?
[00:39:19]  Now, so this is where the nuance comes in.
[00:39:21]  I think it's very contextual.
[00:39:23]  And like I said, if you stratify the relationship between LDL and cardiovascular disease, there's a marked attenuation when people are insulin sensitive versus insulin resistant.
[00:39:33]  So, and the best way to determine whether or not you're getting, um, The LDL is really affecting you is to get the CT angiograms where they can, like, they basically put you inside of a CT scan with dye in your arteries and see how much black you have.
[00:39:46]  Probably the best imaging, yeah, you could do is a CT angiogram.
[00:39:48]  I mean, there's something called a CAC, but it's not as, it's not the same thing.
[00:39:52]  That's probably the CT angiogram, you got to go in that freaking cancer machine.
[00:39:54]  They radiate it.
[00:39:55]  It's a lot of radiation.
[00:39:56]  Right.
[00:39:56]  Yeah.
[00:39:57]  You don't want to do it above age 40.
[00:39:58]  A CAC is pretty good in terms of, uh, uh, let's say a warranty on your heart.
[00:40:05]  Uh, I got a CAC and it said it was zero.
[00:40:07]  Yeah.
[00:40:07]  But I also, um, I think it might have been Dom who told me this that his parents got a CIC and it was zero.
[00:40:13]  And then they also went and got a CT angio right after.
[00:40:16]  And it said they had, like, I don't know if it was, it might have been somebody else.
[00:40:19]  And they said that the CT angio, they had like a high amount of plaque, but their CIC score was still zero.
[00:40:23]  Yeah.
[00:40:23]  Depends what algorithm they use to interpret the plaque.
[00:40:28]  You're getting dangerously close to things that I'm not supposed to talk about.
[00:40:31]  I can talk about it until Friday, but I can talk about it.
[00:40:33]  I can talk about what you know.
[00:40:35]  A couple of things I want to poke at.
[00:40:39]  We can come back to the CAT thing later.
[00:40:40]  I actually want to put on my Jade Tower academic prude hat for a minute for a purpose.
[00:40:48]  Ivory Tower.
[00:40:49]  Yeah, Ivory Tower Harvard prude hat.
[00:40:54]  So, Paul, you effectively said ApoB is not causal.
[00:40:58]  You've said that, right?
[00:40:59]  I don't believe ApoB is causal.
[00:41:01]  I don't believe there's enough evidence to suggest that ApoB is causal.
[00:41:03]  Okay.
[00:41:04]  Which means what again?
[00:41:06]  Necessary but not sufficient.
[00:41:09]  But the way you described it.
[00:41:12]  Seemed like you were talking about.
[00:41:13]  So let me unpack these terms.
[00:41:15]  Causal, definitionally, and this is important, definitionally means it is necessary and part of the causal cascade, effectively.
[00:41:26]  And when you say ApoB, you mean LDL.
[00:41:29]  So just, we should probably define these.
[00:41:32]  ApoB stands for apolipoprotein B.
[00:41:34]  Yes.
[00:41:35]  It is an apolipoprotein on LDL particles.
[00:41:37]  So there are more particles than just LDL.
[00:41:39]  It's a proxy of LDL.
[00:41:40]  It's a proxy of like an LDL particle count.
[00:41:42]  So it's a better marker for LDL, whereas Your standard LDL cholesterol is the cholesterol fraction generally calculated in all the LDL specific type ApoB containing liver proteins.
[00:41:53]  That doesn't make sense.
[00:41:54]  They're proxies for one another as far as we're concerned.
[00:41:57]  If there's a divergence, we will highlight it.
[00:42:00]  Okay.
[00:42:00]  And Paul is saying that it's not causal.
[00:42:02]  Right.
[00:42:03]  And then he's trying to redefine what you mean by causal.
[00:42:10]  And the reason I bring this up is because in these discussions, that little.
[00:42:17]  Chink in the armor is all you need, and you know this, for conventional academics to write you off and leverage that within academia to say, this person doesn't know what he's talking about.
[00:42:29]  Let's go through the evidence proving LDL is causal or Applebee is causal.
[00:42:33]  So, again, it's interesting social dynamics.
[00:42:36]  My position on Applebee is it's causal insofar as it's necessary, but I agree with Paul context, context, context.
[00:42:45]  So, to think about this graphically, If you imagine a simple XY axis, and on the Y axis is the amount of plaque you're accumulating in your heart.
[00:42:56]  The X axis is your exposure to Apple B.
[00:42:59]  And let's say that there is a positive relationship.
[00:43:02]  Is it a really steep line or is it super, super shallow?
[00:43:06]  And if it's super, super shallow, you know, because say you have a positive hormonal and metabolic milieu, then that needs to be weighted when making decisions about what intervention you start or don't or stay on or don't.
[00:43:22]  So, you know, if your absolute risk increase from having high ApoB is actually quite low on an individual basis, there's ways we can figure this out.
[00:43:32]  That's different than I have already had a heart attack and I have metabolic syndrome and I need a standard American diet and my Apple B and L's y'all are through the roof.
[00:43:40]  Those are two very different things.
[00:43:41]  Yes.
[00:43:42]  And the failure to wrap context around this individual marker, that's the issue.
[00:43:48]  The issue is not that the marker doesn't have any value in and of itself.
[00:43:53]  That's more or less my position.
[00:43:56]  And it's also why I'm very comfortable giving recommendations, advice on ways to.
[00:44:03]  To lower your APOB if that's desired, while myself living with crazy high LDL.

=== Two Scenarios for High ApoB (10:28) ===

[00:44:10]  A pattern that arises in my social media that I think confuses people is I'll often talk about things in a positive light that I don't adopt myself.
[00:44:20]  So, for example, particular fibers I think can be very beneficial.
[00:44:23]  I eat basically a zero fiber diet because of my context, because my history of IBD, how it affects me personally, and what works for me shouldn't generalize to another person.
[00:44:32]  Do you eat any fruit at all, like Paul does, or any carbs at all?
[00:44:35]  No.
[00:44:37]  But I will add, Were I not to need a ketogenic diet therapeutically for my IBD, I would happily eat a sweet potato or some fruit.
[00:44:45]  I by no means think those are bad things.
[00:44:47]  And guess what?
[00:44:48]  It would lower my LDL and Apple B substantially, which isolated probably would, all things being equal, be more likely to lower my risk specifically for CVD than other things.
[00:45:00]  So you eat zero carbs?
[00:45:02]  Basically.
[00:45:03]  I'm always in ketosis.
[00:45:04]  Carbohydrates.
[00:45:05]  Carbohydrates.
[00:45:06]  That word carbs is kind of like, Colloquialism, right?
[00:45:09]  People hear carbs, they think like pasta, bread.
[00:45:11]  Yeah, yeah, yeah.
[00:45:12]  So carbohydrates.
[00:45:13]  I don't think you eat any carbohydrates because you definitely don't eat any carbs.
[00:45:16]  Yeah.
[00:45:17]  I mean, I'll have a little bit, but nothing that will kick me out of ketosis for a prolonged period of time.
[00:45:21]  What do you typically eat throughout the day?
[00:45:24]  Now, probably.
[00:45:25]  So I eat two meals a day, probably in like a six to seven hour window.
[00:45:30]  Breakfast, dinner.
[00:45:31]  Yeah, breakfast and dinner, like 11 a.m. noon.
[00:45:34]  I'll have a meal.
[00:45:35]  Probably eggs, cheese, salmon, olive oil.
[00:45:40]  Maybe some macadamia nuts, and then dinner can be fish, chicken, steak.
[00:45:46]  I'm pretty simple.
[00:45:47]  No size, just the meat.
[00:45:48]  Pretty much.
[00:45:49]  Wow.
[00:45:50]  Pretty much.
[00:45:51]  The thing is, I like these foods.
[00:45:52]  If I could, without GI upset or any consequences, have a big dish of Brussels sprouts with dried cranberries and walnuts, that sounds delicious.
[00:46:02]  And I think for a lot of people, it's not worth it for me.
[00:46:06]  It makes me feel unwell.
[00:46:07]  I understand, yeah.
[00:46:08]  And there's a lot of individual context.
[00:46:12]  And so, aceto oils is another good example.
[00:46:15]  Well, actually.
[00:46:17]  And why do you.
[00:46:18]  So there's like a lot of people don't like to eat breakfast.
[00:46:21]  I think breakfast is bad.
[00:46:23]  I mean, you skip lunch.
[00:46:25]  Well, when I say breakfast, I mean when I break my fast.
[00:46:28]  So 11, 12, sometimes.
[00:46:30]  Okay, gotcha.
[00:46:30]  So yeah.
[00:46:31]  Lunch, dinner, if you want to say it.
[00:46:34]  I heard that the metabolism is working way harder in the morning.
[00:46:38]  So it's better to eat in the morning and it slows down at high noon.
[00:46:40]  I think that's kind of a fairy tale.
[00:46:42]  I don't know if there's any evidence for that.
[00:46:43]  That's the Jack Cruz Kool Aid I've been drinking, bro.
[00:46:46]  Come on, don't break my.
[00:46:47]  Can we go back to the lipid stuff?
[00:46:48]  This is super interesting to me.
[00:46:49]  I don't want to miss this point.
[00:46:51]  I wanted to piggyback on something Nick was saying.
[00:46:53]  The reason I think the conversation is so important is because it goes back to what we were talking about earlier in Western medicine.
[00:46:59]  As a doctor, when a patient comes to see you, when someone is sick, it's important to try and understand what is actually at the root cause of their problem.
[00:47:06]  Western medicine really points the finger at LDL.
[00:47:10]  They have blockbuster drugs that lower LDL, and they want to make LDL causal.
[00:47:17]  I agree with Nick.
[00:47:18]  LDL, ApoB containing the proteins, which include LDL, are necessary for atherosclerosis.
[00:47:23]  If you do animal model knockout studies of ApoB, they don't get atherosclerosis.
[00:47:27]  I don't think that that's just maybe I'm incorrectly defining the word causal.
[00:47:32]  It's just sort of maybe we're doing hand waving here.
[00:47:34]  I think that that's not what I mean when I say causal.
[00:47:37]  I think of causal as direct relationship, right?
[00:47:39]  So if your LDL goes up, your cardiovascular risk always goes up because if something causes that, there is sclerosis.
[00:47:44]  LDL, you're sort of inferring that LDL or ApoB can cause lung cancer.
[00:47:48]  Well, can I get to that?
[00:47:50]  Yeah.
[00:47:50]  Yeah.
[00:47:51]  The, you know, if your ApoB goes up, you're sort of inferring that that LDL is directly damaging de novo to the endothelium or something.
[00:47:59]  And I think that what Nick is saying, and I agree with this, is that it's all about.
[00:48:02]  Context that if the context is different, right, if someone is metabolically healthy versus not, that ApoB carries various risks.
[00:48:10]  When I look at that equation, I think that what we should be focusing on is metabolic health and not ignoring LDL, but all of our myopic focus is on LDL.
[00:48:22]  Never in all of my training, medical school, residency, even medicine rotations, surgery rotations, did anyone ask me to get a fasting insulin to assay someone's metabolic health.
[00:48:32]  Within Western medicine, I think one of the greatest tragedies or greatest oversights is that.
[00:48:37]  Physicians are not taught to think about metabolic health as the foundation upon which diseases manifest.
[00:48:43]  And so, if we're looking at metabolic health as the context in which we should interpret LDL and ApoB, why are we not assaying people's metabolic health?
[00:48:52]  When people tell me about their stories, when I was working with patients previously, they would come to me with lipid panels and say, My doctor is concerned about my LDL.
[00:48:59]  And I would say, What's your fasting insulin?
[00:49:00]  And they would invariably say they didn't get one.
[00:49:02]  There are ways to look at a traditional lipid panel that give you a sense of your metabolic health.
[00:49:07]  Triglyceride to HDL ratio is perhaps the most predictive because those are changed in sort of metabolic dyslipidemia.
[00:49:13]  But again, physicians don't do that.
[00:49:15]  They myopically focus on LDL, ApoB containing lipoproteins.
[00:49:19]  So we're forsaking patients by not appreciating the metabolic health.
[00:49:24]  I would argue that it is insulin resistance, also known as metabolic dysfunction, that is the initiating event.
[00:49:31]  That is the determining factor in atherosclerosis.
[00:49:33]  So why are we not looking to treat that?
[00:49:35]  Not necessarily with drugs.
[00:49:36]  Let's ask the questions around what causes metabolic dysfunction.
[00:49:40]  In diet and lifestyle.
[00:49:41]  That's where we need to go.
[00:49:42]  For my money, that's where the return is, right?
[00:49:46]  That's the $64,000 question that very few in Western medicine are asking, and none in the traditional medicine world are being taught to ask, right?
[00:49:55]  What causes metabolic dysfunction?
[00:49:56]  I think most people would agree metabolic dysfunction, synonymous with insulin resistance, is at the root of so many chronic diseases that is reversible.
[00:50:05]  Nick and I have seen that myriad times.
[00:50:07]  You can reverse metabolic dysfunction.
[00:50:09]  So why are we not thinking about that first?
[00:50:11]  And if that determines the context in which your LDL levels, Should be interpreted.
[00:50:15]  Why is that not the first thing we're thinking of?
[00:50:17]  And if the context of LDL determines its cardiovascular risk, then LDL is not really, doesn't make sense.
[00:50:22]  That doesn't make sense to me in terms of linguistics for it to be causal.
[00:50:25]  Yes, it's necessary, not causal.
[00:50:27]  That's how I think about it.
[00:50:28]  Again, we can get into like this splitting hairs, what does the word causal mean?
[00:50:32]  But I think that this is a clarion call that we need to do a much better job in Western medicine understanding someone's baseline metabolic health, how to get there and how to get back there and what makes us less metabolically.
[00:50:43]  That's the most interesting question to me.
[00:50:45]  How important is the LP little a?
[00:50:48]  So, this is an interesting one.
[00:50:51]  I mean, Nick can speak to this also because in the study that he recently did, they stratified this also.
[00:50:55]  The way that I see LP little a, this is lipoprotein little a, it's essentially an LDL molecule with an extra little protein on the outside called an apolipoprotein little a.
[00:51:05]  And as I understand it, that is sort of a mop for oxidized phospholipids in the human blood.
[00:51:10]  Okay.
[00:51:11]  Now, oxidation.
[00:51:12]  English.
[00:51:13]  Oxidation.
[00:51:13]  Okay.
[00:51:13]  So oxidation is essentially loss of electrons.
[00:51:17]  It's rusting, right?
[00:51:18]  It's rancidity.
[00:51:19]  Yes.
[00:51:19]  It's damage of phospholipids.
[00:51:22]  This is starting to.
[00:51:24]  Sort of look toward the seed oils conversation because when we get to the seed oils conversation, we will be talking about susceptibility or propensity for oxidation, right?
[00:51:33]  Which is loss of electrons.
[00:51:35]  That's what we think of technically from an organic chemistry perspective when we say oxidation.
[00:51:40]  So, phospholipids are these molecules that make up the membranes of your cells, and LDL is a membrane bound vesicle and it has phospholipids in the membrane.
[00:51:49]  It also has proteins in the membrane, other compounds in the membrane, but LpA looks to be a mop, a sort of cleaning service for oxidized phospholipids.
[00:52:01]  I think there are two scenarios for LpA.
[00:52:03]  Nick can add if he disagrees with this or wants to add any more to this, or he sees it differently.
[00:52:08]  I think some people have genetically high LpA, and that may not represent an increased cardiovascular risk.
[00:52:14]  But if your LpA goes up acutely, that may suggest an increased burden of oxidation in your phospholipids, and that is suggesting an oxidative stress.
[00:52:24]  And that is indicative of.
[00:52:26]  Increased cardiovascular risk.
[00:52:27]  Does that make sense?
[00:52:28]  Yes.
[00:52:29]  So, in the study that Nick did, and again, Nick should talk about this because he'll be more equipped to do it, there actually was not a distinct correlation between the levels of Lp little a and the plaque score.
[00:52:40]  Interesting.
[00:52:40]  And that's interesting to me because Western medicine, again, says Lp little a, horrible 100% of the time.
[00:52:46]  But I think there's more nuance here.
[00:52:47]  So, I think there's two scenarios for Lp little a.
[00:52:50]  If you know your baseline and you see it acutely rise and you started smoking, or perhaps you started guzzling soybean oil, And you're making your cells and your membranes more full of susceptible, fragile lipids, then yeah, an increase in LpA can be problematic.
[00:53:05]  But I'm not convinced that a baseline high level of LpA, which could be genetic, necessarily indicates that you have this burden of oxidized, that is damaged membrane components.
[00:53:15]  I've only got my LpA measured once.
[00:53:17]  I don't, because it's expensive.
[00:53:18]  Yeah, so generally it's recommended to get it once because it's assumed to be static, which it is assumed to be static.
[00:53:24]  It's more resistant to change generally than, say, LDL.
[00:53:28]  You can lower it with more saturated cells.
[00:53:29]  So is a lower LpA good?
[00:53:33]  Genetically, like a.
[00:53:33]  Conventionally, I would say on balance, yeah.
[00:53:36]  Like, I have a very high LP little a.
[00:53:37]  I inherited it from my dad.
[00:53:38]  It's known as what are called Kringle repeats.
[00:53:41]  So basically, Paul was describing LP little a quite nicely.
[00:53:45]  It's like an LDL, but it's got a little tail.
[00:53:47]  It's called an apple little a tail.
[00:53:51]  And the tail is determined by how many, what are called Kringle repeats you inherit from, you know, one or both of your parents.
[00:53:59]  And the longer tails get the.
[00:54:05]  Particle gets degraded, or the precursor to the particle gets degraded earlier.
[00:54:07]  So, the shorter tails tend to be higher levels and they actually tend to be more damaging on balance.
[00:54:13]  I'll get back to LP the lay in a sec, but I just want to finish the conversation and thought around semantics.
[00:54:20]  I don't want to beat a horse on this, but just from my position, I think causal and most important gets confused.
[00:54:30]  So, like insulin sensitivity, metabolic health, I think it's most important.
[00:54:35]  I still think Applebee is, quote, causal, but that doesn't mean it's most important.

=== Multiomics and Type 2 Diabetes (02:45) ===

[00:54:38]  It's the same with terms like evidence based, quote unquote, and, you know, best medicine.
[00:54:44]  Evidence based medicine is not necessarily the best medicine.
[00:54:46]  So these are things that people get caught in these buzzwords without thinking what they really mean.
[00:54:52]  So, like evidence based medicine, it's like, well, have we checked the boxes on this type of intervention?
[00:54:57]  Not actually, does the intervention help the individual patient or the most people?
[00:55:02]  Actually, there was a Nature letter in 2015 by Nicholas something I was reading the other day.
[00:55:08]  I think the top 10 highest grossing drugs help between one in four.
[00:55:14]  And one in 25 people who take them.
[00:55:17]  Now, the reason that's important is because you can run a double blind, multi million dollar RCT, get statistically significant results, and like sell a product, and it can still not help most people.
[00:55:29]  But what we do, and this is how medicine is built right now, is like we take a heterogeneous group of people and do what's considered a quote gold standard, and then prescribe the outcome to everyone without looking at the individual context.
[00:55:40]  So the theme that keeps coming up is context, context, context.
[00:55:43]  Now, I will hit LP Little like quickly, but I then want to.
[00:55:47]  This is like the Human Genome Project was doing this thing where they basically take people's DNA and they come up with like custom tailored treatments for them.
[00:55:55]  Like if you have a cancer or whatever, they take your DNA and they like figure out the exact type of drug or therapy to like target exactly what's in their body dependent on their biology.
[00:56:07]  It's like a custom.
[00:56:08]  The degree to which we're getting more resolution on not just the genome, but the, and on multiomics.
[00:56:16]  So multiomics like transcriptome, proteome, you know, genome, microbiome.
[00:56:21]  Actually, forgive me one more quick tangent, but this is super cool.
[00:56:24]  One of my favorite labs is the Snyder Lab at Stanford, who are like kings at multiomics.
[00:56:29]  They had a paper last year in Nature Biomedical Engineering.
[00:56:32]  How many types of type 2 diabetes are there, Paul?
[00:56:36]  How many types of type 2 diabetes?
[00:56:37]  Yeah.
[00:56:38]  Are we back to linguistics?
[00:56:40]  Okay, it's a read my mind question four.
[00:56:43]  So, what they did in this study basically, I'll try to make this short, but they did gold standard in lab testing on a cohort of patients and kind of dissected what was the main cause of type 2 diabetes.
[00:56:56]  Two diabetes, so insulin resistance, generally adult onset, obesity, in these patients, because there's different pathophysiologies.
[00:57:01]  Again, context nuance.
[00:57:01]  So you can have incretin dysfunction, liver dysfunction, muscle dysfunction, beta cell dysfunction at your pancreas.
[00:57:07]  Now, the way we diagnose type two diabetes is like, what is your average blood sugar?
[00:57:11]  How do you respond after two hours on a glucose tolerance test?
[00:57:15]  What they did in the study is basically show each patient individually had a dominant one of those four that was driving type two diabetes or two co dominant.

=== Lp(a) as a Wound Healing Marker (02:47) ===

[00:57:24]  And then, and this is what was cool.
[00:57:28]  You can't do this kind of experiment, those kind of lab tests clinically on patients, but they use machine learning and AI to then take the patients, put CGMs on them, and then the CGMs were able to decode from the shape of the CGM curve what the specific underlying pathology was driving type 2 diabetes in that individual patient.
[00:57:50]  Oh, wow.
[00:57:51]  So as we evolve with AI, machine learning, biomonitoring tools, and the reason I'm going on this tangent is I think, and I want to see if Paul agrees.
[00:58:01]  We are going to see a transformation in how medicine is practiced, moving away from quote gold standards RCTs, which use heterogeneous groups of people, moving towards personalized medicine focused on physiology like that.
[00:58:12]  Because now we're getting the tools to measure these things and act on them.
[00:58:17]  And quickly on LP to delay, because it's a fascinating story.
[00:58:21]  I'm personally more concerned about it, I'll just give my high level opinion, than LDL particles.
[00:58:26]  But there's some really interesting work if people want to go down a rabbit hole.
[00:58:30]  I wrote a newsletter and did a video on it that.
[00:58:32]  I can share with you so I don't go on too long right now, but about LP little a as basically a wound healing surrogate evolutionarily for vitamin C. You know about this Pauling work?
[00:58:43]  A little bit.
[00:58:44]  So Linus Pauling, who, smart guy, two Nobel Prizes.
[00:58:48]  In the 90s, him and his colleague, Dr. Rath, developed this idea that LP little a arose as a replacement for vitamin C.
[00:58:56]  So most mammals can synthesize vitamin C, humans can't.
[00:58:59]  And a few other animals can't, like the European hedgehog.
[00:59:03]  And basically, vitamin C has wound healing properties.
[00:59:06]  LpA also has wound healing properties.
[00:59:08]  So, if you want to heal up quickly, evolutionarily, scar, don't bleed to death, yada, yada, yada.
[00:59:13]  First, the evolutionary pattern is fascinating because LpA arose independently in those organisms that lost the ability to synthesize vitamin C.
[00:59:23]  And there's a lot of overlap.
[00:59:24]  And the reason I bring this up is because some people think that if you take high dose vitamin C and also L lysine, it has to do with how the LpA actually binds, called lysine binding sites.
[00:59:38]  you could effectively reduce the stickiness of the LP little a.
[00:59:43]  So there might be ways, again, beyond the quote, gold standard evidence-based RCT, yada, yada, that you could potentially attenuate your LP little a risk.
[00:59:51]  I think, first and foremost, agree with Paul, being med-volc healthy.
[00:59:55]  But beyond that, there's some really interesting physiology that we can talk about.
[00:59:58]  The last thing I'll say about LP little a is, isn't it interesting that 10 years ago, nobody talked about it, and now everybody's talking about it.
[01:00:09]  Popular.
[01:00:11]  I was surprised.

=== Fasting Insulin and LP(a) Risk (02:19) ===

[01:00:12]  It was on my subtech the most popular newsletter I ever wrote.
[01:00:16]  Really?
[01:00:16]  On a pretty, it would seem like an esoteric.
[01:00:18]  I've never heard anybody talk about it.
[01:00:19]  So many people were fascinated by it.
[01:00:22]  The observation I'm making again incentive structures.
[01:00:24]  Ten years ago, people didn't talk about it.
[01:00:26]  Now, there are New England Journal trials on five different medications targeting it.
[01:00:31]  Interesting.
[01:00:32]  So, incentive structures is a point that I keep coming back to.
[01:00:37]  Not people being sinister or corruption scandals, just.
[01:00:41]  Simply, incentive structures.
[01:00:43]  I think we need to understand that, be it science, medicine, influencers talking, in order to really understand the nuances of the debate.
[01:00:49]  But should we get into CDOs?
[01:00:50]  Can we get into metabolic health real quick?
[01:00:52]  I just want people to understand because we touched on this a little bit.
[01:00:55]  I think people are probably, you and I clearly agree that the most important thing is to be metabolically healthy.
[01:01:02]  And I just want people to understand that most doctors do not test for this, but it's super easy.
[01:01:06]  It's a fasting insulin test.
[01:01:08]  You fast overnight, you get an insulin level in the morning.
[01:01:10]  It's not perfect.
[01:01:11]  If you pair a fasting insulin With a continuous glucose monitor.
[01:01:15]  You mentioned those earlier.
[01:01:16]  You have sort of a fasting insulin and you have a proxy for a postprandial insulin with the postprandial glucose.
[01:01:22]  So you can look at the shape of your CGM curve.
[01:01:25]  And I think those two things, a fasting insulin will cost you $30 if you pay cash.
[01:01:30]  And if you look at the distribution of fasting insulin, I think the average in the States is like nine micro IU per ml.
[01:01:36]  But there are other metrics that suggest that 90 plus percent of the United States is metabolically unwell.
[01:01:41]  So I think it's reasonable to suggest to people just to give guidance.
[01:01:45]  That you want your fasting insulin to be far below nine.
[01:01:48]  I think the best level is probably below five.
[01:01:51]  Most of the time when I check mine, it's less than three.
[01:01:54]  And again, fasting insulin is a $30 test.
[01:01:58]  You can get it online.
[01:01:59]  Although it's democratized, lab companies now, if your doctor won't order it for you, you need a new doctor.
[01:02:04]  I think that if every doctor ordered a fasting insulin, you can immediately get a sense of where you are on some sort of a metabolic health curve.
[01:02:11]  No test is perfect, but it's pretty darn good.
[01:02:14]  Pop the hood, oil, check the dipstick.
[01:02:17]  Okay, you're good.
[01:02:17]  You got a fasting insulin of 4.5.
[01:02:20]  Not bad.
[01:02:21]  It should be below five.
[01:02:22]  What is the measurement?
[01:02:22]  It's micro IU per ml.
[01:02:26]  I have to say one more thing before we get to seed oils around psychiatry.

=== Omega-6 Double Bonds Explained (15:45) ===

[01:02:31]  And I just think this is really important for people to hear because the diseases we battle with, when you don't have this metabolic mechanistic picture, they become ephemeral and abstract.
[01:02:45]  And nowhere is that a bigger problem than in psychiatry.
[01:02:50]  Paul was talking about his training, and the nature of the field is that every diagnosis is clinical, you don't really go with biomarkers.
[01:02:58]  And, you know, Because the brain is such a black box, it leads people to thinking that the brain and the mind, which is emergent from it, isn't just a metabolic organ and phenomenon.
[01:03:09]  And so, the emerging research this is one of the areas I find most fascinating is how brain metabolism influences the human mind.
[01:03:15]  So, I'll give a couple examples, both out of top papers that came out this year in 2025.
[01:03:22]  One was on autophagy in the brain, something really interesting.
[01:03:27]  Which means what?
[01:03:28]  Basically, it's a cellular recycling process.
[01:03:30]  We break up and clean things.
[01:03:31]  People often associate it with fasting.
[01:03:35]  There was a study, I think it was in Nature.
[01:03:37]  Again, I can send all the references after the fact, but basically what they showed is that in depression, autophagy is dysfunctional in a brain region called the lateral habanula, which, think about it, the depression center leads to a buildup of the receptors for the excitatory neurotransmitter in the brain called glutamate.
[01:03:53]  It basically dials up your quote unquote depression.
[01:03:57]  And another interesting thing is the drugs we use to treat human beings, so SSRIs, selective serotonin reuptake inhibitors, ketamine, Different classes of antidepressants converge on this pathway to alter this basic metabolic function.
[01:04:11]  Or another example, again, this is all literally the Cell Science Nature Press 2025 data.
[01:04:17]  There's another one, Paul, I'll have to share this one with you.
[01:04:19]  You'll love it.
[01:04:20]  But on a neurotransmitter called homovanilic acid, which is in the dopamine pathway.
[01:04:26]  Now, a pet peeve of mine is when people say 90% of the serotonin is made for the gut, therefore it's good for your brain to make gut serotonin.
[01:04:33]  Serotonin doesn't cross the blood brain barrier, homovanilic acid does.
[01:04:37]  Interestingly, in humans, Homo vanillic acid levels are low in depression.
[01:04:43]  And there's also decreased levels of the gut bugs that make this neurotransmitter.
[01:04:47]  So, this neurotransmitter is made in the gut, it goes to the brain, and it can alter mental function.
[01:04:52]  We know it's low in humans with depression.
[01:04:55]  And in animal models, where you can, like, you know, chop off heads, do your brain staining, animal models of depression, just giving homo vanillic acid or either of the gut bugs is sufficient to reverse depression phenotypes.
[01:05:09]  Whoa.
[01:05:09]  So, so.
[01:05:11]  Again, it can't be considered quote unquote gold standard, you know, evidence based medicine because there hasn't been a human RCT because nobody's funded and done that.
[01:05:21]  But the fact, first of all, the physiology is incredible that your diet, the way you live, can change your gut bacteria.
[01:05:28]  Those gut bacteria make a neurotransmitter that we know can cross the blood brain barrier and alter the mind.
[01:05:35]  What more link do you need to say, yeah, what you do in your lifestyle, how you sleep, eat, Live affects the mind.
[01:05:45]  And I think once we can, like, people can internalize just how much lifestyle impacts the roots of the tree of metabolic diseases, and that manifests in all the metabolic diseases obesity, cardiovascular disease, depression, Alzheimer's, you name it.
[01:06:01]  Highlighting that importance is, I think, somewhere where we're unified.
[01:06:05]  It's really important for people to understand what you just said.
[01:06:06]  I'll highlight that all those diseases, which are taught to us in medical school as disparate conditions, they're all siloed, they're all connected, right?
[01:06:14]  They're all sort of.
[01:06:15]  Systemic metabolic dysfunction arising at the level of the mitochondria, the gut, it's all connected.
[01:06:19]  But Nick said Alzheimer's, depression, cardiovascular disease, the list goes on, autoimmune conditions.
[01:06:26]  In medicine, I think last time I checked, there were over 10,000 diagnoses and there were probably 75,000 different drugs or maybe 25,000 different drugs.
[01:06:35]  So medicine is, in my opinion, medicine is trying to make it more complicated.
[01:06:39]  And when you think about it, like from my perspective, the more I pulled back, and this is really why I left traditional medicine, it's like, wait, wait, there's probably like five things going on in humans, right?
[01:06:47]  You didn't sleep enough.
[01:06:48]  You ate crappy.
[01:06:50]  You had a A stressful event in your life, you got exposed to a toxin, like these, these can probably be linked to most of the issues we have because they affect us physiologically.
[01:06:59]  But I wasn't taught about any of those diagnoses in Western medicine.
[01:07:01]  You're taught, you know, you're taught, you know, chronic myelogenous leukemia.
[01:07:05]  You're, you know, you're taught these diagnoses, which are esoteric pigeonholes, silos, and they're not connected, but they're all connected.
[01:07:13]  And to understand that depression, physiology, neurochemistry in the brain may have at its root many of the same things that affect inflammatory bowel disease, that's wild.
[01:07:23]  And that's where Western medicine has completely lost the plot.
[01:07:25]  Yeah, it seems like it's all connected.
[01:07:27]  And just trying to treat one thing is like playing whack a mole.
[01:07:29]  Medicine is siloed, metabolism is unified.
[01:07:31]  That is a fact.
[01:07:33]  It's totally whack a mole.
[01:07:33]  And then when you give things, right, you give a statin, somebody comes in with elevated LDL, and maybe they do have insulin resistance.
[01:07:41]  You give them a statin, you just crush their GLP.
[01:07:44]  Right.
[01:07:44]  And, you know, that's crazy.
[01:07:45]  And then, you know, now you're playing whack a mole down the road.
[01:07:48]  And this is why we get polypharmacy.
[01:07:50]  And I think that this third leading cause of death is still medical intervention.
[01:07:53]  You know, you have heart disease, cancer, and then medical intervention.
[01:07:56]  So, We're clearly.
[01:07:57]  Is medical intervention number three?
[01:07:58]  I think it is.
[01:07:59]  Wow.
[01:08:00]  That's crazy.
[01:08:01]  You can fact check it.
[01:08:02]  What about, quick little, so I don't want to spend too much time, but a quick question.
[01:08:05]  What about, what is the shit I'm taking again?
[01:08:08]  Azetamib.
[01:08:09]  Is that bad?
[01:08:11]  I think it's the most benign in terms of side effects of the LDL lowering drugs.
[01:08:14]  It basically.
[01:08:15]  It cut my LDL in half.
[01:08:17]  I think it changed your cardiovascular risk.
[01:08:20]  Right, I don't know.
[01:08:21]  And why did you take it in the first place?
[01:08:23]  Because it lowered my LDL.
[01:08:25]  And did they get a fasting insulin?
[01:08:27]  That's a good question.
[01:08:27]  I haven't looked at it.
[01:08:28]  I got my blood work.
[01:08:29]  You think it would change fasting insulin?
[01:08:30]  No, no.
[01:08:31]  Whoever prescribed you azetamide.
[01:08:32]  I'm going to give you context.
[01:08:33]  Whoever prescribed you azetamide didn't look at your metabolic health.
[01:08:37]  You were eating keto.
[01:08:38]  Presumably, Danny, I'm telling you your own story here.
[01:08:40]  You were eating keto.
[01:08:41]  Your LDL goes up.
[01:08:42]  They give you azetamide to lower your LDL under the premise that it's increasing your cardiovascular risk.
[01:08:47]  They did nothing to assay your cardiovascular metabolic health.
[01:08:51]  Medicine is the art of making decisions at an individual basis given incomplete and imperfect data.
[01:08:59]  So.
[01:09:00]  Again, down to the individual level, Danny, it might be a very reasonable thing for you to do, all things being equal, depending on your individual cost benefit analysis, to take that, even if it doesn't necessarily have a positive effect and doesn't change your life course.
[01:09:14]  So it's complicated, and people want clear definitives.
[01:09:18]  And now I really want to get into the seed oil debate, but I think broadly what you're going to find my position is there's reason to be concerned.
[01:09:27]  We need more studies and humility on the precautionary principle.
[01:09:32]  I avoid them defined as highly industrialized oils, but I think a lot of the claims are way overstepping, and I don't like the leak into vilifying omega 6 fatty acids broadly.
[01:09:45]  So I'd like to start the discussion, but I would like to be very clear and distinguish when we're talking about linoleic acid and omega 6 versus seed oil.
[01:09:55]  So if we bring back up the complex, actually, you can do the complex or simple version of the seed oil map, Steve.
[01:10:05]  The simple version here.
[01:10:08]  I think if we think about it like this so linoleic acid's at the middle, focus on the side and the bottom.
[01:10:15]  How is it processed outside the body and how is it processed inside the body?
[01:10:18]  Because there are huge contextual factors here.
[01:10:21]  So we can start wherever you want.
[01:10:24]  I think wrapping some context around all the things that can happen to omega 6 inside the body, depending on individual factors, would be fun.
[01:10:31]  If people understand what linoleic acid is, we might want to back up and do fats.
[01:10:35]  I mean, go ahead.
[01:10:36]  Yeah.
[01:10:37]  So we touched on this earlier.
[01:10:41]  Can you see if it's on there?
[01:10:43]  Oh, your insulin?
[01:10:44]  Yeah.
[01:10:46]  I'm betting you a meat stick.
[01:10:48]  That I brought you.
[01:10:49]  You already gave me the meat stick, so I'm not giving it back.
[01:10:52]  Those are mine.
[01:10:52]  I'm betting you're delicious.
[01:10:53]  I'm taking one back if it's not on there.
[01:10:56]  I'm South African.
[01:10:56]  I will fight you for that drug horse.
[01:10:59]  So, when we have fats, we have saturated fats, right, which is a chain of carbons, and all the carbons have hydrogens.
[01:11:06]  All of the positions of the carbon atom are occupied by hydrogen.
[01:11:11]  When you have a monounsaturated fat, you have one double bond.
[01:11:14]  You owe me a meat stick.
[01:11:15]  Oh, it's on there?
[01:11:16]  He gets a meat stick.
[01:11:17]  3.2.
[01:11:17]  That's pretty good, right?
[01:11:18]  Less than five microRU per ml.
[01:11:21]  So, just to complete the discussion there.
[01:11:23]  If you didn't know who ordered this for me, you wouldn't have made that bet.
[01:11:26]  Yeah.
[01:11:26]  Maybe they were listening.
[01:11:27]  They were listening to some of these conversations around this more broadly.
[01:11:31]  So, you know, from my perspective there, I would say, okay, you're pretty metabolically healthy.
[01:11:36]  Let's actually look at your risk with this LDL.
[01:11:40]  I would not have recommended azetamib to you.
[01:11:42]  I'm not your physician.
[01:11:43]  Okay.
[01:11:44]  So, anyway, that's the conversation there.
[01:11:46]  And then cut it out.
[01:11:47]  Well, don't take my advice.
[01:11:48]  I'm not your doctor.
[01:11:49]  Really?
[01:11:50]  I take all my medical advice from the internet.
[01:11:52]  You're a sovereign human.
[01:11:53]  You're a sovereign human.
[01:11:56]  So, back to the fats.
[01:11:57]  You have saturated fats, monounsaturated fats, and polyunsaturated fats.
[01:12:00]  Saturated fats sound bad, but again, this is because of the zeitgeist.
[01:12:03]  It's because we've been programmed to do.
[01:12:04]  Saturated fats are chains of carbons with a carboxylic acid on one end, and they have no double bonds.
[01:12:12]  Monoounsaturated fats have one double bond.
[01:12:14]  Polyunsaturated fats have two or more double bonds.
[01:12:17]  Right.
[01:12:17]  So, linoleic acid is an 18 carbon omega 6 polyunsaturated fat with two double bonds.
[01:12:25]  The omega 6 means the first double bond is.
[01:12:28]  At the carbon six positions from the end of the molecule, okay.
[01:12:31]  So that's just how we name fats because we'll talk about omega 3s.
[01:12:35]  We can talk about omega 3, first double bond is closer to the end of the molecule.
[01:12:40]  That's all that means, right?
[01:12:41]  So, polyunsaturated fats for the layman are seed oils, right?
[01:12:45]  Not necessarily, right?
[01:12:47]  Because a polyunsaturated fat technically just means it has two or more double bonds, right?
[01:12:53]  If let's take soybean oil, which is the most commonly consumed seed oil, as an example, soybean oil.
[01:12:59]  We can fact check this.
[01:13:00]  I'd say it's around 50 plus percent linoleic acid.
[01:13:05]  So 50 plus percent of what's in soybean oil is linoleic acid.
[01:13:10]  But maybe one or two percent of what's in soybean oil might be alpha linoleic acid, which is an omega-3 polyunsaturated fat.
[01:13:18]  And there's also going to be monounsaturated fats in soybean oil and a very small amount of saturated fats in a soybean oil.
[01:13:25]  So no seed oil is purely polyunsaturated fat.
[01:13:30]  And no animal fat, butter is not purely saturated either, right?
[01:13:34]  Right.
[01:13:34]  So, polyunsaturated fat is not synonymous with seed oils.
[01:13:38]  Part of the concern for me with seed oils is that they do contain large amounts of polyunsaturated fats, right?
[01:13:46]  Specifically, omega-6 polyunsaturated fat.
[01:13:49]  That is linoleic acid.
[01:13:51]  When you're talking about fish oil, you're talking about omega-3 predominant polyunsaturated fats.
[01:13:56]  Our consumption of linoleic acid, linoleic acid is by far.
[01:14:02]  The single greatest polyunsaturated fat that we consume in our diets.
[01:14:08]  Not even close to omega 3s, right?
[01:14:10]  We're talking about, you know, a few people who are supplementing with fish oil might have two grams or a gram to two grams of omega 3.
[01:14:19]  In 2025, the average American consumes five tablespoons of seed oils, which is a day.
[01:14:25]  A day.
[01:14:25]  When you say seed oils, are you saying linoleic acid and omega 6?
[01:14:29]  Or are you saying, so the way.
[01:14:31]  So let's break it down simple for people.
[01:14:33]  Okay.
[01:14:33]  For people that don't know, for people that get all their information from YouTube and from RFK, seed oils are bad for you.
[01:14:41]  And fish oils and things like avocado oil and olive oil and butter, these things are good for you, right?
[01:14:48]  A little more complicated than that.
[01:14:49]  Yeah, it is a little more complicated, but if you want to break it down, make it binary, that's basically how most people understand it.
[01:14:55]  So I think the main confusion point is poly.
[01:14:59]  So I'm holding up, I don't know if people can see a little diagram here of fatty acids.
[01:15:03]  There's saturated and unsaturated.
[01:15:05]  We can talk about saturated separately, a very complex group in and of itself.
[01:15:09]  Within unsaturated, there's monounsaturated, one double bond.
[01:15:13]  Or polyunsaturated.
[01:15:15]  Within polyunsaturated, there's omega 3, so like fatty fish, fish oil, and then there's omega 6.
[01:15:21]  And this is omega 6, more or less synonymous with linoleic acid, just because of the proportions that are consumed.
[01:15:27]  The way I want to define seed oils and stick to these terms as best we can, because I think this, if nothing else, is the main confusion point.
[01:15:37]  If omega 6 rich foods are highly refined and processed to get the oil that is heated and has additives added to it, that is.
[01:15:46]  The highly industrialized seed oil.
[01:15:49]  And I think one of the big issues that arises is conflating omega 6 and seed oil.
[01:15:55]  So let's start because I think this is where we're going to have the biggest disagreement about omega 6.
[01:16:01]  So the physiologic impacts of omega 6 specifically, and then we'll talk about processing.
[01:16:06]  Well, we can talk about relative amounts because I think this is an interesting point.
[01:16:09]  So, what Nick is saying, so just back to what we were just saying, so the average American consumes five tablespoons of seed oils per day.
[01:16:16]  The most commonly consumed seed oil is soybean.
[01:16:18]  perhaps followed by canola.
[01:16:20]  Soybean is approximately 50%, give or take, linoleic acid.
[01:16:23]  And where are they getting all of this from?
[01:16:24]  It could be in, it's probably French fries, it's in breads, it's in salad dressings.
[01:16:30]  So the majority of seed oils people are consuming are heated.
[01:16:33]  That's an important point also.
[01:16:34]  Just basic processed foods.
[01:16:36]  Processed foods.
[01:16:36]  And so, and I think a lot of it is French fries, a lot of it is chips, right?
[01:16:41]  Those oils are boiled and heated.
[01:16:42]  So there are, there's even nuance in the seed oil conversation that goes deeper, right?
[01:16:47]  You can have a seed oil, which as Nick correctly points out, is industrially refined, bleached, and deodorized oil.
[01:16:53]  Soybean oil, canola oil, peanut oil, sunflower oil, safflower oil.
[01:16:57]  It's sitting on the shelf in a grocery store in a plastic container that can leach antimony into the oil.
[01:17:02]  It's a transparent plastic container.
[01:17:04]  So, that is a fragile oil by nature of being polyunsaturated that is being exposed to light and oxygen for months at a time.
[01:17:13]  And then you take those oils, and most of those oils that we consume today are then heated, right?
[01:17:18]  You're either frying with them in a pan or you're deep frying with them.
[01:17:21]  So, there are levels to perhaps the potential harm of these oils.
[01:17:25]  As you heat an unstable oil, it becomes more problematic.
[01:17:28]  More inflammatory mediators are generated.
[01:17:30]  So, we can talk about heated seed oils.
[01:17:32]  We can talk about unheated seed oils.
[01:17:34]  And as Nick is pointing out, we should differentiate that from not even processed sources of omega 6, things like walnuts, right?
[01:17:43]  Walnuts contain moderate amounts of omega 6.
[01:17:45]  They also contain moderate amounts of omega 3.
[01:17:47]  But what I wanted to point out here is that, so let's just say corn.
[01:17:52]  Corn oil is another commonly consumed oil, seed oil, industrially refined, bleached, and deodorized oil in our diet today.
[01:17:59]  Again, Chips, cakes, cookies, packaged foods.
[01:18:03]  You look at labels there everywhere.
[01:18:04]  French fries, obviously.
[01:18:06]  It's in bread at all the fast food restaurants, processed foods.
[01:18:10]  In order to get five tablespoons of corn oil, you would have to eat 60 ears of corn, right?

=== Essential Linoleic Acid Context (15:45) ===

[01:18:17]  Something that humans would never have done historically.
[01:18:20]  Five tablespoons of soybean oil is two and a half pounds plus of soybeans.
[01:18:27]  Five tablespoons of peanut oil, something the same.
[01:18:29]  You know, you can look at these amounts.
[01:18:32]  It's just to say, like a walnut, the amount of linoleic acid in a walnut pales in comparison to a tablespoon of nobody's doing walnut oil is not really a seed oil because it's so unstable, it has so much omega-3 people never use walnut oil, it gets rancid so fast.
[01:18:48]  But, like, a soybean is not the same as a tablespoon of soybean oil, right?
[01:18:53]  A tablespoon of soybean oil is the equivalent of you know hundreds of soybeans, sure.
[01:18:57]  And that's that's not even the best example.
[01:18:58]  You know, you have two and a half plus pounds of soybeans to get five tablespoons of oil.
[01:19:02]  These are evolutionarily, and again, I'm sort of stacking the deck in my favor, I'll just but I'm trying to say this as just uh in an unbiased way as possible.
[01:19:11]  These are evolutionarily difficult amounts of oils to obtain from the actual parent foods.
[01:19:18]  That's interesting.
[01:19:18]  So, we have those three differentiators.
[01:19:20]  We're talking about omega 6 linoleic acid occurs in most unprocessed foods that you or I eat today.
[01:19:27]  There is omega 6 linoleic acid in a grass fed steak.
[01:19:30]  It's a small amount, right?
[01:19:32]  It's perhaps 1%.
[01:19:34]  1% of the fat in a steak is linoleic acid.
[01:19:38]  50% of the fat in soybean oil is.
[01:19:41]  So, you see, there's a spectrum, right?
[01:19:44]  An egg yolk contains linoleic acid.
[01:19:47]  So, there's a difference between saying linoleic acid is per se harmful, or is there a dose, or is there a form factor here as well?
[01:19:58]  So, yeah, and we can differentiate all those things.
[01:20:01]  But that's just something I wanted to differentiate for people.
[01:20:04]  Historically, our consumption of linoleic acid today is 10x, 1000% higher than it ever has been historically.
[01:20:13]  Because of our consumption.
[01:20:15]  Do we know when our consumption, this five tablespoons per day, started?
[01:20:21]  When did this start and how has it grown?
[01:20:24]  The first seed oil was introduced in 1911.
[01:20:26]  Procter Gamble made Crisco.
[01:20:28]  So, before 1900, there were essentially 99% of the fat we ate was animal fat in 1900.
[01:20:35]  And just to give context, again, record keeping not the same, but the heart attack wasn't even a thing.
[01:20:40]  There was no diagnosis of heart attack in 1900.
[01:20:43]  Wow.
[01:20:44]  Humans didn't have chest pain.
[01:20:46]  Like that, this clinical syndrome is not defined until much later, yeah.
[01:20:51]  So, two holy global production of vegetable oil is the same thing, yeah.
[01:20:55]  Vegetable oil is the euphemism, right?
[01:20:57]  So, seed oil is oh, look, it shows all of them palm, soybean, canola.
[01:21:01]  Wow, so 1911 is Crisco, and then more and more become a part of it.
[01:21:06]  There's interesting history from Procter Gamble and the American Medical Association that I can mention because we're on the topic.
[01:21:12]  So, the American Medical Association, I think, was started in the 1850s, but it didn't really rise to prominence until.
[01:21:18]  The mid 1900s.
[01:21:19]  And part of that was a major grant from Procter Gamble to the AMA.
[01:21:24]  So there's a lot of speculation.
[01:21:26]  Again, it's just purely speculation, but Procter Gamble makes Crisco.
[01:21:30]  Procter Gamble was really behind the popularization of, at that time, hydrogenated seed oils into the public sphere in place of butter and lard, right?
[01:21:41]  Because animal fats, 1900, 99% of what we eat is animal fat.
[01:21:45]  And then Procter Gamble makes Crisco.
[01:21:47]  They say it's cheaper, it's healthier, it's white.
[01:21:50]  It's not going to raise your LDL as we begin to understand lipoproteins.
[01:21:53]  We can talk about saturated fats versus monounsaturated and poly and their effect on ApoB and LDL.
[01:21:58]  In 1939, I think, give or take, Procter Gamble makes the equivalent today of a $100,000 donation to the American Medical Association for their sort of radio show.
[01:22:07]  And then the American Medical Association begins to sort of get more on this polyunsaturated fat bandwagon.
[01:22:13]  You can find ads from, I would say, the 1950s and 60s.
[01:22:18]  These are incredible ads.
[01:22:19]  I think they're from maybe Mozzolla Corn Oil, but you can see this becoming a part of the zeitgeist.
[01:22:24]  And there's a great ad.
[01:22:25]  Maybe you can find it, Steve.
[01:22:26]  It's like Denise or whoever it is polyunsaturated her family tonight.
[01:22:30]  They're talking about cooking with this corn oil.
[01:22:33]  What?
[01:22:33]  There are these crazy ads.
[01:22:34]  Yeah.
[01:22:34]  So, like, anyway, they become a part of the conversation and the cultural milieu over the last, let's say, 100 years, give or take, starting in 1911.
[01:22:43]  Before that, essentially, cottonseed oil was made in the 1860s, but not used in food until 1911.
[01:22:49]  Previously, most people know this, but previously, seed oils were used for lamp oils and for engine oils.
[01:22:54]  And they were used in World War II on submarines and ships because they retain their slipperiness when they're wet.
[01:22:58]  Right.
[01:22:59]  And when did this food pyramid get constructed?
[01:23:02]  Do we know what year that happened?
[01:23:03]  There's been a couple of them, but I think the first one, I want to say the 80s.
[01:23:06]  The one with bread at the bottom, right?
[01:23:08]  I think it was the 70s or 80s, I'm guessing.
[01:23:10]  And that had to do with that was funded by some of these industries as well, right?
[01:23:15]  There is evidence of industry funding.
[01:23:18]  Can I make an imposition and a challenge, which is when I observe discussions around seed oils and just research in general, it does tend to devolve into.
[01:23:34]  History, talking about funding.
[01:23:36]  It's not that it's not important.
[01:23:37]  You're not incentive structures.
[01:23:38]  It's super important.
[01:23:39]  No, no, no.
[01:23:40]  I'm really not trying to color the conversation.
[01:23:41]  I just think it's important.
[01:23:42]  We're trying to break down your ivory tower today.
[01:23:43]  It's important for context.
[01:23:44]  It's important for context.
[01:23:45]  I'm a sleeper agent.
[01:23:47]  We'll get to the science, but it's important for context, I think.
[01:23:50]  I appreciate that.
[01:23:51]  And I apologize.
[01:23:52]  I'm not trying to color the conversation.
[01:23:53]  I just think that's.
[01:23:54]  And Danny was cured.
[01:23:55]  And I think that's a really interesting question because when, just intuitively, again, this is not a double blind, randomized, placebo controlled trial.
[01:24:04]  Right.
[01:24:05]  When humans introduce new things into their diet and environment, we probably should be cautious.
[01:24:10]  Yes.
[01:24:10]  And again, that's just philosophical.
[01:24:14]  Not everything that gets introduced is bad for us.
[01:24:16]  One of the things I want to do is draw out what I believe to be Paul's quite nuanced perspective as differentiated from the caricatures and memes that get propagated around each of us because of the way media works.
[01:24:31]  And what I hear you saying, Paul, is.
[01:24:36]  You know, the way these seed oils are introduced into our diet is evolutionarily unprecedented, it's coincident with a decline in metabolic health.
[01:24:47]  Therefore, we should.
[01:24:48]  We didn't talk about the coincidence with metabolic health, but I don't like to draw those because I think there are so many things that do that.
[01:24:54]  But yes, that's it.
[01:24:55]  We agree on that.
[01:24:56]  So I see that as different.
[01:24:58]  I see it as different saying, look, this could be a problematic compound.
[01:25:02]  Here are the reasons.
[01:25:04]  And let's do some more research than people going on, you know, like.
[01:25:09]  I'll just say it.
[01:25:10]  Robert F. Kennedy Jr. going on and saying, like, seed oils are, what was it, the most unhealthy thing in the human diet.
[01:25:16]  That is a claim.
[01:25:17]  That is a direct claim that I don't think could be substantiated.
[01:25:19]  RFK said that?
[01:25:20]  I'm pretty sure.
[01:25:21]  Didn't he say something to that effect?
[01:25:22]  I don't know.
[01:25:22]  It's the most unhealthy.
[01:25:23]  I don't know if he said that.
[01:25:24]  We can, Steve, you can find it and people can fact check me.
[01:25:26]  I'm 99% sure he said something.
[01:25:28]  He also said that EMFs cross the blood brain barrier.
[01:25:32]  He did say something on Rogan about it.
[01:25:33]  Anyway, so I don't think he's the best scientific resource.
[01:25:36]  Not to talk about him as a human.
[01:25:37]  He's a great human.
[01:25:38]  He's got good intentions.
[01:25:38]  He's a great dude.
[01:25:39]  Intentions count.
[01:25:40]  I love intentions count.
[01:25:41]  But I guess.
[01:25:43]  I want to challenge listeners to say, like, yeah, this is important context, but now let's talk about, like, let's talk about the science.
[01:25:50]  Science and what we can claim, what we can't claim.
[01:25:52]  So let's talk about not processed seed oils.
[01:25:54]  Let's start with linoleic acid.
[01:25:57]  Is it bad?
[01:25:57]  Is it bad in the body?
[01:25:59]  Well, okay.
[01:26:00]  Can I just back up?
[01:26:00]  I appreciate what Nick is saying because a lot of times you will see this graphical overlay and it's a correlation, right?
[01:26:08]  And you can add your correlative element here, right?
[01:26:13]  Because we know that in the last 100 years, coincident with the introduction of seed oils, glyphosate, vaccines, choose your boogeyman, right?
[01:26:21]  We have had an explosion of chronic disease in this country obesity, infertility, cancer, dementia, depression.
[01:26:28]  I think it has a lot to do with.
[01:26:28]  Technology too, people being sedentary.
[01:26:30]  Exactly.
[01:26:31]  Choose your boogeyman.
[01:26:32]  And I don't like those overlays.
[01:26:33]  I think that Nick is right to point out that that correlation, you can make that correlation with a lot of things, right?
[01:26:37]  You can correlate the number of movies Nicolas Cage appears in per year and the number of drownings in pools, right?
[01:26:46]  These are not the right way to do it.
[01:26:47]  Now, it is an interesting thing to say, okay, all of these things have become introduced into our society.
[01:26:53]  Let's ask the questions around glyphosate.
[01:26:55]  Let's ask the questions around vaccines.
[01:26:57]  Let's ask the questions around ultra processed foods, which are complex and are not.
[01:27:02]  Simply containing seed oils.
[01:27:03]  They contain many things, right?
[01:27:05]  Let's ask the questions around other pesticides.
[01:27:07]  Let's ask the questions around technology and devices and blue light and circadian rhythm destruction.
[01:27:10]  There's a lot of things.
[01:27:11]  I think that the interesting thing, the important thing is that we're asking the questions as physicians or as laypeople.
[01:27:17]  We're trying to understand what is causing us to be so unhealthy as opposed to just, you know, like let's just give us a medication.
[01:27:25]  You know, you're sick.
[01:27:26]  Here's a med.
[01:27:26]  No, no, let's try and figure this out.
[01:27:28]  But yeah, the correlation is not terribly instructive.
[01:27:31]  Do you want to start talking about linoleic acid physiology or you want me to?
[01:27:35]  Let me say a word and then I'll let you add to it.
[01:27:37]  Yeah.
[01:27:38]  So, from my perspective, I don't know exactly what Nick's going to say about linoleic acid physiology.
[01:27:44]  The background that I have on it is that linoleic acid, an omega 6 polyunsaturated 18 carbon fatty acid, is essential, quote unquote, for humans.
[01:27:54]  Now, the levels which we need are questionable.
[01:27:56]  We can talk about it in this conversation.
[01:27:58]  But to become deficient in linoleic acid, you would essentially have to eat a diet of basically rice.
[01:28:05]  I'm not even sure.
[01:28:06]  You probably wouldn't even become deficient in linoleic acid if you ate only rice.
[01:28:09]  If you ate Purely like some sort of very, it'd be very, very difficult to become deficient in linoleic acid.
[01:28:16]  No one becomes deficient in linoleic acid by avoiding seed oils.
[01:28:19]  There's linoleic acid in steak, there's linoleic acid in fish.
[01:28:24]  I agree.
[01:28:25]  Fish and egg yolks.
[01:28:26]  It's in all, it's in all whole foods, right?
[01:28:29]  Yeah.
[01:28:29]  Now, so it's considered to be an essential fatty acid because when you deprive rats or mice of linoleic acid, yeah, they don't do well.
[01:28:37]  But you have to feed them a very specific diet.
[01:28:39]  I don't think that many humans.
[01:28:41]  In recent memory, they are deficient in linoleic acid.
[01:28:44]  We could argue differently for omega 3s, perhaps, but linoleic acid does become incorporated into our cell membranes.
[01:28:50]  It's an essential part of human physiology.
[01:28:53]  It is a precursor for many, let's just say, second messengers in the human body, and those generally have both inflammatory and anti inflammatory roles.
[01:29:03]  And even framing it that way, let's just say inflammation is not always a bad thing, right?
[01:29:08]  When you work out, you need inflammation to repair and rebuild.
[01:29:11]  And if you abrogate or you blunt that inflammation, You don't become as strong.
[01:29:15]  And so, inflammation often gets billed as a horrible thing that you just want to completely annihilate from your body.
[01:29:19]  That doesn't work.
[01:29:20]  You need, we mentioned oxidation earlier today.
[01:29:22]  You need oxidation, right?
[01:29:23]  In the mitochondria, you generate reactive oxygen species, you generate superoxide species.
[01:29:28]  These are essential for proper signaling, both at the level of insulin.
[01:29:31]  And we can't complete, we're not trying to get rid of all oxidation in the human body, right?
[01:29:35]  We're not trying to get rid of all inflammation.
[01:29:37]  And so, anti inflammatory and inflammatory second messengers do come from both omega 6 and omega 3 fats.
[01:29:44]  And so, they're a part of our diets.
[01:29:46]  The interesting thing for me about linoleic acid that I'll add is more context without trying to color it too much is that the polyunsaturated fats, whether it's omega 3 or omega 6, are stored in the human body.
[01:29:57]  The human body can make saturated fats and we can interconvert those into monounsaturated fats, but we cannot make polyunsaturated fats, which is why they're essential.
[01:30:07]  That also means that we store them.
[01:30:08]  So the amount of linoleic acid and other polyunsaturated fats, which could be omega 3s, found in human cells, human membranes, human adipose tissue, And the tissue, the actual tissue you're looking at matters.
[01:30:21]  That is in many ways directly correlated to intake.
[01:30:24]  Not always.
[01:30:25]  Sometimes there are some nuances there, but we as a human species, and this has been done by Stefan Guyane, did a great paper about this, I think, in the early 2000s.
[01:30:34]  It's been shown that human adipose tissue has accumulated far more linoleic acid in the last 70 years.
[01:30:39]  Because we eat more, we hold on to more.
[01:30:40]  Whether or not that's good or bad, I'm trying not to pass judgment there, but we do hold on to fatty acids.
[01:30:45]  The amount of omega 3s and omega 6s in our body, specifically our adipose tissue, And some other tissues correlate pretty well with intake.
[01:30:54]  So, we don't get rid of them easily.
[01:30:56]  The turnover of these fatty acids is slow.
[01:30:58]  So, it's just something to consider that if you eat saturated fat, right, that's going to have certain effects on your body, but your body can already make saturated fat and your body can interconvert saturated fat with monounsaturated fats and vice versa.
[01:31:10]  The polyunsaturated fats stay in our membranes, and that's just something to think about.
[01:31:13]  Interesting.
[01:31:15]  Steve, can you bring up adipose tissue cardiovascular mortality?
[01:31:21]  The bottom one.
[01:31:21]  The bottom one.
[01:31:24]  What do you make of this graph?
[01:31:26]  It's from a meta.
[01:31:26]  I think you actually shared it with me, if I recall correctly, Paul.
[01:31:30]  So, this is what it's showing the hazards ratio for cardiovascular related death, heart disease related death, as a function of omega 6, and specifically linoleic acid, in human fat tissue.
[01:31:44]  And it shows a favorable effect for childhood.
[01:31:46]  So, what do you make of that?
[01:31:47]  There are other studies they didn't include that show an unfavorable effect of human adipose tissue.
[01:31:52]  Yeah, I can show you one.
[01:31:54]  Yeah.
[01:31:55]  So, can you explain this?
[01:31:56]  SHHEC308?
[01:31:58]  Those are just the names of the studies.
[01:32:01]  The cases is the number of patients.
[01:32:03]  And basically, the way you read this is it's reported as a hazards ratio.
[01:32:07]  Basically, everything to the left of the vertical line, the 1.0, is a favorable effect in terms of linoleic acid concentrations.
[01:32:17]  Okay.
[01:32:18]  And if it's to the right, it's unfavorable.
[01:32:20]  So, here it's showing a favorable effect.
[01:32:25]  Okay.
[01:32:25]  Now, here's my favorite favorable effect to cardiovascular mortality of having higher linoleic acid levels in the body.
[01:32:32]  Now, so having more seed oils is better for cardiovascular, first of all, linoleic acid I wouldn't conflate with seed oils.
[01:32:38]  Okay, and also off of this, I'm not making the claim just to be clear this shows linoleic acid reduces cardiovascular mortality.
[01:32:49]  But if the claim is it increases it, then observations like this it's just not consistent with that observation.
[01:32:56]  So if we're talking about storage in the body.
[01:32:59]  And considering that, quote, bad, how does this effect even arise?
[01:33:04]  Now, maybe they omitted some studies, it's possible, but like still, it's tough.
[01:33:09]  It's an interesting one because, so one of the things that gets pointed out a lot is that if you look at linoleic acid levels in the blood, higher levels of linoleic acid in the blood, like we're looking at adipose here, right?
[01:33:21]  Yeah.
[01:33:22]  But higher levels of linoleic acid in the blood do often correlate with better cardiovascular outcomes.
[01:33:27]  Interesting.
[01:33:28]  Now, what's interesting about linoleic acid levels in the blood.
[01:33:32]  Is that that is not a great proxy for linoleic acid intake.
[01:33:37]  the best indicator of linoleic acid in the blood is a measure of, it serves as the best measure of the activity of an enzyme called D6D, delta-6 desaturase, also known as fatty acid desaturase II.
[01:33:52]  So without getting too granular, like in the human body, linoleic acid gets broken down into intermediates.
[01:33:59]  One of them is DGLA, and then another one is arachidonic acid.

=== Conflicting Cardiovascular Evidence (15:02) ===

[01:34:02]  And what we see pretty clearly is that if you have higher levels of this enzyme D6D, Right?
[01:34:11]  That is consistently linked with worse cardiovascular outcomes, right?
[01:34:15]  And D6D is acting on linoleic acid in the cascade to move it to downstream metabolites, specifically arachidonic acid.
[01:34:22]  Downstream from arachidonic acid, you get things that are called oxlams, so oxidative products of linoleic acid metabolism.
[01:34:29]  And that's where things get quite complex because those are myriad, the names are very esoteric, and they're linked to all sorts of problematic things for humans.
[01:34:36]  So there are actually, I want to come back to this and I want to show you the study that actually looks at.
[01:34:41]  Levels of linoleic acid in the fat tissue and shows different results than this.
[01:34:45]  But specifically with regard to D6D, there are Mendelian randomizations which suggest that D6D is causal for cardiovascular disease.
[01:34:53]  And that's just saying if you look at a bunch of people with various levels of delta 60 saturase based on their genetics, the people that have higher levels of delta 60 saturase, an enzyme that moves linoleic acid down this synthetic pathway, tend to do worse from a cardiovascular perspective.
[01:35:08]  And this is all part of this broader conversation around levels of linoleic acid in the blood and why that can be a little bit misleading for people.
[01:35:14]  Because When you have higher linoleic acid in the blood, that's probably saying less of your linoleic acid is moving downstream, right?
[01:35:21]  And lower levels of linoleic acid, which are linked with worse cardiovascular outcomes, mean linoleic acid is moving down the pathway toward arachidonic acid and potentially these oxlam molecules.
[01:35:32]  So that's interesting because that's the first piece to understand are you looking at D6D activity?
[01:35:37]  Are you looking at linoleic acid being biotransformed into things in the human body?
[01:35:41]  Or are you actually looking at linoleic acid levels?
[01:35:43]  Adipose, as I said, is a decent marker of.
[01:35:46]  Linoleic acid consumption.
[01:35:48]  It's not perfect.
[01:35:50]  And so when you look at this, this was interesting when Nick showed me this, but there are other studies, I need to find it for you, that look at linoleic acid in the fat and show different results in cardiovascular mortality.
[01:36:01]  The problem with this, you look at the cases, so it's 308 cases, 110 cases for these two cohorts.
[01:36:06]  It's like, it's difficult.
[01:36:08]  Yeah.
[01:36:08]  It's not the full deciding factor, but it's confusing for sure.
[01:36:12]  I don't think you can disregard based on.
[01:36:14]  One second.
[01:36:15]  Steve, what happened to our background, bro?
[01:36:17]  What do you got going here, Paul?
[01:36:20]  It disappeared.
[01:36:21]  I can bring it back up.
[01:36:22]  I didn't want to distract her.
[01:36:23]  Okay, let's keep going.
[01:36:24]  First, just in general, because this comes up again and again, the sample size of a study doesn't say much about its quality per se.
[01:36:33]  The only reason I mentioned is because the other one I was going to show, I think, was similar size or a little bit bigger than one of them.
[01:36:37]  Oh, yeah.
[01:36:38]  Well, I think I can put that as a sticky note for something I need to write independent content on.
[01:36:42]  I can go through each of the three studies.
[01:36:43]  But that aside, just to kind of reinforce what Paul is saying, because I think.
[01:36:49]  Sometimes analogies pop into my mind and I want to share them.
[01:36:52]  And I think it's a good point and an important point.
[01:36:53]  So, like, I've been seeing a lot of Lord of the Rings reels, girlfriend, boyfriend reels on Instagram.
[01:36:59]  So now I'm thinking it's like if linoleic acid is orcs storming helms deep, you have the orcs that are outside the linoleic acid in circulation, and then those that get through the barrier are, say, bio transformed into something more harmful.
[01:37:14]  And so Paul is right that it can be misleading to look just at the orcs outside the wall.
[01:37:20]  And what's important is how much your wall is broken down.
[01:37:22]  So, in this case, you know, how much bioconversion do you have into things that are harmful?
[01:37:29]  I guess what I'd add here is a couple things.
[01:37:32]  One, we can't have a whack a mole game here.
[01:37:35]  We need to be like, well, what is actually the health proxy?
[01:37:38]  Is it delta 6 desaturase activity?
[01:37:41]  We can measure that.
[01:37:42]  Is it linoleic acid in adipose tissue?
[01:37:44]  Is it circulating?
[01:37:45]  Like, what are these things that are informative?
[01:37:46]  Because if we're having a conversation where we're talking about one biological pathway, then people pull up contradictory data, then we jump off that marker onto another, we're never going to have a full conversation.
[01:37:56]  So I think a lot of this is in the realm of curiosity and speculation.
[01:38:04]  And I want to keep it there because.
[01:38:09]  Paul said, you know, it's complicated the pathways, even in just fat tissue, for what can happen to linoleic acid.
[01:38:15]  And that is context keeps coming up heavily contextual.
[01:38:19]  So I'll give you an example of one good thing that can happen.
[01:38:22]  I'm not saying this is the bulk pathway.
[01:38:23]  I just want to kind of like broaden people's minds about like what happens to this once it's in the body.
[01:38:27]  In fat tissue, in particular brown and beige fat, it can be turned into a derivative, an oxylipin called 1213 di.
[01:38:39]  H O M E.
[01:38:40]  Oh, dihomey.
[01:38:42]  That's what I said to you, I think, like earlier.
[01:38:44]  I don't actually know if I've ever heard it said out loud, but yeah, 1213 dihomey sounds kind of cool.
[01:38:47]  So we'll say that.
[01:38:48]  So, interesting thing about 1213 dihomey is it decreases with age and has really beneficial effects on the heart.
[01:38:56]  So, it can inhibit perivascular fibrosis, basically the hardening of vessels.
[01:39:02]  So, dihomey keeps the arterial walls more flexible, improves cardiovascular function, inhibits things that are bad metabolically, like ER stress.
[01:39:11]  And again, this is an oxidized.
[01:39:13]  You lose this as you age.
[01:39:14]  You lose this as you age.
[01:39:15]  But interestingly, and then this is just a context mind opener, you can increase it with lifestyle interventions.
[01:39:22]  So there are human trials showing you can increase 12, 13 dihomie levels by about 39% from a cold plunge.
[01:39:28]  Really?
[01:39:29]  Yeah, because this is something made in brown and beige fat.
[01:39:31]  There were studies done that show this?
[01:39:32]  Yeah, human studies.
[01:39:33]  I have a YouTube video where I get input from, I think it was the first one.
[01:39:36]  Which study was it?
[01:39:38]  I can find it while Paul is responding.
[01:39:41]  Steve, can you show my screen?
[01:39:44]  But, yeah, this is the study I was mentioning.
[01:39:46]  Holy shit, that worked good.
[01:39:48]  So, you see there, I highlighted the platelet linoleic acid concentration was also positively associated with CAD.
[01:39:54]  This is adipose tissue concentration of linoleic acid, positively associated with the degree of coronary artery disease in a cross sectional study of 226 patients undergoing coronary angiography.
[01:40:03]  And this is from what?
[01:40:04]  This is just an independent study, right?
[01:40:07]  Okay.
[01:40:07]  So, we're just showing that when we're looking at adipose tissue, the results are conflicting and confusing.
[01:40:12]  Yeah.
[01:40:13]  I think that to Nick's earlier point, We have to sort of decide what markers do we care about the most with linoleic acid?
[01:40:21]  Do we look at RCTs?
[01:40:22]  Because we can talk about randomized controlled trials like Minnesota and Sydney.
[01:40:26]  Do we look at adipose levels and correlation with coronary artery disease?
[01:40:30]  I think Mick is starting to talk about oxylipins.
[01:40:32]  I think it's useful to talk about oxlams, which are these oxidative products of linoleic acid metabolism.
[01:40:38]  And I think that we should probably talk some about oxidation of LDL, which is another problem.
[01:40:42]  So, broadly, the way that I see the seed oil conversation, well, I guess we're We're sort of talking about linoleic acid versus seed oils now, but broadly, I think what we're looking at here is.
[01:40:56]  Linoleic acid comes from seed oils, though, right?
[01:40:59]  Not exclusively, right?
[01:41:01]  Because it's found in things like an almond has a little bit, right?
[01:41:04]  An egg yolk has a little bit.
[01:41:05]  We talked about this, right?
[01:41:06]  Right, right, right.
[01:41:07]  Steak has a little bit of linoleic acid.
[01:41:09]  But primarily, it comes from.
[01:41:10]  I think that the major source of exposure for humans to linoleic acid in the last 100 years is seed oil.
[01:41:16]  Yes, okay.
[01:41:17]  If you look again, going back to the history, historically, like indigenous groups, they're getting one to two, two and a half percent of their calories from linoleic acid because there's a small amount in meat and eggs and quail and birds.
[01:41:30]  So, how many do we know how many of these either independent studies or published studies, trials, whatever, do we have supporting the idea that linoleic acid increases cardiovascular disease?
[01:41:45]  And then, how many do we have that say that there's no effect or a better effect?
[01:41:50]  It depends on the quality of the trial, right?
[01:41:52]  So, on my ex account, I pinned a thread that I did a few years ago and I looked at all 11 randomized controlled trials looking at saturated fat versus seed oils.
[01:42:05]  And when you go through the thread, you can pull that one up.
[01:42:07]  I don't know if you want to, I can pull that up here if you want, Steve.
[01:42:13]  Quickly, the name of the well, there are several papers, but the one about cold exposure cold induced changes in plasma signaling lipids are associated with healthier cardiometabolic profile independent of brown adipose tissue.
[01:42:23]  Cell Reports Medicine 2024, first author.
[01:42:26]  Guardo Fasoli.
[01:42:28]  And they gave, how many people were they putting in the cold plunge?
[01:42:32]  And what was the, I have to look back at the stuff.
[01:42:36]  64.
[01:42:37]  Because I was only aware of one study that was like a, it was on like Scandinavia.
[01:42:44]  I forget who, Huberman always talks about it.
[01:42:46]  Oh, was it the dopamine one?
[01:42:47]  The one where dopamine increased peripherally?
[01:42:51]  Anyway, we can get back to that.
[01:42:52]  I don't think so.
[01:42:52]  I think this was a cardiovascular one.
[01:42:54]  Go ahead, Paul.
[01:42:55]  So this is just one thing that you were asking about.
[01:42:58]  Danny, it's like, okay, so when we're talking about seed oils, if we're just kind of in that realm and we're saying, okay, what are the randomized controlled trials that have been done with seed oils?
[01:43:07]  Right.
[01:43:08]  You'll look here.
[01:43:08]  So I summarized about 11 of them, and there's roast corn oil.
[01:43:12]  There's Azo Diet Heart.
[01:43:13]  There's one called the Medical Research Council Trial, Los Angeles Veterans Trial, Sydney Diet Heart, Minnesota Coronary, the Diet and Reinfarction.
[01:43:21]  There's St. Thomas Atherosclerosis National Diet Heart Study, the Finnish Mental Health Hospital Study.
[01:43:26]  There's Houtsmuller Diabetic Angiography.
[01:43:30]  Or angiopathy trial.
[01:43:31]  And so these are all done between, let's say, 1958 and 1980s.
[01:43:37]  Okay.
[01:43:37]  We don't have any more recent trials on seed oils.
[01:43:40]  Wow.
[01:43:41]  And if you go through them, I mean, we can go through them individually if you'd like, or I can give you a high level from what I think.
[01:43:47]  If you go through them, what you find is that the trials are consistently poorly constructed.
[01:43:53]  We have some trials which say seed oils increase the risk of cardiovascular disease.
[01:43:58]  And you have some trials which say seed oils don't increase the risk.
[01:44:03]  Increase the risk of cardiovascular disease or potentially even lower it.
[01:44:06]  And so there are some that say it lowers it.
[01:44:08]  There are some that say it lowers it.
[01:44:09]  But in my analysis, this is my analysis, Nick can look at these or he can give us his sense of what he thinks about the RCTs broadly as well.
[01:44:18]  When you look at the ones that say seed oils are benign or beneficial, you can basically pick something wrong with every single one of those trials.
[01:44:26]  For instance, if you look at the Ozodiet Heart study, we can double click on this one.
[01:44:29]  Can we see who funds these trials too?
[01:44:31]  They're from so long ago.
[01:44:32]  So here's Ozodiet Heart, 1958 to 1963, right?
[01:44:36]  Five year follow up.
[01:44:38]  412 participants.
[01:44:40]  It's a control group, and the experimental group is getting 76% of its calories from soybean oil in the experimental group.
[01:44:47]  Now, the experimental group had a significant reduction in serum cholesterol, which was associated with a reduced coronary heart disease relapse rate.
[01:44:55]  And I said here, so they had more seed oils, and they had decreased coronary heart disease relapse rate.
[01:45:00]  Now, the potential flaw is the control group, right, had 9.6% of their calories from trans fat.
[01:45:07]  This is the problem is that in the 1950s and 60s, we didn't really understand trans fat.
[01:45:10]  So, this is what I mean when I say these trials are poorly constructed, right?
[01:45:14]  The experimental group, which is the seed oil group, was also encouraged to eat more nuts, fruit, and vegetables and to restrict their intake of refined grains and sugars.
[01:45:22]  So, this is a randomized controlled trial that gets included in a lot of meta analyses that will conclude, oh, seed oils are benign.
[01:45:31]  But you see how poorly constructed the trial is.
[01:45:33]  Like, okay, now you can go down here.
[01:45:36]  We can look at another one.
[01:45:38]  What's a good one here?
[01:45:39]  The Finnish Mental Hospital Studies.
[01:45:41]  Why don't we do these studies anymore?
[01:45:43]  If it's such a hot topic inside.
[01:45:45]  I was reading the Minnesota Coronary.
[01:45:46]  Experiment study, which is done in a multi center, multiple mental hospitals.
[01:45:49]  And actually, I was joking with someone because there's a section where they're like, and this is why we didn't get patient consents.
[01:45:55]  Bottom line, ethics have changed around doing these sort of experiments.
[01:45:59]  Ethics have changed.
[01:46:00]  Millions of dollars also, and who funds it?
[01:46:02]  And I would argue, and this is just my perspective, the ultra processed food industry is comfortably ensconced, right?
[01:46:09]  They are making billions of dollars on these foods.
[01:46:12]  If a trial came out that said CDOLs were harmful, someone stands to lose.
[01:46:17]  Billions, if not trillions of dollars.
[01:46:20]  Who pays for this?
[01:46:21]  This is a 15 to 20 million dollar study over seven years plus, potentially, right?
[01:46:27]  The ethics are difficult.
[01:46:28]  And we're kind of stuck back to the ApoB thing also because it's probably difficult within Western medicine to do any trial that could potentially raise your ApoB because we're stuck in this perspective that anything that raises your ApoB will increase your cardiovascular risk.
[01:46:40]  And we know pretty clearly, as we'll see if we look at Minnesota coronary experiment, that and many of these, like Sydney Diet Heart, also.
[01:46:48]  Giving someone cereals lowers their LDL.
[01:46:51]  But oftentimes, and I would say in the best constructed trials, not perfectly, in the best constructed trials, that doesn't equate to a decrease in cardiovascular disease.
[01:46:59]  So there are all sorts of problems in terms of our sort of paradigm today, in terms of how we look at things.
[01:47:05]  And there's this who funds it and why would it get done, right?
[01:47:08]  Let's just look at the Finnish mental health, mental hospital study.
[01:47:12]  So this is pretty commonly included in meta analyses, 1959 to 1971, 676.
[01:47:19]  Subjects, control diet, which is often the saturated fat rich diet, versus the experimental diet.
[01:47:25]  It was carried out in two mental hospitals near Helsinki.
[01:47:28]  One of the hospitals received a cholesterol lowering diet, a diet low in saturated fat and cholesterol relatively high in polyat saturated fats from soybean oil.
[01:47:35]  The other was served as a control with a normal hospital diet.
[01:47:37]  After six years diets were reversed.
[01:47:39]  Now the use of the cholesterol lowering diet was associated with significantly reduced mortality from coronary heart disease.
[01:47:45]  Okay now there was significantly more trans fat in the control diets.
[01:47:49]  The hospital K had 2% Trans fat in the control diet versus zero in the experimental group, and the hospital N had 0.6% trans fat versus 0.2.
[01:47:59]  There were minor differences in baseline characteristics such as age, BMI, smoking, and blood pressure between the two groups.
[01:48:05]  And there was a cardiotoxic medication, thyroidazine, which we don't use anymore, that was more commonly given to people in the control group.
[01:48:14]  So there was inadequate randomization also between the two things.
[01:48:16]  So you can see how obfuscated these trials are.
[01:48:20]  How could you say what's going on?
[01:48:21]  You're giving a control group.
[01:48:24]  In hospital K and hospital N, a diet with significantly more trans fat, which we know is cardiotoxic.
[01:48:32]  And then there's more patients in the control group getting a cardiotoxic medication like thyridazine, and that's going to make the saturated fat group look worse.
[01:48:40]  So, this is what happens with these trials, right?
[01:48:42]  Now, you can go through all of them and look at these, but what's important to point out here is that meta analyses are written today and they have these trials in the meta analysis.
[01:48:52]  And they'll say, oh, look at the combined.
[01:48:54]  Like if you do a forest plot, With the results of all 11 of these trials, you might find a combined effect which favors seed oils.
[01:49:01]  But what if you throw out the trials that are obviously poorly constructed?

=== Rebutting the Diet Heart Hypothesis (15:11) ===

[01:49:04]  Right.
[01:49:05]  So then you have.
[01:49:06]  That's the foundation of all the new stuff we come up with these poorly done studies.
[01:49:09]  Yes, these poorly done studies, which will probably never be repeated.
[01:49:13]  That's crazy.
[01:49:14]  So we end up in this situation where we almost have to look at mechanisms because the randomized controlled trials, and then you can look at stuff like, we can look at Cindy.
[01:49:22]  And who was the guy Huberman was talking about?
[01:49:25]  There's some guy at Stanford, a brain surgeon or something, who said, and Huberman said this, he said that this guy from Stanford, this brain guy, said like 60 to 80% of all the medical literature is either incorrect or outdated.
[01:49:39]  Bhattacharya has talked about that.
[01:49:40]  Or, no, it's John Ioannidis.
[01:49:42]  No, I think he had like an Asian last name, like a Chinese or Japanese or something like that.
[01:49:48]  It's one thing to say incorrect, another thing to say incomplete.
[01:49:54]  He said either incorrect or new stuff has basically.
[01:49:58]  Oh, yeah, I believe that.
[01:50:00]  You evolve models.
[01:50:00]  That's what science is.
[01:50:01]  It's never complete, it's always probabilistic and evolving.
[01:50:04]  That's what's beautiful.
[01:50:06]  I do want to get back into mechanism, but I think something to highlight.
[01:50:12]  There is no perfect study.
[01:50:14]  So you can always poke holes in a study.
[01:50:16]  I think one that would be good to talk about that actually is on balance a pretty decent study that has gotten some heat is the Minnesota coronary experiment, if we're going to delve into one.
[01:50:24]  Yeah, I can talk about it.
[01:50:25]  So, yeah, just to kind of give a high level breakdown of this, there were patients kept at mental hospitals in, I think, one nursing home, and they were given a diet that was either very elevated in linoleic acid, I think it was close to 14%.
[01:50:42]  Of kcals from linoleic acid?
[01:50:44]  18 to 20.
[01:50:45]  Of calories from linoleic acid?
[01:50:47]  Are you sure?
[01:50:48]  Can you punch it on this, Steve?
[01:50:49]  Her experimental diet goal was to provide 18 to 20% of calories from polyunsaturated fat, while the control diet aimed for 18% of calories from saturated fat.
[01:50:56]  There were 9,000 give or take participants.
[01:51:00]  I think it ended up being like 13.
[01:51:02]  I actually have the primary paper up here.
[01:51:06]  Something like 13.
[01:51:09]  Anyway, that aside, there was a larger.
[01:51:12]  One minute.
[01:51:13]  13.2% of calories versus 4.7%.
[01:51:15]  So there was a randomized controlled trial, in this case, it was actually double blinded, supposedly, where there was a group that was given more linoleic acid in the form of corn oil versus a group that got a higher saturated fat diet, relatively.
[01:51:29]  Right.
[01:51:30]  And then the results were a massive drop in LDL in the corn oil group, but trending towards worse mortality, so more deaths and more cardiovascular disease, including on autopsy.
[01:51:43]  So they had autopsies of these people, especially in the older.
[01:51:46]  The older age groups, over 65.
[01:51:48]  It appeared to be the case.
[01:51:49]  The fact is, a lot of the data weren't available.
[01:51:51]  They were like in the basement on like nine track tapes and they had to be recovered.
[01:51:55]  There's a crazy story about this one.
[01:51:56]  Yeah, Malcolm Gladwell.
[01:51:57]  You should have talked about this.
[01:51:58]  Nick, yeah.
[01:51:59]  Malcolm Gladwell did a podcast about this on his revisionist history called The Basement Tapes.
[01:52:04]  The history of this is that Ansel Keyes, so who is kind of an infamous researcher.
[01:52:09]  Yeah.
[01:52:09]  I didn't mean to interrupt you, Nick, but I'll just add this and then I'll let you run with it again.
[01:52:13]  Infamous researcher in the 1950s and 1960s was one of the primary authors of this paper.
[01:52:18]  Yeah.
[01:52:19]  He and the main author did not publish the results for many, many years.
[01:52:23]  And then Chris Ramsden, who's done a lot of interesting work in the space that we can talk about some other stuff that he's done, actually found the information in one of these primary authors' basements and redid the analysis many years later, 16 years later, I think.
[01:52:39]  And that's this stuff?
[01:52:40]  That's this study.
[01:52:42]  Wow.
[01:52:42]  Yeah, so it wasn't originally published.
[01:52:45]  Antel Keyes obviously was in favor of the hypothesis that polyunsaturated fats were good for humans.
[01:52:51]  He was kind of the beginning of this diet heart hypothesis, and this didn't fit his results.
[01:52:55]  So, that this possible that he wasn't happy about this, who knows?
[01:52:58]  Whoa, or they just got lost.
[01:53:00]  Yeah, so I again come back to it's interesting framing.
[01:53:04]  Is it possibly suppressed?
[01:53:06]  Maybe I don't even know that that's a functional way to look at it.
[01:53:08]  So, we can talk a little bit more about the study and the criticisms of it.
[01:53:12]  Steve, can you go copy the PubMed ID in Paul's tweet and then go to figure six in the paper?
[01:53:18]  It's going to become relevant in a second.
[01:53:20]  But, high level, the criticisms as I understand them, because again, there is no perfect study.
[01:53:29]  It's been being talked about recently because I think Mark Hyman did a pretty viral reel on it, where, like you said, in the other trials, there was more trans fat in one group.
[01:53:37]  It's being argued that the higher trans fat diet was the corn oleo diet.
[01:53:41]  And that accounted for the effect.
[01:53:43]  And also, about three quarters of the patients dropped out of the trial.
[01:53:50]  It's complicated.
[01:53:50]  My two cents on this is okay, first of all, I don't know how much the trans fat difference between the groups actually was, if at all.
[01:54:01]  It's interesting, Ramsden and I'll actually talk about this in the paper.
[01:54:05]  They talk about how Ansel Key's new trans fats elevated saturated fat, so it would have designed the diet in such a way that.
[01:54:11]  They elevated LDL.
[01:54:12]  Trans fats, elevated LDL.
[01:54:13]  Elevated LDL.
[01:54:14]  So it would have been designed in a way to potentially minimize the trans fats.
[01:54:18]  It's all speculative as to whether there was actually a difference in trans fats and what that difference would be.
[01:54:23]  Now, even if there was a difference, I really find it unlikely that it drove.
[01:54:29]  You might go to my screen, Steve.
[01:54:30]  Oh, yeah.
[01:54:31]  I have that.
[01:54:32]  And you want figure.
[01:54:33]  I was going to show six in the panel on the bottom left.
[01:54:37]  You'll know what I mean when I say it, show it.
[01:54:41]  I don't think that the trans fat difference.
[01:54:43]  Even if it exists, it would drive the full effect.
[01:54:45]  It's possible.
[01:54:46]  Figure five or figure six?
[01:54:47]  Six.
[01:54:48]  Okay.
[01:54:50]  You know, and then the other thing with the attrition, because this keeps on coming up, it's very easy to try to discredit studies like this by saying, oh, they lost 75% of their participants.
[01:54:59]  But when you think about how it was constructed, the only way you get this sort of control is like hospitalized patients.
[01:55:06]  And guess what?
[01:55:06]  Patients get discharged.
[01:55:08]  So they selected to do the analysis on patients who had been in the study over a year and three quarters or more or less.
[01:55:15]  Got discharged from the hospital.
[01:55:16]  But there's no reason, and I was talking with another scientist about this study, and I was making the point do you have any reason to believe that would actually bias the results?
[01:55:25]  They still had over 2,000 people.
[01:55:27]  Yes, the end value decreased, but I don't see any reason why the attrition would lead to bias.
[01:55:31]  So I don't think that can account for the findings.
[01:55:34]  So how do you account for findings like are we seeing Paul's screen?
[01:55:37]  If you go down to the, scroll down a tiny bit, Paul, like the bottom left, you can read the caption death from any cause and change in cholesterol in the cohorts receiving the diets for one year or more.
[01:55:48]  And what do you see?
[01:55:49]  Like, There's actually a pretty clear dose response from cholesterol lowering and probability of death.
[01:55:54]  That's what it's saying.
[01:55:55]  The more right to you go, the lower the cholesterol drops as a result of the intervention and the higher the probability of death.
[01:56:00]  The lower the cholesterol goes, the more people die.
[01:56:02]  And again, it's really important to be clear about what claims I am making and what claims I'm rebutting or not making.
[01:56:11]  So I'm not saying omega 6 linoleic acid kills.
[01:56:15]  I'm not making that claim.
[01:56:16]  What I'm saying, and actually, if you read the Ramsden paper, They more or less make this point this is highly inconsistent with the current diet heart hypothesis, and that we need to be more humble about our knowledge based on the evidence and not make sweeping recommendations like chop saturated fat, increase unsaturated fat, and LDL is bad, and if you lower it, it's good.
[01:56:45]  It's again the idea of the myopic focus on LDL.
[01:56:49]  Yeah.
[01:56:50]  Rebutting a claim, not necessarily making the extreme opposite claim.
[01:56:54]  And I think that's super important.
[01:56:56]  I mean, these might be interesting to look at.
[01:56:57]  The higher the cholesterol, the lower the mortality rate?
[01:57:02]  As the cholesterol dropped, more people died.
[01:57:05]  So, as people in the, we talked about this earlier, as people got the seed oil group, they, they, cholesterol drops.
[01:57:12]  When you give people polyunsaturated fats, you're, you will lower the LDL.
[01:57:15]  We can talk about the potential mechanisms there.
[01:57:17]  And so, in the Minnesota coronary experiment, and these are the Kaplan Meyer survival curves we can talk about as well.
[01:57:22]  Okay.
[01:57:23]  In the Minnesota coronary experiment, the people that had the highest degree of cholesterol lowering had the highest increased rate of death, right?
[01:57:31]  The most increased rate of death.
[01:57:32]  And what Nick is saying is that this is in contradistinction to the mainstream recommendations that cholesterol lowering is always good.
[01:57:38]  And this is why Minnesota has been talked about so much.
[01:57:40]  It's the largest trial that we have.
[01:57:43]  It was very rigorously conducted.
[01:57:44]  Again, Ansel Keyes, a proponent of the diet heart hypothesis, was one of the key investigators here.
[01:57:49]  It was double blinded.
[01:57:50]  So, what that means is that the patients nor the doctors knew what was in these burger patties that they got.
[01:57:55]  This is like the equivalent of Beyond Beef in the 1950s and 60s.
[01:57:59]  Some people got burger patties that were enriched in corn oil, and some people got burger patties that were enriched in other saturated fat rich margarines.
[01:58:05]  As Nick has pointed out, both groups probably got trans fats.
[01:58:08]  And one of the criticisms of this study has been well, did the Experimental group get more trans fats, and then as Nick and I, I believe, are both arguing, what we know about trans fat is they raise LDL, right?
[01:58:23]  And in the experimental group, the LDL tended to go down, right?
[01:58:26]  So, if the amount of trans fat in the experimental group were significant enough to skew the results, then why did the LDL go down so much in the experimental group, and why was it that the more the LDL went down, the higher there was the incidence of death, right?
[01:58:42]  So, you're You're having worse outcomes.
[01:58:44]  Essentially, it's trending toward worse outcomes when you give people more seed oils, potentially, which is different than what the experimenters expected.
[01:58:51]  Yeah, I think it's just a matter of even if people are like, okay, well, there's a very potent specific trans fat that accounts for the effect.
[01:59:03]  What I'm trying to say, and I think Paul's trying to say the same thing, is yeah, but practically in the zeitgeist and in medicine today, we still myopically focus on the biomarker LDL.
[01:59:16]  Stuff like this proves that is a mistake.
[01:59:20]  Even if there are other factors, I'm not actually attributing increased death to the change in LDL.
[01:59:24]  I'm not.
[01:59:25]  But it reinforces that the dogmatic blanket statements, reduce saturated fat, increase poly, get your LDL down, they're problematic.
[01:59:35]  And you hear this again and again these platitudes, lower is better with respect to LDL and Applebee.
[01:59:39]  And it's like, well, lower is better with respect to what?
[01:59:42]  Just cardiovascular risk?
[01:59:44]  How did you lower it?
[01:59:44]  What were the other effects of the interventions?
[01:59:46]  Are you looking at other factors beyond just cardiovascular risk?
[01:59:48]  There's so much context.
[01:59:50]  And the reason people get pissed off is because even if you can't understand all the nuances of Delta 60 saturates, 12, 13 dihome, yada, yada, yada, people can tell when they're being patronized to.
[02:00:02]  And I think what modern medicine has a problem with now is dumbing it down way too far.
[02:00:09]  Right.
[02:00:09]  And speaking down to people like, oh, lower is better.
[02:00:13]  Don't worry about the details.
[02:00:14]  We got that.
[02:00:16]  And then we just end up speaking past each other.
[02:00:17]  So it's important to entertain studies like this because they do have relevance.
[02:00:23]  To what recommendations we make.
[02:00:25]  And I want to tap upon Harvard School of Public Health did a rebuttal to it.
[02:00:30]  Actually, one of the people said in the rebuttal is someone I'm quite close with and think on balance highly of.
[02:00:35]  But they call this study an interesting historical footnote that has no relevance to current dietary recommendations.
[02:00:43]  There's some interesting patterns in this rebuttal.
[02:00:45]  I can send it to you, we can link it in the notes.
[02:00:47]  But a few interesting things that I want to point out To dietary recommendations.
[02:00:53]  It says no relevance.
[02:00:53]  Whose dietary recommendations?
[02:00:55]  It says no relevance.
[02:00:56]  The way they go about rebutting it again is like it's interesting to see how when contradictory evidence comes up, people tend to divert.
[02:01:03]  So they talk about, oh, well, omega 3s are important.
[02:01:06]  I'm like, well, yeah, but I don't think that changed much from the study.
[02:01:08]  And that's kind of like off point anyway.
[02:01:10]  Or, and this was funny.
[02:01:12]  I'm trying to find the exact line.
[02:01:15]  Basically, they say, well, in this study where people were eating 13.8% linoleic acid, oh, yeah, here.
[02:01:24]  The diet used in the Minnesota coronary experiment was never consumed by any appreciable number of Americans.
[02:01:29]  And the level of Of linoleic acid was well above the range recommended by the American Heart Association or any other group.
[02:01:37]  So it sounds, when you read that, like a concession that too much linoleic acid could be bad, but it's a diversion.
[02:01:46]  And what the words actually mean is there is an RDA or like a target.
[02:01:51]  So, say, for vitamin D, I think it's 800 international units, which you want to go that or above.
[02:01:56]  The way it's reading here is like, well, we can disregard the study because they were eating so much linoleic acid, but have you ever heard?
[02:02:03]  Any like media outlet that is associated with conventional medicine or doctor or guidelines say, hey, don't get more than this much linoleic acid.
[02:02:12]  But if you look at it, you're right.
[02:02:14]  And if you look at it, I mean, most Americans are eating that exactly that amount of linoleic acid today 10 to 15% is the average linoleic acid in most of our diets today.
[02:02:22]  So for Walter Willett to say that 13% was far in excess of what is recommended or what is achieved by Americans, like he's a little bit out of touch because it doesn't take much to get 13%.
[02:02:31]  I mean, remember that fat traditionally is nine calories per gram.
[02:02:34]  And so if you're eating salad dressing with seed oils and You're going to McDonald's for fries or eating some processed food during the day.
[02:02:41]  And even if you're going to Chipotle where they're cooking the chicken and the rice in seed oils, I mean, they're pervasive.
[02:02:46]  I saw that video you did.
[02:02:46]  They're pervasive, right?
[02:02:48]  It's pretty easy to get 10 plus percent of your calories from linoleic acid.
[02:02:52]  So it's an interesting criticism.
[02:02:53]  But yeah, and as Nick is saying, I mean, we certainly don't hear from the American Heart Association, like, don't get more than 10 percent of your calories from it.
[02:03:02]  It's totally false what Willett is saying here.
[02:03:05]  In distinction, they definitely tell you to limit your saturated fat.
[02:03:07]  Right.
[02:03:08]  And so it's a matter of like, Double standards.
[02:03:10]  I really like, I read it before, but I'm going to read it again.
[02:03:12]  How this paper ends.
[02:03:14]  Ramsden et al. say, given the limitations of current evidence, the best approach might be one of humility, highlighting the limitations of current knowledge.
[02:03:21]  They don't say this, but with respect to linoleic acid, omega 6, and saturated fat, and setting a high bar for advising intakes beyond what we can provide by natural diets.
[02:03:31]  So basically, they boil it down to, and I love to get into the weeds, but like, you know, if you're eating, this is how I read it, like steak, eggs, walnuts, whole foods, It's probably the most pragmatic approach.
[02:03:43]  Right.
[02:03:44]  In the absence of high quality evidence saying, you know, these foods are bad.
[02:03:49]  And when I say these foods, I mean foods naturally rich in these components.
[02:03:53]  Because, yeah, like steak and butter get vilified based on much weaker evidence, in my opinion, than like this study.
[02:04:01]  Oh, well, we can talk about it.
[02:04:03]  But, you know, I don't want to get, I want to finish talking about seed oils.
[02:04:06]  But the evidence that saturated fat is harmful for humans is weak.
[02:04:10]  Weaker than that.
[02:04:12]  It's extremely weak.
[02:04:13]  And, you know, there's lots of evidence.
[02:04:14]  This is just a Kaplan Meyer curve.

=== Diverging Kaplan-Meyer Curves (02:53) ===

[02:04:15]  So you can see on the bottom right, the red dotted line is the experimental group, and the blue dotted line is the control group.
[02:04:23]  And, you know, the bottom right is women over age, actually all participants over age 65.
[02:04:29]  You can see a large divergence there.
[02:04:31]  And what you see is that the over age 65, the people who were getting the experimental diet that was rich in the seed oils, corn oil in this case, had a much quicker death, right?
[02:04:41]  So in a Kaplan Meyer curve, or maybe I mixed them up.
[02:04:45]  No, you're right.
[02:04:45]  So, lower survival if the red line is lower than the blue line.
[02:04:49]  Yeah.
[02:04:50]  In the over 65 group.
[02:04:51]  And so, I don't think.
[02:04:53]  The diet group is the blue line.
[02:04:54]  I'm sorry.
[02:04:54]  So, in this way, it's going up.
[02:04:56]  So, the people, the cumulative proportion of death, they kind of reversed it.
[02:04:59]  The cumulative proportion of death, the blue line is the experimental group.
[02:05:01]  The red line is the control group.
[02:05:03]  Experimental group meaning what?
[02:05:04]  The seed oils.
[02:05:05]  So, the seed oil group was dying faster.
[02:05:07]  You can see how much that blue line diverges from the red line in the bottom right, especially starting at 400 days, by 450, 500 days.
[02:05:15]  So, right here, you see this clear divergence.
[02:05:17]  Yes.
[02:05:18]  It pretty much, you can see that the experimental group, the blue line, is making up a larger cumulative proportion of the deaths.
[02:05:25]  Than the experimental group getting the higher saturated fat.
[02:05:28]  So, this is interesting, right?
[02:05:30]  And this diverges from the mainstream guidelines at the time.
[02:05:33]  And this is just one randomized controlled trial.
[02:05:35]  We can look at some other ones, but this is what's tricky about the data, the RCT data on cereals versus saturated fat.
[02:05:42]  As I said in the beginning, it's all done 30 to 40 years ago at best.
[02:05:47]  None of it's perfect.
[02:05:48]  If you look at the best trials, in my opinion, I would argue they show things like this.
[02:05:52]  And the trials that show different results, you have pretty major fatal flaws in the design of the study.
[02:05:57]  This is what we're dealing with, though.
[02:05:59]  And I think it's why, hopefully we'll get into this in a moment, we can also kind of step back, maybe look at some animal data and look at some mechanisms to try and guide us.
[02:06:06]  And why I did kind of want to frame it for people from a historical perspective, because I think ultimately what we're dealing with here is the question, there are two major questions maybe to this podcast.
[02:06:15]  Do I have to worry about my elevated LDL?
[02:06:17]  And should I be eating butter?
[02:06:19]  I'm oversimplifying this, obviously.
[02:06:21]  Should I be eating butter or should I be eating soybean oil?
[02:06:23]  What do I do to be healthy?
[02:06:25]  Got it.
[02:06:26]  Now, what is your current LDL?
[02:06:29]  Is it still in the 500s?
[02:06:30]  My last check was 574.
[02:06:31]  574, and you're letting it ride at 574.
[02:06:33]  I'm monitoring my cardiovascular health by coronary CT and GR.
[02:06:40]  Right, right, right.
[02:06:40]  And last check, it was zero.
[02:06:42]  Zero.
[02:06:43]  I might also have, you know, there's a lot of context around this, including family history.
[02:06:47]  My mom is actually in a similar boat, but she's 60.
[02:06:51]  So her LDL, funnily enough, she probably has some sprinkling of a congenitally high LDL.
[02:06:58]  So she's always had high LDL, but then she went keto and it went to like the 400s.
[02:07:03]  So she's given permission to talk about this.
[02:07:06]  And by the way, she's an MD, PhD as well.
[02:07:08]  So, like, I'm not really.

=== Western Diets and Obesity Susceptibility (13:19) ===

[02:07:09]  Yeah.
[02:07:09]  So she can make her own medical decisions.
[02:07:11]  But we ended up talking about, like, well, what should she do?
[02:07:14]  Her lifetime exposure to LDL and Applebee is astronomical.
[02:07:18]  Got a coronary CT angiography?
[02:07:20]  Zero.
[02:07:22]  65.
[02:07:23]  60.
[02:07:23]  So, how can LDL be causal, right?
[02:07:25]  Well, it's individual.
[02:07:27]  There are better things to look at now than LDL.
[02:07:31]  And LDL, I don't think, should ever be looked at in isolation.
[02:07:35]  Does she know we're fasting insulin?
[02:07:36]  It's low.
[02:07:37]  Presumably.
[02:07:38]  Yeah, I've seen it.
[02:07:38]  It's probably like three years.
[02:07:39]  She's metabolically healthy.
[02:07:40]  She's very metabolically healthy.
[02:07:41]  Wow.
[02:07:42]  Phenotypically or by blood work?
[02:07:43]  Yeah, yeah.
[02:07:45]  She looks like she's like 40.
[02:07:46]  Yeah, right.
[02:07:47]  What do you think the ultimate cause?
[02:07:49]  I know there's probably multiple causes, but what do you think the ultimate cause is of why so many people are obese in America?
[02:07:54]  This is the big question.
[02:07:56]  So actually, this is a good place to talk about mechanisms.
[02:08:00]  Do you think seed oils can cause obesity?
[02:08:02]  And if so, how?
[02:08:03]  Okay, so let me pull up another study that I found this one in preparation for this podcast.
[02:08:07]  I think you guys will find this interesting.
[02:08:10]  So there are a couple of things here.
[02:08:15]  Could endocannabinoids.
[02:08:17]  Yeah.
[02:08:18]  So this one is interesting.
[02:08:21]  This is a trial from 2020, and it looked at levels of 2AG and anandamide.
[02:08:28]  These are endocannabinoids, similar to cannabinoids that you would get from like marijuana, in 183 obese females from Iran.
[02:08:37]  And what they found was that there were three major dietary patterns, Western, healthy, and traditional.
[02:08:42]  And the women, the obese women who had the Western dietary pattern had higher levels of 2AG and AEA.
[02:08:51]  The reason this is interesting to me is because these can affect appetite and satiety in a negative way, right?
[02:08:57]  So you get the munchies from smoking weed, right?
[02:09:00]  And conversely, there's a drug called Ramonabant, which is a CB1 antagonist.
[02:09:05]  So cannabinoid receptor one antagonist is Ramonabant.
[02:09:09]  Ramonabant works very well to reverse cardiovascular disease in trials.
[02:09:16]  It reverses obesity in many ways, it minimizes appetite in a lot of ways.
[02:09:21]  From a psychiatric level, It creates suicidality.
[02:09:26]  Oh, shit.
[02:09:26]  So it's off the market in the United States.
[02:09:28]  But when you block the CB1 receptor mechanistically with Ramonaban, you get positive metabolic outcomes.
[02:09:36]  So it's interesting to me that in obese women who eat a Western dietary pattern, which of course encompasses many things, but will include seed oils, also processed grains, processed sugars, that does correlate with higher levels of endogenous cannabinoids, 2AG and AEA.
[02:09:54]  2AG and AEA are Some of the breakdown downstream products from arachidonic acid from linoleic acid.
[02:10:01]  So it's possible, right, that in predisposed individuals, potentially individuals who have polymorphisms in D6D, right, so fatty acid desaturates 2, or who are predisposed, is it possible that consuming linoleic acid or Western foods increases the production of 2AG and AEA, leading to appetite dysregulation?
[02:10:25]  It certainly happens in animal models.
[02:10:26]  If you give Mice or rats, linoleic acid, you see levels of 2AG and AEA rise.
[02:10:32]  I can show you that study too.
[02:10:33]  No one's actually done that study in humans.
[02:10:36]  Nobody has looked at levels of 2AG and AEA in humans when they give linoleic acid.
[02:10:42]  But it's interesting that in obese females with a Western dietary pattern, you can correlate that with higher levels of these.
[02:10:47]  So this is just one punitive mechanism by which seed oils may affect satiety.
[02:10:53]  Interesting.
[02:10:53]  But when we're looking at, I'll say this and then I'll pause, Nick, and let you add whatever you want.
[02:10:57]  When we're looking at obesity, I think that appetite and satiety are key, right?
[02:11:03]  Because you probably know this, Danny.
[02:11:07]  It's pretty hard to overeat unprocessed food.
[02:11:11]  Like when you're eating steak and squash, you just get full and you're kind of done.
[02:11:16]  But something different happens when you add a potato chip or whatever.
[02:11:20]  It's like you can't stop.
[02:11:21]  It's like crack.
[02:11:21]  A Coca Cola, right?
[02:11:22]  Something.
[02:11:23]  And this may tie into leptin and fat and the hypothalamus, and it can talk to that as well if you want.
[02:11:28]  But there is some.
[02:11:31]  Saboteur to our satiety, I believe, within our food supply, right?
[02:11:35]  It's not, Nick said he doesn't believe it's calories that are making us obese, and I would agree with that.
[02:11:40]  My take on that is it's the quality of the foods you eat, not the amount of calories you eat, because I sort of feel, and this is again just my perspective, that if you are eating generally high quality, unprocessed food, you will become a predominantly healthy human and your satiety mechanisms will be intact and you will be unlikely to overeat.
[02:12:01]  If I put a gun to your head and force you to overeat, I could.
[02:12:03]  Right.
[02:12:04]  But generally speaking, in a free living human, you're not going to overeat steak, potato, right?
[02:12:11]  Right.
[02:12:11]  Unprocessed food.
[02:12:12]  You're going to overeat chips, tostitos, Takis, brownies, Coca Cola.
[02:12:16]  So there's something going on with satiety.
[02:12:18]  So when I saw this, I was like, that's really interesting.
[02:12:21]  Is it possible, again, just a possible putative mechanism, that some people are more predisposed to this?
[02:12:27]  Western dietary patterns affect the levels of these endogenous cannabinoids and make us hungrier.
[02:12:31]  There are lots of other potential mechanisms by which seed oils may affect obesity, but that's just one of them that I thought was cool.
[02:12:38]  I think it's an interesting hypothesis.
[02:12:40]  I want to.
[02:12:43]  You would agree, I don't mean this to be offensive, but that is stretching, do you think?
[02:12:48]  Well, I mean, you see higher levels of these in women with a Western dietary pattern.
[02:12:53]  In animal models, giving linoleic acid leads to higher levels of 2AG and AEA.
[02:12:58]  I think every piece is there.
[02:13:01]  In studies where the levels of linoleic acid are decreased, you can see these also go down.
[02:13:08]  Let me phrase this a different way.
[02:13:09]  When people lose weight, these go down.
[02:13:11]  Let me put it a different way then.
[02:13:13]  Even if this is part of the puzzle, what percentage would you attribute the obesity epidemic to this mechanism and then seed oils in general?
[02:13:22]  Who knows?
[02:13:23]  Who knows?
[02:13:24]  It's impossible to, I can't tease that out, right?
[02:13:25]  Because seed oils most of the time co-occur with other things, right?
[02:13:33]  So broadly speaking, I think that we can take a step back and say, we can all probably agree that a Western dietary pattern is harmful for humans.
[02:13:44]  A Western dietary pattern is essentially, you can think of the epitome like a piece of, like a processed sweet roll of bread, right?
[02:13:51]  It's processed flour, processed sugar, processed seed oils, potentially some dyes, some dough conditioners, and some preservatives.
[02:13:57]  We know that that is a metabolic nightmare for humans.
[02:14:00]  And so, if we try and tease it out, it's difficult to do that, right?
[02:14:04]  We have these randomized controlled trials where we're looking at saturated fats versus seed oils specifically.
[02:14:09]  But I think it's impossible for me to attribute specifically to seed oils.
[02:14:14]  I think that when I look at the evidence on balance, seed oils look to be harmful for me.
[02:14:20]  Yeah.
[02:14:21]  I want to ask a few.
[02:14:23]  This is really helpful.
[02:14:24]  I think people are going to appreciate hearing this from you.
[02:14:26]  You have a big following, a lot of clout.
[02:14:28]  That's easy to name.
[02:14:29]  So, I'm going to ask you some like on a scale of zero to 10, how confident are you?
[02:14:33]  Okay.
[02:14:34]  So, on a scale of zero to 10, how confident are you that linoleic acid can cause obesity in humans?
[02:14:42]  Now, obesity wouldn't be the first outcome that I would think of.
[02:14:48]  When I think of linoleic acid, the thing I'm most concerned about are the two things I'm most concerned about are propensity for LDL oxidation and incident coronary artery disease.
[02:14:59]  Okay.
[02:14:59]  And downstream effects of oxlams.
[02:15:05]  And then obesity is just more complex.
[02:15:07]  All right, so we'll start with negative downstream effects on LDL oxidation and production of oxlams.
[02:15:12]  Zero to 10.
[02:15:13]  How confident?
[02:15:13]  Those are two different outcomes.
[02:15:15]  Oxidation of LDL.
[02:15:16]  Pretty confident.
[02:15:18]  Give me a number.
[02:15:19]  Eight to nine.
[02:15:20]  Multiple randomized controlled trials showing that more linoleic acid leads to higher levels of oxidation of LDL.
[02:15:25]  And how about obesity, out of curiosity?
[02:15:27]  And if it's a two, then say two.
[02:15:28]  Obesity is such a complicated thing, right?
[02:15:31]  So is your question.
[02:15:33]  What contribution to obesity do seed oils have?
[02:15:36]  Omega 6, and then I'm going to ask about seed oils.
[02:15:38]  Those are two different questions.
[02:15:39]  Oh, okay.
[02:15:39]  So you're asking about omega 6.
[02:15:40]  Omega 6.
[02:15:41]  Well, I guess I don't know that we can necessarily differentiate those because omega 6 don't occur.
[02:15:47]  Like, are you talking about like walnuts?
[02:15:49]  Yeah.
[02:15:49]  I don't think walnuts cause obesity much.
[02:15:51]  But to be clear, like, three ounces of walnuts is something like 31, 32,000 milligrams of omega 6.
[02:16:00]  It is more, there's a ton of omega 6.
[02:16:02]  Let's check that.
[02:16:03]  Yeah.
[02:16:04]  Steve, you want to check how much omega 6?
[02:16:07]  Is in an ounce of walnuts.
[02:16:09]  I think it's something like 10,000 plus milligrams.
[02:16:11]  Well, that's less than a tablespoon, but okay.
[02:16:15]  I mean, you know, well, if we're talking grams, right?
[02:16:18]  Okay, 10 grams.
[02:16:18]  10 grams, yeah, yeah.
[02:16:21]  Of just linoleic acid.
[02:16:22]  Yeah.
[02:16:23]  An ounce of walnuts contains roughly 10.8 grams of omega 6 fatty acids.
[02:16:28]  Yeah, sure.
[02:16:29]  Okay.
[02:16:29]  So, and I think I understand your position on this, but I don't think most people do.
[02:16:35]  This is why I'm asking the question, not to be a dick.
[02:16:38]  It also contains 2.5 grams of omega 3s.
[02:16:40]  ALA.
[02:16:41]  Yeah, we can talk about that later.
[02:16:42]  But, okay, so, you know, if somebody were to consume four ounces of walnuts, that's like, you know, on the order of 43, 44 grams of just linoleic acid.
[02:16:55]  Right.
[02:16:55]  So that's going to be, you know, multiple, like near almost 400 calories from just linoleic acid.
[02:17:01]  You're on a 2,000 calorie diet, that is 20% of your calories from linoleic acid.
[02:17:05]  So could four ounces of walnuts be bad for you?
[02:17:08]  Cause obesity?
[02:17:09]  I think it depends on the context, yeah.
[02:17:11]  I think that in general, if we're talking about walnuts specifically, maybe.
[02:17:15]  You're like, you're a very unconfident, this is interesting, maybe, but we don't know.
[02:17:19]  Yeah, we don't know.
[02:17:20]  Okay.
[02:17:20]  I think that's useful to hear.
[02:17:22]  Now.
[02:17:23]  And again, like, the walnuts conversation is very different than the seed oil conversation.
[02:17:27]  I agree.
[02:17:27]  But the reason I'm asking these questions so explicitly, again, not just to give you a hard time, but because I really think we understand the distinction in our minds.
[02:17:36]  I just don't think it gets discussed.
[02:17:38]  Like, I have literally.
[02:17:40]  The degree of domino chain logic creep that you see is like, okay, highly oxidized processed seed oils are bad.
[02:17:46]  Then it's.
[02:17:48]  Omega 6 are all bad.
[02:17:49]  Then it's polyunsaturated fats.
[02:17:51]  They're fragile and they're bad for you.
[02:17:53]  I've literally had people tell me that Quest candy bars, non ironically, are healthier than sardines because they're high in pufa.
[02:18:04]  Sardines are high in pufa or Quest candy bars are high in pufa?
[02:18:06]  Sardines, they have omega 3.
[02:18:09]  I'm just saying that is at the extreme end of the interpretation.
[02:18:12]  Sure.
[02:18:12]  But triage point one, if people get nothing out of it, is.
[02:18:19]  Linoleic acid, omega 6, in whole food is very different than the heated process stuff.
[02:18:25]  Right?
[02:18:25]  It's certainly going to occur with many other cofactors, vitamin E, et cetera.
[02:18:30]  Right.
[02:18:30]  Right.
[02:18:30]  But also, there's going to be, just to complete the picture on what happens once it's in the body, even aside from outside, you mentioned obesity.
[02:18:40]  One thing I think is really interesting as a hypothesis is could a certain metabolic state, let's call it obesity, make you more susceptible to omega 6?
[02:18:47]  So you talked about LDL oxidation.
[02:18:50]  One enzyme and a biomarker, you can go to Quest or LabCorp and get this measure.
[02:18:54]  It's called myeloperoxidase, MPO.
[02:18:56]  Myeloperoxidase is really interesting because it increases cardiovascular risk in several ways.
[02:19:01]  One way is increasing the oxidation of LDL from within the vessels.
[02:19:06]  Interestingly, it's produced by fat, actually around blood vessels, called perivascular adipose tissue.
[02:19:12]  It decreases fat browning and decreases energy expenditure, at least in animals, and then decreases adiponectin, which is kind of like a yoga class for your arteries.
[02:19:20]  So basically, this.
[02:19:22]  Fat produced hormone that does go up in obesity makes blood vessels stiffer, oxidizes LDL.
[02:19:28]  So, just the oxidation effect if you have an environment where you're more susceptible to oxidation, have higher levels of this enzyme because you have more fat tissue secreting it, you might be more susceptible to damage from quote unquote excess omega 6 versus, say, you're lean, healthy, and on a ketogenic diet.
[02:19:46]  Little lake acid is incredibly ketogenic.
[02:19:48]  Turns out I can boost my ketone levels with sesame oil over 20 hours to like six millimoles.
[02:19:54]  Yeah, whether that has any.
[02:19:55]  Clinical relevance is questionable.
[02:19:57]  The point is whether we're talking about 12, you know, 13 dihomia, I guess we're calling it, oxidation by myeloperoxidase, generation of 4 HNE, turning into ketones, this biomolecule has so many paths.
[02:20:10]  Sure, linoleic acid can go a lot of different places.
[02:20:12]  And the metabolic milieu, your metabolic status influences how you partition, I mean, how you partition everything, how you partition calories, how you partition linoleic acid into different biomolecules.
[02:20:23]  So I emphasize this because I want people to be thoughtful, just like applying it to their own life.

=== Acrolein, Hexane, and Benzene Risks (08:50) ===

[02:20:28]  What food are we talking about?
[02:20:30]  And what is my metabolic status?
[02:20:32]  If you have pre existing obesity and you're eating a mixed macronutrient diet, maybe you shouldn't be cooking.
[02:20:36]  I would think you shouldn't be cooking with corn oil.
[02:20:38]  I can agree with you on that.
[02:20:39]  Your lean, healthy keto are, you know, two ounces of walnuts bad for you?
[02:20:43]  I don't think so.
[02:20:44]  I don't think so.
[02:20:45]  Yeah.
[02:20:45]  I mean, it's a different situation.
[02:20:46]  Yeah.
[02:20:46]  Oh, I agree.
[02:20:47]  And I just, I think that's really, those are extreme examples.
[02:20:50]  Yeah.
[02:20:51]  But they highlight a very important point.
[02:20:54]  Yeah.
[02:20:54]  I think what most of what I think is important about this conversation is the oxidized, well, presumably oxidized, refined, bleached, and deodorized seed oils.
[02:21:02]  Okay.
[02:21:02]  Yes.
[02:21:03]  I want to ask you now refined, bleached, and deodorized.
[02:21:06]  Big $10 scary words.
[02:21:08]  Right.
[02:21:08]  Specifically, what's going on that you're concerned about in that the refining, the heating, Oxidation, we can table that.
[02:21:14]  That's obvious.
[02:21:15]  Refining, bleaching, deodorizing.
[02:21:19]  What specifically in that chemical process is increasing risk?
[02:21:22]  What is the, isn't there something called hexane or something?
[02:21:25]  There is hexane, yeah.
[02:21:26]  Yeah, you can measure it.
[02:21:27]  And that's neurotoxic.
[02:21:28]  Benzene also.
[02:21:29]  Hexane is neurotoxic.
[02:21:30]  But again, it's a question of.
[02:21:31]  And hexane comes off of when you do the bleach and the oxidizing of these oils.
[02:21:35]  So it's used to extract the oil from something where.
[02:21:38]  Right, right, right.
[02:21:39]  You can imagine it's hard to extract oil from corn.
[02:21:42]  So it's used to like, you know, separate out the oil.
[02:21:44]  And then they try to remove the hexane, but some residual remains.
[02:21:47]  I tried to look for how much residual remains, and it does vary.
[02:21:52]  I think there's like one study out of Iran or something like that I found.
[02:21:54]  But my question is again, this comes down to what do we know and what do we don't know.
[02:22:01]  The fact that there is something that has neurotoxic potential used to treat food, I think, is eh, that concerns me.
[02:22:09]  But that's very different from someone saying seed oils contain neurotoxins and implying.
[02:22:17]  That there's actually seed oil associated neurotoxicity, which it's hard because you wouldn't go off of what is required to cause acute toxicity.
[02:22:29]  It's not like you're going to have a tablespoon of corn oil and get neurotoxicity.
[02:22:33]  So there's the argument of, well, small cumulative doses are problematic.
[02:22:37]  It's a reasonable hypothesis.
[02:22:39]  The thing is, I don't think we'll ever really know.
[02:22:43]  There have been studies on this.
[02:22:45]  Steve, will you show my screen real quick?
[02:22:48]  So, we have, I mean, this is a study on the estimated trace amounts of benzene in solvent extracted vegetable oils and seed oil cakes.
[02:22:55]  I mean, all seed oils are solvent extracted.
[02:22:58]  So, again, they're tucking vegetable oils versus seed oils, but you can look in here and you can see if you read the paper that there are often trace amounts of benzene, which is a known carcinogen in seed oils.
[02:23:11]  There are other potential contaminants also.
[02:23:13]  So, we have studies looking at.
[02:23:16]  I think Acrolean is one.
[02:23:18]  Acrolein is one that's when you heat the oil.
[02:23:22]  You can look at the presence of heavy metals in vegetable oils.
[02:23:25]  That's been looked at.
[02:23:27]  Now, I mentioned this early in the podcast.
[02:23:30]  Antimony is probably the biggest issue.
[02:23:32]  It's migration from the polyethylene containers of edible vegetable oils.
[02:23:38]  And then the third one to consider is that the vegetable oils are actually quite high in phthalates.
[02:23:43]  We haven't talked about this at all.
[02:23:45]  Phthalates are endocrine disrupting, sort of fragrance.
[02:23:49]  Phthalates are in vegetable oils?
[02:23:50]  Yeah.
[02:23:51]  And this is, they say it in the title, Non Negligible Exposure Source to Humans.
[02:23:55]  Wow.
[02:23:55]  And they actually give a relative amount here.
[02:24:00]  In this paper, they do the calculated average estrogenic equivalence of several major phthalates in edible oils.
[02:24:07]  It falls into the range of 2.7 to 958.1 nanograms of estradiol per liter, 45 to 396 times those in bottled water.
[02:24:17]  So this is a non.
[02:24:21]  Non negligible amount of estrogenic equivalents from these phthalates.
[02:24:25]  I mean, you know, we're talking like there's a massive exposure to humans today cumulatively to these phthalates.
[02:24:32]  So, if I've never heard many people talk about this in seed oils and whether this is coming from the processing or the storage in the plastic containers, you could solve this by putting a soybean oil into a glass container, but that's never going to happen, right?
[02:24:46]  Most of these oils are in these polyethylene plastic containers on the shelf for many times, for many, many months.
[02:24:53]  Yeah, it's interesting.
[02:24:54]  I wasn't aware of buying the oils in glass.
[02:24:58]  I knew glass bottles would probably be better, but I wasn't aware of.
[02:25:02]  The importance of having a glass bottle that doesn't have exposure to UV light.
[02:25:06]  The UV light has some sort of effect on the oil in the bottle.
[02:25:09]  It's part of the oxidation process.
[02:25:11]  Light, heat, and oxygen are part of this process that breaks down the oils.
[02:25:15]  Yeah.
[02:25:15]  There's another study that I can find in a moment that actually looked at the peroxide value in omega 3 and omega 6 oils, and they might have looked at acrolein or other breakdown products.
[02:25:26]  I know we talked about a study, Nick, where they heated oil, right?
[02:25:30]  And this is interesting.
[02:25:30]  So you can take, we discussed this earlier in the podcast.
[02:25:34]  Again, we're differentiating this from a handful of walnuts in function here in practice.
[02:25:39]  You don't put walnuts into a deep fryer, but you put soybean oil into a deep fryer.
[02:25:44]  If you go to Five Guys, if you go to In N Out, if you go to McDonald's, if you go anywhere, I've asked them what's in their fryer.
[02:25:51]  It's usually some mix of soybean oil, corn, and canola oils.
[02:25:54]  And they change the oil once a month.
[02:25:55]  Once a week, probably, which is pretty crazy when you think about you're going 24 hours or 16 hours a day in the fryer oil.
[02:26:02]  Yeah.
[02:26:03]  I just texted you the graph.
[02:26:04]  Your computer's hooked up.
[02:26:06]  You can pull it up.
[02:26:07]  Yeah, well, if you look at what's in some of these oils, these are the aldehydes, and some of these aldehydes are quite high with heating.
[02:26:18]  There's another graph in the paper where they talk about the amount of specific aldehydes and acrolein specifically.
[02:26:26]  The amount of acrolein in a large French fry at McDonald's is equivalent to the amount of acrolein in a pack of cigarettes.
[02:26:37]  Now, this is just one compound.
[02:26:39]  And when I've said this in the past in my content, people like to say, Paul Saladino is saying that seed oils are worse than cigarettes, which is not what I just said.
[02:26:48]  People can rewatch the tape, but it's basically saying that of this one compound, which is a carcinogen, which is very likely, it is pretty significant.
[02:26:58]  So this is a quote from there 154 gram potato chip serving, aldehyde contents are not dissimilar to those arising from a daily allocation of 25 tobacco cigarettes.
[02:27:09]  So this is.
[02:27:11]  This is a specific use case of seed oils, right?
[02:27:13]  This is a heated fry.
[02:27:14]  This is potentially the worst use case of seed oils.
[02:27:17]  Right.
[02:27:18]  That looks to be very bad, but at least in terms of that one compound.
[02:27:23]  So there's a spectrum here.
[02:27:25]  So, what about like Steak and Shake down the road?
[02:27:28]  They're advertising that they cook all their fries in tallow now.
[02:27:31]  So, my perspective is this doesn't solve the equation completely.
[02:27:34]  If you actually, when you read into that one, they never solved this problem where the fries were pre soaked in seed oils.
[02:27:41]  Oh, no.
[02:27:41]  So they're cooking them in tallow.
[02:27:43]  The tallow they're cooking them in has been altered.
[02:27:47]  It's refined.
[02:27:48]  So it has less saturated fats and more monounsaturated fats, so they can work with it more easily.
[02:27:53]  So it's a liquid at room temperature.
[02:27:56]  Tallow is not usually liquid in 73, 74 degrees.
[02:28:00]  So the steak and shake tallow is a refined tallow that has more monounsaturated fats, less saturated fats, just a simple organic chemistry equation, like a peroxide value.
[02:28:11]  The more unsaturated an oil is, the more quickly it's going to be damaged when you heat it.
[02:28:16]  And so, theoretically, if you had a higher saturated fat content oil like a pure tallow, which is a refined, which is sort of an oil that is from beef fat, right?
[02:28:26]  So, people don't know tallow, it's a beef fat.
[02:28:30]  it's solid room temperature.
[02:28:31]  If you were to heat that oil, it's going to have a lower degree of oxidation, not zero, but a lower degree of oxidation relative to olive oil.
[02:28:38]  Olive oil will have a higher degree of oxidation, you know, a lower degree of oxidation relative to a seed oil down the road we go.
[02:28:46]  And so theoretically, steak and shake cooking and their fries and tallow decreases the amount of things like this acrolein, these aldehydes, somewhat.
[02:28:56]  But I just think that for human health long term, look, we're all going to, I've eaten French Fries in my life, we're all gonna eat french fries.
[02:29:02]  But if you have any significant amount of your diet that's from a deep fried food, no matter what it's cooked in, you're probably not optimizing.
[02:29:08]  Yeah, and I don't think it completely absolves it.
[02:29:10]  You can't just cook in tallow, a deep fry something in tallow, and expect it to be right, not have any oxidative liability in the human organism.
[02:29:18]  Um, so there's a lot.

=== Blue Zones and Meat Consumption (03:22) ===

[02:29:19]  This is like, like we talked about.
[02:29:20]  I mean, this is just like one siloed part of this giant game of whack a mole that I feel like affects the human body.
[02:29:28]  And like, anecdotally, I don't know what it is.
[02:29:32]  But I'm sure you can attest to it.
[02:29:34]  Like when you go to Costa Rica, I can go to Costa Rica for a couple weeks and just eat pizzas, burgers, tacos, all the junk food they offer there.
[02:29:44]  And I still feel way better than if I just eat something from fucking Chipotle.
[02:29:50]  Like if I eat a Chipotle burrito, I feel like I just ate a bag of concrete.
[02:29:55]  But I can eat all the garbage that they offer in Costa Rica and I still feel better than that.
[02:30:00]  I don't know what that is.
[02:30:02]  About, like, how it's processed or about, like, the ingredients they used or what it is.
[02:30:06]  Is this environment?
[02:30:07]  Is this light energy and magnetism?
[02:30:08]  Yeah, is that part of it?
[02:30:09]  And then, like, another part, like, I know, like, I don't know how legit it is, but I've heard that, like, Costa Rica is one of the countries that has the highest lifespan.
[02:30:20]  It's, like, considered one of the blue zones or whatever.
[02:30:22]  It's not true.
[02:30:22]  It's not true.
[02:30:23]  It's only the Nicoya Peninsula.
[02:30:24]  The blue zones are kind of a myth.
[02:30:26]  Yeah.
[02:30:26]  Okay.
[02:30:27]  But, like, I don't know.
[02:30:28]  Maybe it's a myth, but I just always thought about that being like the people there, they don't.
[02:30:34]  live this rat race that people live in America.
[02:30:37]  They just, most of the people there, they wake up and they're just looking for waves.
[02:30:41]  You know what I mean?
[02:30:42]  They're enjoying the environment and they're not, they're not sitting in a cubicle all day in front of a screen trying to like optimize their return on investment for whatever the fuck they're doing.
[02:30:54]  There's something there.
[02:30:55]  So I live, people may not know this, but I live in Costa Rica mostly full time now for the last four plus years.
[02:31:03]  People in Costa Rica are pretty friendly.
[02:31:05]  A lot of people work outdoors.
[02:31:07]  They do some degree of, Moderate level activity in an outdoor context.
[02:31:13]  And family is a big deal.
[02:31:15]  So these are all things that make a difference, purpose.
[02:31:19]  And these are all things that have been highlighted in the Blue Zones discussion.
[02:31:22]  I think that the major failing of the Blue Zones paradigm is that the Blue Zones are not prominently plant based.
[02:31:29]  If you look at the Blue Zones, whether you're talking about Sardinia or Okinawa, or you're talking about Icaria, or you're talking about, I mean, basically that's most of them.
[02:31:38]  The significant amounts of meat, meat is a central part of their diet.
[02:31:43]  I mean, there's a well known dish in Sardinia called sarda pig.
[02:31:47]  Icaria, if anyone's been to that island in Greece, they're roasting lamb and other pigs on spits all the time.
[02:31:54]  So to suggest that the blue zones are plant based is just falsification.
[02:31:58]  But a good takeaway from the blue zones is yeah, having moderate activity outdoors, not sitting in a cubicle, not looking at blue light all day, having family, having purpose.
[02:32:09]  These things are valuable for humans and not inconsequential variables to our planet.
[02:32:13]  Different values, different overall values.
[02:32:15]  They don't value.
[02:32:17]  Earning a huge salary as we do in America.
[02:32:19]  They don't.
[02:32:19]  They take time off.
[02:32:21]  And I know this because you see it.
[02:32:24]  These are very humble people.
[02:32:26]  And when there is a holiday, everyone takes off.
[02:32:29]  They're not making any semblance of what we would make on a dollar-per-dollar basis in the United States.
[02:32:37]  And they're taking every single day of vacation they can.

=== Infrared Light as Essential Food (03:07) ===

[02:32:41]  And they're generally spending that time at the beach with their family.
[02:32:46]  It's families on the beach, at least where I live, right?
[02:32:48]  And where you've visited it.
[02:32:49]  These are coastal towns, but family is a big part of the ethos there.
[02:32:53]  So these are other pieces of the conversation that are not able to be ignored.
[02:32:56]  Yeah, there's definitely so many pieces, too.
[02:33:00]  I know I've heard that UV light can also have a huge effect on things like cholesterol.
[02:33:07]  Is that right?
[02:33:08]  Or is it vitamin D?
[02:33:09]  Vitamin D levels can, if the sun exposure can lower things like Alzheimer's, cholesterol, heart disease, this kind of stuff.
[02:33:20]  I think there's a small effect of like infrared light on PCSK9 and lowering LDL.
[02:33:25]  I don't think it's going to be that tremendous though.
[02:33:28]  I think when you're getting sunlight, you're doing a lot of things, right?
[02:33:31]  We know that sunlight affects sex hormones.
[02:33:34]  Ultraviolet light has been associated with higher levels of testosterone in males.
[02:33:38]  So that's been shown multiple times.
[02:33:41]  UV light affects the gut microbiome, actually increases diversity of the gut microbiome.
[02:33:46]  Certainly, from a circadian perspective, getting ultraviolet light is critical.
[02:33:49]  And that is sort of the orchestration of all the hormones throughout the day.
[02:33:52]  So there are many, many benefits to, I would say, full spectrum outdoor light with UV and IR and things you've talked about with other people in the podcast.
[02:34:01]  I mean, yeah.
[02:34:01]  You know, I had Tristan on my podcast too, and we talked about infrared.
[02:34:04]  That was super fascinating to me that indoors you have no infrared light, right?
[02:34:08]  So, are we as a species also deficient in infrared light?
[02:34:12]  Because outdoors you're getting infrared.
[02:34:14]  Does the infrared balance the UV?
[02:34:15]  You have whole.
[02:34:16]  I think of.
[02:34:17]  He brought a big incandescent light bulb and he shined it in our faces during the podcast.
[02:34:21]  Oh, yeah, like his chicken light.
[02:34:22]  Some people, yeah, go a little overboard with the stuff.
[02:34:27]  I mean, maybe it's not overboard, but it's like, you know, you're bringing a light bulb with you everywhere you go.
[02:34:31]  I lived for all my teenage years in a room with giant iguanas that had a big.
[02:34:35]  Heat lamps.
[02:34:35]  Oh, yeah.
[02:34:35]  That did my medical.
[02:34:36]  I mean, that's why eating a standard American diet, I was resistant as a waking.
[02:34:40]  It's, it's, that was the secret.
[02:34:41]  The economy is the one.
[02:34:42]  Yeah.
[02:34:42]  You think of, I think of sunlight.
[02:34:44]  I'm joking, everybody, by the way.
[02:34:45]  I think of sunlight as like whole food, you know, and then indoor light as like processed food.
[02:34:50]  These are very similar, you know.
[02:34:51]  A processed food has had certain components stripped away.
[02:34:54]  We gave the example of the seed oils, the refining, the bleaching, the deodorization.
[02:34:57]  Other processed foods are similar.
[02:34:59]  And indoor light, I mean, these lights in here, right?
[02:35:01]  This is blue light.
[02:35:02]  It's flickering.
[02:35:02]  It has no, it's not even the actual reproduction of the outdoor light spectrum.
[02:35:07]  It has no UV.
[02:35:08]  Has no IR.
[02:35:09]  It's flickering.
[02:35:09]  So there's a lot of parallels there between, and people have done this far in advance of what I'm saying here.
[02:35:15]  They've likened light to food in many ways.
[02:35:18]  We talked about the light diet and things like this, and just the idea that the quality of light that you consume affects you in ways that are not dissimilar from food.
[02:35:30]  Yeah, not just from a biological perspective, but from a mental health perspective too.
[02:35:36]  I think one of the best analogies I ever heard was Alexis Cowan explained, like, Being inside all day in front of blue lights is the equivalent to orcas in a tank at SeaWorld.

=== Fusion Fission in Mitochondria (06:43) ===

[02:35:48]  So, there's actually a study in Nature Mental Health.
[02:35:51]  Day and night light exposure are associated with psychiatric disorders.
[02:35:54]  It's an observational study in over 85,000 people.
[02:35:57]  I'll just read from the abstract.
[02:36:00]  Greater nighttime light exposure was associated with increased risk for major depressive disorder, general anxiety disorder, PTSD, psychosis, bipolar disorder, and self harm behavior.
[02:36:08]  Independent of nighttime light exposure, greater daytime light exposure was associated with reduced risk of, and then all those terrible things.
[02:36:15]  But, Did you, if you haven't, Paul, you'll love it.
[02:36:19]  There was a paper out of Oxford in Nature on the mitochondrial origins of sleep pressure.
[02:36:24]  I think I saw you talking about that.
[02:36:26]  Yeah, it was fascinating.
[02:36:27]  So, ironically, the first author happened to be at the department where I got my PhD at Oxford.
[02:36:31]  So, we ended up corresponding about this.
[02:36:32]  But basically, why do we sleep?
[02:36:36]  It's still kind of an open question.
[02:36:37]  Like, why did we originally evolve to sleep?
[02:36:40]  And this paper presents interesting data, and I think rather compelling data that it has to do with a mitochondrial dang.
[02:36:46]  Is there any animal that doesn't sleep?
[02:36:48]  No, all animals.
[02:36:48]  So, this is very, very primordial.
[02:36:51]  Basically, like, you know, billions of years ago, one cell consumed another smaller cell.
[02:36:57]  That smaller cell became our mitochondria.
[02:36:59]  They developed a symbiotic relationship, endosymbiosis.
[02:37:01]  Incidentally, actually, might have to do with autoimmune disease.
[02:37:04]  Another paper, another time.
[02:37:06]  But mitochondria aren't just like static little engines.
[02:37:10]  People say powerhouse of the cell.
[02:37:11]  They're not just like static.
[02:37:13]  They dance together.
[02:37:14]  And what I mean by that is they fuse together.
[02:37:16]  Like different mitochondria will come and fuse together, and then they will break apart.
[02:37:19]  It's called fusion and fission.
[02:37:21]  And this happens in cycles.
[02:37:23]  So fusion helps with energetic efficiency, sharing components.
[02:37:26]  Fission helps isolate out components for recycling, so damage mitochondrial components.
[02:37:30]  So, Like anything, biology, nature, they operate in cycles.
[02:37:34]  And this fusion and fission cycle is really important and it corresponds with sleep.
[02:37:38]  But really interestingly, what they were able to find in this study is you have to do this experiment in animals because you have to manipulate them, but you can change levels of the proteins that promote fusion and fission.
[02:37:48]  So to bias the balance, fusion versus fission.
[02:37:51]  And they could change sleep drive by altering the mitochondrial fusion fission balance.
[02:37:58]  Long story short, we think about the sun as the base of the food system.
[02:38:04]  But I think it interacts with biology in so many more fundamental ways, as in, like, the light coming through the atmosphere at different times of day, which there's going to be different spectra, go into your eyes, change mitochondrial dancing effectively in your brain.
[02:38:20]  You know, the clinical implications of that can be intuited through, like, the study we just discussed about mental health.
[02:38:28]  Now, I don't have the exact domino chain of things that occur, but when we think about just how fundamental sun is to our biology, having studies showing that.
[02:38:36]  You know, mitochondrial dynamics, which interact with daytime light exposure, can like literally change the dance of mitochondria, which can create, it's not a clear picture.
[02:38:48]  It's a complex, awe inspiring one.
[02:38:51]  And that's always what I come back to.
[02:38:53]  I said the other day when somebody left a comment, I forgot what the comment was, but like, I pity the people who can't be confused, awed, and humbled by physiology and metabolism.
[02:39:04]  I find so much joy in life from like learning these things and be like, I don't fully see how this fits together.
[02:39:10]  I like putting the puzzle together, but it's never going to be complete.
[02:39:13]  And that's what's so cool.
[02:39:15]  And also, just incidentally, because we were talking about blue light, in the newsletter I did on this, I looked at data separately on how blue light impacts mitochondrial fragmentation.
[02:39:25]  So there's data, Paul, I actually just texted you a picture of a mouse study.
[02:39:29]  You have to do it in mice because you have to pluck their eyeballs out.
[02:39:31]  But they showed that high blue light exposure caused mitochondrial fragmentation in the retina, literally the mitochondria fracturing apart, a giant boost in oxidative stress.
[02:39:40]  So the red.
[02:39:41]  Here on this image is oxidative stress.
[02:39:44]  It's black.
[02:39:44]  Oh, there we go.
[02:39:45]  In the retina.
[02:39:46]  So you can see blue light exposure, way more oxidative stress.
[02:39:48]  Wow.
[02:39:49]  And what ends up happening is if you check out the other picture, the retina thins.
[02:39:54]  That is.
[02:39:55]  That's crazy.
[02:39:55]  On the right, like the thinned retina from blue light exposure.
[02:39:58]  And humans, there's like risks of things like age related to the retina.
[02:40:01]  Well, it's crazy because there's a lot of big, there's a couple that I'm aware of, like big time video gamers, competitive video gamers, who have, they play the games, but on the computer screen right in front of them.
[02:40:12]  And they've had retinal detachments and they've had to have surgeries because of that.
[02:40:16]  That's just like, that picture is just crazy to me.
[02:40:19]  Like, and a mouse retina and a human retina and, like, you know, chronobiology, it's pretty conserved.
[02:40:26]  Yeah.
[02:40:26]  So this is not saying like you can't like watch a movie with your partner at night, but like.
[02:40:33]  Get a big red light panel, blast it in your face while you're watching the movie.
[02:40:36]  The retina is a really interesting thing.
[02:40:37]  I mean, there's.
[02:40:38]  We can circle this back to cedar rolls if we want, or we can just leave that dead horse.
[02:40:42]  Well, because there's a lot of just general oxidation in the retina.
[02:40:46]  It's actually kind of a good model for all the different fatty acids.
[02:40:48]  Yeah.
[02:40:49]  And there's very clear.
[02:40:50]  Well, there's at least pretty strong associational evidence.
[02:40:54]  I'll find it's called the Blue Mountain Study on the.
[02:40:59]  Age related macular degeneration and seed oils.
[02:41:01]  This is the Blue Mountains Eye Study.
[02:41:04]  Evidence of protection against early AMD from eating fish, greater consumption of omega 3 fatty acids, low intakes of foods rich in linoleic acid was protective for AMD.
[02:41:14]  Wow.
[02:41:15]  I mean, it's very physiologically possible combination of high blue light and things that it can oxidize.
[02:41:21]  Yeah, the retina is rich.
[02:41:22]  So, this is a great model system, I think, that you have the blue light as an oxidant on a fragile tissue that is pretty close to being exposed to the environment.
[02:41:32]  And then you see.
[02:41:33]  And Lise, this is again just a, it's an observational study, but there was a pretty strong, pretty strong association here between lower consumption of linoleic acid and better outcomes, meaning less incidence of age-related macular degeneration.
[02:41:48]  That's striking.
[02:41:49]  I mean, that makes sense mechanistically.
[02:41:51]  Well, Jack Cruz told me a story, which was an anecdotal story on the podcast, that somebody he knew who was older had to get cataract surgery.
[02:42:00]  And I guess like six months leading up to his surgery, Jack told this gentleman to sit in front of his red light panel.
[02:42:08]  He gave him a red light panel and he told him to sit in front of it for an hour every day in like 20 minute increments.
[02:42:12]  And the guy went in for his like pre op, like a week before the surgery.
[02:42:18]  And they like checked his eyes and they were like, you don't need cataract surgery anymore.
[02:42:21]  Your eyes are fixed.
[02:42:23]  And Jack attributes that to the red light.
[02:42:24]  The cataracts, that's in the lens.
[02:42:26]  So that's the front part of the eye.
[02:42:28]  The retina is a little bit deeper.
[02:42:29]  Maybe it wasn't cataracts.
[02:42:30]  It's interesting.
[02:42:31]  Maybe it was a different surgery.

=== Vegan Diets and Health Misattribution (07:58) ===

[02:42:32]  It probably was.
[02:42:32]  Yeah.
[02:42:33]  It's interesting.
[02:42:33]  No, the red light and the cataracts is interesting.
[02:42:35]  All the anecdotal stories are super interesting to me.
[02:42:37]  You know?
[02:42:38]  It was funny.
[02:42:38]  I was going through and ranking the arguments for and against seed oils just as an exercise and for something else I was doing.
[02:42:47]  And I think an argument that often comes up is people talk about their n equals ones.
[02:42:51]  Their what?
[02:42:52]  Their n equals ones.
[02:42:52]  Their anecdotes.
[02:42:53]  Their stories.
[02:42:54]  Oh, okay.
[02:42:54]  Like as in, I cut out seed oils or X, Y, and Z, and then this happened.
[02:42:58]  Yeah.
[02:42:58]  And there's a couple ways to rank that.
[02:43:00]  In terms of scientific rigor, clearly it's not very strong.
[02:43:03]  In terms of individual applicability, it's the strongest thing you can have.
[02:43:08]  So I think we.
[02:43:09]  We don't value it enough.
[02:43:11]  From a scientific perspective, it's great for hypothesis generation.
[02:43:15]  Take Oreo versus Staten as an example.
[02:43:17]  But at the individual level, it's like the way we have done science historically has been studying populations of heterogeneous humans.
[02:43:27]  There's always a lot of a cloud, a noise cloud of the data.
[02:43:33]  And where you fall in it, you're not going to, like when we plot out graphs, we're looking at like Kaplan Meyer survival curves.
[02:43:39]  It's unlikely you're going to be right on the curve.
[02:43:42]  You're going to be above or below it.
[02:43:43]  And where you fall with respect to any given metric, you can only figure out by engaging in life as an n equals one experiment.
[02:43:52]  Now, the more scientific training you have, the better resolution you can have and what conclusions you draw.
[02:43:58]  But if someone makes a lifestyle intervention, say they quote unquote cut out seed oils, and then they say I had this miraculous recovery from X, Y, and Z, I'm inclined to give that more weight.
[02:44:14]  Actually, a lot of weight in that individual context.
[02:44:16]  And I think one problem we have is we all have our stories.
[02:44:21]  So, mine is a ketogenic diet for IBD.
[02:44:24]  Yours is a diet for eczema and other conditions.
[02:44:27]  And I, these form our interests and they're very valuable at an individual level.
[02:44:36]  And I think one area, one vulnerability that creates a lot of confusion is people get threatened by other people's stories or when their story doesn't match the data.
[02:44:50]  And to me, that's so silly.
[02:44:51]  Like, I kind of get it.
[02:44:55]  It's confirmation bias, but at the same time, why should your story lose anything if a given paper or another person's journey is divergent?
[02:45:05]  So, if I say, and I believe this, I believe a ketogenic diet saved my life.
[02:45:10]  If someone else does a low fat vegan diet and they get better results and they're healthier from where they were and they attribute their low fat vegan diet to their improved health, I think generally there's an instinct in trying to poke holes in that story and maybe there's a misattribution.
[02:45:24]  I don't think it really matters.
[02:45:26]  And the thing I love about metabolic health.
[02:45:28]  And I hope we're unified on this.
[02:45:29]  Is in truth, it's approach agnostic.
[02:45:34]  Unlikely if you're eating McDonald's and Oreos every day, you're going to be optimally metabolically healthy.
[02:45:38]  But if you get to a good place, that's awesome.
[02:45:43]  And what we've talked through here, I think what we've hopefully risen is a lot of curiosity and uncertainty.
[02:45:52]  Because there's not definitive answers for a lot of the questions we want to ask.
[02:45:57]  And that's okay.
[02:45:59]  I think the similarities of how people get there are interesting as well between divergent paths.
[02:46:05]  It's always been interesting for me because I was a carnivore for a while.
[02:46:08]  I was eating meat, and I've seen a lot of people improve autoimmune disease doing that.
[02:46:12]  And there are many stories of people who improve autoimmune disease doing vegan diets.
[02:46:16]  And so you think, okay.
[02:46:17]  Yeah, yeah, definitely.
[02:46:19]  I mean, some people's autoimmune conditions get worse on vegan diets, some people get worse things, but certainly people have improved ulcerative colitis doing vegan diets.
[02:46:26]  And I think that there's the similarity that I see there is oh, wow, they're cutting out processed food, right?
[02:46:30]  That's great.
[02:46:30]  That's super interesting.
[02:46:31]  So, there's the similarity that we can kind of take away from that.
[02:46:34]  Like, I think that if someone is suffering from an autoimmune condition, a chronic health illness, a chronic health issue, then it's pretty clear that if you improve the quality of your food, if you kind of go back to the beginning of this conversation, if you put aside the idea of energy balance and all of these psyops that have been foist upon us, you don't think about calories, right?
[02:46:54]  You think about food quality.
[02:46:55]  There are a lot of ways to improve your health that may not look the same on the beginning.
[02:46:59]  How well each of these is going to work.
[02:47:00]  Work long term is probably bio individual.
[02:47:03]  Carnivore didn't work great for me because of electrolyte stuff.
[02:47:06]  I've seen a lot of people do vegan diets and then end up with nutrient deficiencies long term, but at least in the short term, elimination of these ultra processed foods, which even can be equated on a caloric basis, that results in improved health in a lot of people.
[02:47:18]  So that's fascinating to me.
[02:47:19]  And we can kind of go back to that theme like, okay, this westernized diet containing all these ingredients looks to be very harmful for humans.
[02:47:26]  And so the similarities across those outcomes is really interesting to me.
[02:47:30]  And then, I mean, speaking of N equals one experiments with seed oils, I have to bring this one up because it's so strong.
[02:47:36]  You can probably find a thread.
[02:47:37]  I don't have a thread on my ex account, but whenever I post about this, the community survey is unanimous, or it's actually, I shouldn't say that, it's very strong.
[02:47:47]  The idea that people who cut out seed oils, at least in terms of their personal experience, tend to burn less.
[02:47:52]  And I think this kind of mirrors the macular degeneration.
[02:47:54]  Burn less?
[02:47:55]  Burn in the sun.
[02:47:56]  Yeah.
[02:47:57]  Oh, interesting.
[02:47:58]  Yeah.
[02:47:58]  It's not that they burn their food less, it's that their skin burns less.
[02:48:02]  Interesting.
[02:48:02]  So their human experience is.
[02:48:04]  When you decrease the amount of polyunsaturated fat, again, this is just observation, sort of like community surveying, which is fascinating.
[02:48:11]  And as Nick says, hypothesis generating, you have less propensity, at least in these communities, to have UV susceptibility.
[02:48:19]  That's interesting to me.
[02:48:20]  And then if you look at the dermatology literature, there is backing for this.
[02:48:24]  When you give animals higher linoleic acid diets and you expose them to UV light, they do tend to develop more aggressive cancers when the cancers develop.
[02:48:31]  Yeah, I heard the same thing about vitamin D.
[02:48:33]  The lower your vitamin D, the more you'll burn and develop things like melanomas.
[02:48:37]  And the same thing with, I think Alexis also said, when you wear sunglasses, and this is also anecdotal, but sunglasses in the sun tend to burn more when you're blocking your eyes and only. exposing your skin or something like this.
[02:48:52]  Well, yeah, there's a connection there, I think, between the brain and the skin in terms of melanin production in the skin.
[02:48:58]  Melanoma is a widely misunderstood cancer.
[02:49:00]  It's the most aggressive skin cancer, but it's also not as sun-associated as people think it is.
[02:49:06]  Moderate-level sun exposure across multiple populations, there was just a study published on this.
[02:49:10]  I can pull it up.
[02:49:12]  Moderate sun exposure is often protective against melanoma.
[02:49:16]  And melanoma, your risk, I think, in population studies is increased if you have multiple burns in childhood, but across your life, if you have moderate-level exposure, it's protective.
[02:49:25]  So, melanoma is interesting.
[02:49:27]  In terms of observational studies, there's another observational study that correlates the amount of seed oil consumption with increased rates of melanoma as well.
[02:49:33]  If we're into this oxidative hypothesis around multiple pathologies here.
[02:49:38]  So, yeah, sun stuff is fascinating, and I think it definitely parallels these macular degeneration ideas in the retina, too.
[02:49:46]  If you think your skin and the retina on your eyes is very exposed to stressful circumstances from the UV and the way that you populate those cells, just like we talked about.
[02:49:58]  Red blood cells, adipose tissue, being composed of a representative amount of linoleic acid based on your diet, I think that the retina will be and the skin will be as well.
[02:50:09]  Another thing that's interesting too is I've heard people say that eating not just healthy meats like fish, but eating fish that are native to the area you're in, right?
[02:50:25]  Instead of like eating fish that's imported from another part of the world like Alaska.

=== Salt, Mercury, and Hormonal Control (12:54) ===

[02:50:30]  If I'm here living on the Gulf of Mexico, you're not taking my sockeye salmon.
[02:50:33]  I should be eating fish that was caught in the Gulf of Mexico.
[02:50:38]  Is there any.
[02:50:39]  I think that's a sustainability thing.
[02:50:41]  Not that I'm aware of.
[02:50:43]  The problem I have with fish in general is it's just so full of heavy metals, microplastics, PFAs.
[02:50:48]  Yeah.
[02:50:50]  More so farms.
[02:50:52]  Even the wild stuff's pretty bad today.
[02:50:54]  Do you have a test you suggest getting?
[02:50:56]  I'll get it in a report, but I eat a ton of fish.
[02:50:58]  Fuck it.
[02:50:59]  You check your serum.
[02:50:59]  Yeah, I eat a ton of snapper and grouper that's caught right out here.
[02:51:02]  Check your serum heavy metals.
[02:51:03]  Just start with that.
[02:51:04]  I have.
[02:51:05]  Lead, mercury, cadmium.
[02:51:06]  Lead, mercury, cadmium are all fine.
[02:51:08]  Or some like?
[02:51:09]  I don't recall.
[02:51:10]  Yeah.
[02:51:11]  But, I mean, the mercury is on the, it was like nine ish.
[02:51:14]  It wasn't like low, low, but I also don't eat like, I try to avoid like swordfish and, you know, like big eye tuna.
[02:51:21]  So like sockeye salmon, sardines.
[02:51:24]  Actually, you can go like online and just Google the mercury content of these things and you need to eat like.
[02:51:28]  Sardines are really low mercury, right?
[02:51:29]  Like sockeye salmon or sardines, you need to eat it like every day for 40 days to equate to like one.
[02:51:36]  You know, mass equivalent of swordfish.
[02:51:38]  So, like, the distribution across fish is massive.
[02:51:41]  It's big.
[02:51:42]  So, there's no tests for microplastics and PFAs that are widely available.
[02:51:47]  Yeah.
[02:51:48]  These are interesting to me.
[02:51:50]  I just think the thing we keep coming back to as you were speaking is like context in the human body and the vilification of single components in food.
[02:52:01]  So, another example we were talking about, I think we're talking about with both of you off air, was like salt.
[02:52:06]  Like, is salt bad?
[02:52:07]  People say saturated fast bad.
[02:52:08]  I'm like, this, that, and the other salt.
[02:52:10]  I was down a rabbit hole the other day.
[02:52:12]  And again, interacting with individual biology.
[02:52:15]  There's some data suggesting if you have pre existing obesity, it could increase your blood pressure and actually make you more salt sensitive.
[02:52:21]  So the mechanism appears to be, and I'm basing the mechanism off rodent studies, but there are human studies, including in the 80s and 90s in the New England Journal, that I think make the case pretty compellingly.
[02:52:34]  But basically, your fat releases leptin.
[02:52:37]  The more fat you have, the more leptin you have circulating around.
[02:52:41]  And one of the things leptin does is that it acts on brain cells at the blood brain barrier.
[02:52:46]  Their supportive cells to neurons are called astrocytes.
[02:52:48]  So, leptin can bind to receptors on astrocytes and do all sorts of things.
[02:52:52]  One thing it'll do, activate a protein called HIF1 alpha, increase levels of a hormone called VEGF that makes vessels grow.
[02:53:00]  So, what they find, at least in animals, is that more, like an obesogenic diet that increases fat mass, the diet doesn't directly increase blood pressure immediately.
[02:53:11]  But as the fat mass goes up and the leptin goes up, the blood vessels around the hypothalamus, basically the master control center of the body's endocrine system, They thicken.
[02:53:22]  I actually think, Steve, I think I sent an image.
[02:53:25]  It might be the one with the blue inset.
[02:53:28]  Maybe I did, maybe I didn't.
[02:53:31]  Yeah, blood brain barrier image, too.
[02:53:33]  So, this is an image of the basal membrane at the blood brain barrier.
[02:53:38]  And so, what you see on the left is the control.
[02:53:40]  And on the right, you can see highlighted in blue is the thickening of the membrane in an obesogenic context.
[02:53:48]  So, in obesity.
[02:53:50]  The point here is literally the vascular around the brain's.
[02:53:53]  Master controller of the whole body's hormone system is changing.
[02:53:56]  And this ends up changing things like nervous system tone.
[02:54:00]  So that can increase blood pressure, including nervous system tone to the arteries and the kidneys.
[02:54:05]  It also increases susceptibility to inflammation, which can drive up blood pressure.
[02:54:08]  But interestingly, so you can't do these controlled experiments in humans, but you can look at human genetic cases or interventional trials and see is there a lineup?
[02:54:21]  So, what do we see in human obesity?
[02:54:23]  Increased blood pressure.
[02:54:25]  What would we predict to see if you had human obesity but no leptin signaling?
[02:54:32]  No increase in hypertension.
[02:54:33]  So, you would expect in congenital leptin deficiency, which is for people to have massive obesity because you don't have leptin signaling to suppress appetite, but you would actually expect weirdly the blood pressure to be lower normal.
[02:54:46]  That's exactly what we see.
[02:54:48]  And people have argued that, well, if you give back leptin, it doesn't increase blood pressure, but you're not like super physiologically dosing it.
[02:54:55]  So, it's complicated, but there's that.
[02:54:57]  And then if you look at.
[02:54:59]  Studies done in like, I think it was 1989 in the New England Journal.
[02:55:03]  Can you bring up, Steve?
[02:55:04]  New England Journal bar graph.
[02:55:06]  This was a trial, a few up.
[02:55:09]  This was a one down, one down.
[02:55:11]  There we go.
[02:55:12]  Yeah.
[02:55:13]  This was a trial done, published in the New England Journal with lean people or people with obesity where they gave them a very high salt diet.
[02:55:19]  It was something like 15 grams of salt versus a very low salt diet.
[02:55:22]  They're testing sodium restriction.
[02:55:24]  What is the effect of sodium restriction on blood pressure?
[02:55:27]  Obesity, it drops it.
[02:55:29]  Non obese, it doesn't affect it at all.
[02:55:31]  Nothing at all.
[02:55:32]  Which is fascinating.
[02:55:33]  And actually, if you go to any.
[02:55:36]  That's crazy.
[02:55:36]  Go to any JM dot plot.
[02:55:38]  It's messy.
[02:55:39]  There's a lot of variability, of course.
[02:55:40]  Humans have heterogeneity, but this is the association between percent body fat and change in blood pressure with salt restriction.
[02:55:47]  So, what you see is as your body fat drops, the drop in blood pressure you get from restricting salt, again, it was an astronomical drop in salt.
[02:55:55]  They got a tiny salt diet versus a massive salt diet.
[02:55:58]  So, the low body fats on the far left.
[02:56:01]  Yeah.
[02:56:01]  So, as you drop at 30% body fat and below, The change basically drops to zero.
[02:56:07]  So again, context.
[02:56:09]  The story I'm telling here, which I'm not 100% definitive, and I don't think this is the whole answer in humans, but it's a pretty compelling mechanistic story where leptin from fat tissue can remodel vasculature around the brain and change the way your body's hormones function and actually how your kidneys function.
[02:56:25]  So, there's a direct effect of leptin on the kidneys that causes it to retain salt.
[02:56:29]  So, this is a scenario, again, where you go up and look at the AHA recommendations for salt.
[02:56:34]  They're like, everybody should eat less than 2.3 grams.
[02:56:37]  And it's just like you have studies, even from the Framingham cohort, showing that.
[02:56:41]  Very low salt can associate with higher blood pressure.
[02:56:44]  And then studies like this, the New England Journal, there's no refining the message to account for various metabolic conditions, various metabolic factors.
[02:56:54]  So, when it comes to saturated fat, omega 6, salt, what we keep on seeing again and again, and this is the theme, is that there is metabolic context that we can understand and use that to inform what the individual should be concerned about.
[02:57:12]  So, if you have obesity, And you're eating a mixed macro diet and you're sedentary, should you be relatively more concerned about omega 6 and salt?
[02:57:20]  Probably.
[02:57:21]  If you're lean and keto, should you be concerned about omega 6 from whole foods and salt?
[02:57:27]  I don't think the data support that.
[02:57:29]  So it's context, context, context.
[02:57:30]  When I read this one on your Substack, Nick, I wanted to ask you this.
[02:57:33]  So I'm curious for your perspective, because we see this a lot, right?
[02:57:36]  When you have the fat mass, the fat mass talks, right?
[02:57:39]  The fat mass is secreting these adipokines, leptin, which can be problematic when there's leptin resistance.
[02:57:46]  What do you think is the main driver of the fat mass?
[02:57:49]  Because, I mean, I just, in my mind, I always want to pull it back to like what caused it, what caused it, what caused it.
[02:57:54]  And I think Western medicine never challenged us to do this in medical school.
[02:57:58]  So, in your perspective, what are the major drivers of the obesity and the fat mass in these people?
[02:58:03]  Because you can say, okay, you have more fat mass, more leptin.
[02:58:06]  This is driving hypertension.
[02:58:08]  Where did the fat mass come from?
[02:58:11]  So, when I think about this, depending on what portion of the web, the network I want to talk about, I kind of think about it as like, There's always an upstream driver.
[02:58:25]  And then some places in the network where various things converge.
[02:58:29]  So we can talk about like circadian disruption and how that alters hunger hormones.
[02:58:34]  We can talk about high insulin levels and how that directs energy to fat cells and causes them to expand.
[02:58:41]  So I want to point out there's lots of different things converging on the fat.
[02:58:45]  And then as the fat expands, it can cause downstream metabolic damage from harming.
[02:58:53]  The brain barrier, et cetera, et cetera.
[02:58:55]  So, in this mental image, I kind of see the fat mass as one convergent point in the mechanism.
[02:59:02]  With respect to what causes the fat to expand, I would analogize this somewhat to the study I talked about earlier about the four types of type 2 diabetes, where I think there are lots of different causes that are going to carry different weight in different people.
[02:59:17]  If I were to identify what I think the biggest lever is for someone struggling with obesity in this day and age, I think it's high insulin resistance and excess of dietary carbohydrates that are going to boost the insulin.
[02:59:36]  Because I think, you know, one thing that will happen is the higher insulin levels cause partitioning of more energy to the fat cell.
[02:59:43]  So you're saying insulin resistance?
[02:59:45]  Yes.
[02:59:45]  Which is kind of like metabolic dysfunction.
[02:59:48]  Yeah.
[02:59:49]  So it's a hand wavy or it's a wide umbrella, but intentionally.
[02:59:55]  Sure.
[02:59:56]  Yeah.
[02:59:56]  Because I think to get like, To say XYZ is the sole piece of the puzzle will be misleading.
[03:00:01]  Do you think all carbohydrates cause that to the same extent?
[03:00:04]  Because there are lots of populations like the Tucasinta in the highlands of Papua New Guinea who have 90% of their diet is carbohydrates from sweet potatoes.
[03:00:13]  So maybe this is akin to the seed oil conversation.
[03:00:15]  So I don't see.
[03:00:16]  No, I don't.
[03:00:17]  Yeah, I don't see excess carbohydrates as a major driver of insulin resistance.
[03:00:21]  It's not sufficient.
[03:00:23]  Right.
[03:00:24]  It's not sufficient.
[03:00:25]  But I think when you're in an environment where, let's say you already have a creeping degree of insulin resistance, there's a difference between the seed and what helps the seed grow.
[03:00:37]  I'm so interested in the seed, though.
[03:00:39]  I agree.
[03:00:39]  I agree.
[03:00:40]  But it could start at, like, we were talking, for example, I think before we recorded about artificial sweeteners.
[03:00:46]  And there was a study out in the proceedings of the National Academy of Science.
[03:00:50]  This isn't obesity per se, but it was showing that even very low dose aspartame can cause transgenerational inheritance of anxiety.
[03:00:58]  So if you give male mice, it was the equivalent of two to four diet cokes or diet sodas.
[03:01:03]  They literally say it in the paper that that's the dose equivalent.
[03:01:06]  Not only do the mice have more anxiety, and there's mechanisms to explain this, I think there's even one human.
[03:01:11]  Randomized control trial where they did different doses of aspartame was like coded as irritability, but that aside, not only did the mice have more anxious behavior and they're a validated test for that, but the kids of the mice and even the grandkids of the mice have more anxious behavior.
[03:01:25]  And then we also have data from like I think it's the the the what was it wasn't the Dutch hunger winter, but there was another natural experiment, I think after World War II was like 1953, where sugar rations changed in Europe and like isolated.
[03:01:45]  Massive increase in sugar intake.
[03:01:47]  I can find the study.
[03:01:48]  It was like 100 days of life exposure.
[03:01:50]  It was in science.
[03:01:51]  I think last year was a big story.
[03:01:52]  But basically, there was a natural experiment where sugar rationage changed, sugar intake skyrocketed, and then they followed people, followed babies based on where they were pre ingestation or afterwards, and basically found a hint of what appears to be epigenetic remodeling that predisposes to metabolic disease.
[03:02:15]  From a processed sugar.
[03:02:16]  So when you're talking about the seed, I think it starts pre birth.
[03:02:19]  That develops your susceptibility.
[03:02:23]  And it ends up being the hand you're dealt.
[03:02:25]  So, another reason I bring these things up is, and this is a general truth, like what you do with your lifestyle doesn't just affect you.
[03:02:34]  And I don't mean to be telling pregnant women how to live their life.
[03:02:39]  That 29 year old white cis male saying you should do this in pregnancy is not a great look, but I'm wise enough not to mansplain that one.
[03:02:49]  Just talking about the data, the fact is, we'll never, you want to go, oh, the gold standard evidence randomized control trial, we're never going to have that RCT in humans.
[03:02:56]  Transgenerational RCT on diet, Coke, and anxiety.
[03:02:59]  It's not possible to do.
[03:03:01]  So, what are we left with?
[03:03:02]  We're left with the evidence we actually can collect and what we can conclude from that, which is, I think, this actually could be a concern.
[03:03:11]  Then, at the individual level, how much does it cost you to do an intervention?
[03:03:15]  In this case, drinking water or seltzer instead of Diet Coke.
[03:03:19]  And that's not for me to tell you.
[03:03:20]  It's just like, this is interesting data.
[03:03:23]  What do you guys think?

=== Fructose Assaults on the Liver (15:03) ===

[03:03:24]  I'm sure you've seen Mark Bell's sugar diet.
[03:03:28]  Have you seen this?
[03:03:29]  I've covered it.
[03:03:31]  Yeah.
[03:03:31]  Yeah, you made a video about it.
[03:03:32]  Yeah.
[03:03:33]  What is going on there?
[03:03:35]  I'm fascinated by it.
[03:03:37]  So this is one of those things where, you know, to be honest, when it comes up, there are certain things where, like, you have your own mental heuristics.
[03:03:44]  And I'm like, I'm triaging this to the junk pile.
[03:03:46]  But coincidentally, a paper came out in Nature Metabolism right around the same time.
[03:03:52]  This did not actually influence.
[03:03:53]  Just a coincidence.
[03:03:54]  It didn't influence Mark's decision to do it, but it was an experiment, actually, three controlled studies, separate, three controlled studies in nature metabolism.
[03:04:02]  I think it was like Nicholson at all, 2025.
[03:04:05]  And they showed that protein restriction.
[03:04:09]  So, a sugar diet's one type of protein restricted diet.
[03:04:12]  If you're eating just fruit and fruit juice and candy, you're going to protein restrict.
[03:04:16]  Protein restriction causes about, in the lean, healthy men, a 600 ish increase in energy expenditure per day without any increase in activity.
[03:04:30]  So, it was a 19 to 21% increase in total energy expenditure without changes in activity, no changes in.
[03:04:35]  Thyroid hormone or other hormones generally associated with changes in energy expenditure was very consistent when they went back to a higher protein diet.
[03:04:42]  So the protein restriction was 9% of calories from protein.
[03:04:46]  And then when they went back up to like 18% calories from protein, their metabolic rate lowered.
[03:04:51]  And what they were able to show is in these mice sorry, in these people it was an increasing level of this hormone called FGF21, mostly made from the liver, which appeared to be signaling to fat cells.
[03:05:06]  To make the fat cells expend more energy.
[03:05:08]  So then they did mouse models because you can manipulate mouse models to kind of prove causality.
[03:05:15]  Yeah, I can find the study in a second.
[03:05:17]  And they were able to show a causal pathway whereby FGF21 changes fat cell metabolism, increases energy expenditure quite massively.
[03:05:25]  Again, a 600 calorie effect.
[03:05:28]  A couple interesting things about this study.
[03:05:29]  First of all, they tested a high carb, low protein diet.
[03:05:34]  So 70% carb, 9% protein.
[03:05:37]  That wasn't the only one they did.
[03:05:40]  They replicated that.
[03:05:41]  And then in the third study, they did high carb and high fat.
[03:05:44]  It was 9% protein, 41% carb, 50% fat, if I recall.
[03:05:49]  So you could engineer this with ice cream, basically.
[03:05:52]  Okay.
[03:05:53]  Same effect.
[03:05:54]  Same massive increase in energy expenditure.
[03:05:56]  And the participants, the way they do it is they also have the participants increase their energy intake to try to not lose weight.
[03:06:03]  And I think in most of the studies, they needed to increase their energy intake by quite a lot.
[03:06:07]  And then they still lost a little bit of weight.
[03:06:10]  So they did high carb and high carb, high fat.
[03:06:13]  I then actually did another video where I replicated this using a ketogenic diet.
[03:06:17]  So, a four to one ketogenic diet, which is 90% fat.
[03:06:20]  So, also low protein.
[03:06:22]  Same effect.
[03:06:22]  I literally could not eat enough to keep the weight on.
[03:06:25]  I was just up titrating the calories.
[03:06:28]  And in like three weeks, I lost over six pounds.
[03:06:31]  And by the end, I was, I'd increased my caloric intake on average over to like the whole up titration by over 300 calories per day.
[03:06:38]  I think I calculated it as like I should have been in a quote unquote 6,000 calorie surplus, but I lost 6.4 pounds.
[03:06:44]  So, it's a low protein, which is the compound.
[03:06:46]  A low protein.
[03:06:47]  And people are going to ask about the whole muscle thing.
[03:06:49]  There wasn't significant effects on muscle loss, and there was a change in nitrogen balance.
[03:06:54]  There was a trend towards decreasing muscle mass or lean mass, but that's also coupled with a decrease in overall body mass.
[03:07:00]  So it's not clear how this would affect physiology in the long term.
[03:07:04]  And then just to add one more very interesting nuance is, subsequent to that, another paper came out in cell metabolism where they genetically manipulated mice to increase FGF21 just at the fat cells.
[03:07:17]  And then this happened.
[03:07:18]  The mice live longer in an obesogenic context, but they live longer with the same or increased energy expenditure and improvements in body composition.
[03:07:29]  The reason I find this really interesting is not because I think F2F21 signaling of fat cells is going to increase human lifespan substantially, but the mere fact that in mammals, you can change fat cell metabolism with one hormone and change a mammal's lifespan speaks to how incredibly important fat cell metabolism is for our overall health.
[03:07:52]  It was pretty good.
[03:07:53]  Whoa.
[03:07:54]  I think the problems with the honey diet or the sugar diet are that it doesn't really work that way.
[03:07:57]  It's not sustainable long term, right?
[03:07:58]  Right.
[03:07:59]  So, it doesn't, it's not going to do well long term.
[03:08:02]  We don't know what the effects are long term with uncoupling this sort of metabolism at the level of the mitochondria with FGF21.
[03:08:09]  I think that it's interesting.
[03:08:11]  Like Nick is saying, it's instructive.
[03:08:12]  It's like a human petri dish.
[03:08:14]  Yeah.
[03:08:15]  But I think that maybe it helps people jumpstart, you know, their weight loss a little bit.
[03:08:20]  But the problem is like, you need amino acids for other things, right?
[03:08:23]  You need amino acids to make neurotransmitters.
[03:08:26]  You need amino acids to, you know, to build and repair things in your human body.
[03:08:30]  So, yeah.
[03:08:31]  This doesn't work great long term.
[03:08:32]  It's not the, Panacea?
[03:08:33]  No.
[03:08:34]  Right.
[03:08:34]  It's an interesting illustration of metabolism.
[03:08:37]  Yeah.
[03:08:38]  I'm not condoning it by any means, but it's one of these things where sometimes BS is BS.
[03:08:43]  Other times you can pick at the BS and there's something fascinating underneath as a teaching point.
[03:08:48]  I put the sugar diet in that category.
[03:08:49]  Do I think it's a good idea?
[03:08:50]  No.
[03:08:51]  You can even get the same effects by eating a non sugar diet that's protein restricted.
[03:08:56]  So this is like a subset of protein restricted diets and that's how it works.
[03:08:59]  But you can imagine in popular media, If you can do a sugar diet and can make it work, that's going to be the thing that takes off.
[03:09:08]  It's the same reason that my Oreo versus statin study took off.
[03:09:11]  When we did this before with like sweet potatoes and fruit, it didn't.
[03:09:14]  So it's what gets amplified incentive structures.
[03:09:16]  We come back.
[03:09:17]  You know what else works?
[03:09:18]  It's just eating good quality food.
[03:09:19]  Yeah, exactly.
[03:09:22]  You know, and not restricting protein because we know that, I mean, there's so many good variables or so many good effects of protein in the human body.
[03:09:28]  So I think people, it's, I think like Nick is saying, it's an illustration of human metabolism as a teaching point, but man, like, Show me the person that, and Mark Bell's done this in the past, that eats a high quality ketogenic diet and doesn't lose weight, right?
[03:09:42]  Doesn't improve their fertility, doesn't improve their mental health and their sleep.
[03:09:45]  Right.
[03:09:45]  Show me the person that eats an animal based diet with meat and fruit and unprocessed food and doesn't have the same effects.
[03:09:50]  It's like, okay, yeah.
[03:09:52]  I wanted to ask you when is there a certain time you choose to eat fruit during the day or all day?
[03:09:57]  All day you eat fruit.
[03:09:58]  So you're not necessarily in ketosis.
[03:10:00]  Never.
[03:10:01]  Really?
[03:10:02]  Never.
[03:10:02]  Only eating meat and fruit, so you're never in ketosis.
[03:10:05]  Never.
[03:10:05]  Interesting.
[03:10:06]  No.
[03:10:07]  And do you experience the same?
[03:10:10]  Do you feel the same energy levels as if you didn't have the fruit added in?
[03:10:16]  Or is there a huge difference to you adding the fruit in?
[03:10:19]  Personally, I feel better with the carbohydrates from fruit, things like honey or fruit or squash.
[03:10:25]  I feel better with that.
[03:10:26]  So my energy is more steady.
[03:10:28]  I don't have the electrolyte insufficiency.
[03:10:29]  My testosterone is higher.
[03:10:30]  I sleep better.
[03:10:32]  I had a lot of side effects to long term keto.
[03:10:35]  I had a lot.
[03:10:36]  Heart palpitations at night.
[03:10:37]  Yeah.
[03:10:38]  And interestingly, you know, if you look at my labs, I just got my blood work, you know, my fasting insulin is 2.3, right?
[03:10:43]  So the fruit doesn't impair metabolic health in any way, shape, or form for me.
[03:10:47]  Interesting.
[03:10:48]  Remain metabolically healthy.
[03:10:49]  Yeah.
[03:10:50]  Again, there's complexity and nuance.
[03:10:52]  So, like with fruit as an example, I don't, you know, the cell metabolism, like how fructose gets processed in the small intestine.
[03:10:59]  This is something that I think often gets overlooked.
[03:11:01]  Yeah, but this one's, there's some nuance here that I want to talk to you about because, yeah.
[03:11:05]  I'll say my bit and then I'll let you go.
[03:11:06]  Yeah, go ahead.
[03:11:06]  Yeah, yeah.
[03:11:07]  Like, I do not think fruit is bad.
[03:11:10]  I do think fructose as a biomolecule can be uniquely harmful when it's in the wrong place.
[03:11:16]  So, like, you know, at the liver, there's a lot of things, and we can get into the biochemistry if we want that it can do, but that's not the point.
[03:11:22]  The point is rather that I don't love this phrase, but the body is smart.
[03:11:27]  So, if you have like glucose, you can consume glucose, it'll go, get absorbed, go through the portal vein, hit the liver.
[03:11:33]  The same thing won't happen with fructose.
[03:11:35]  Fructose actually gets biotransformed by the small intestine.
[03:11:39]  Into glucose and other organic acids.
[03:11:41]  So, when you say have like a handful of blueberries, the amount of fructose in those blueberries, a negligible amount actually gets to the liver.
[03:11:48]  It's bio transformed into other sugars and organic acids beforehand.
[03:11:52]  So, in this case, it's one of those things where, like, when we're talking about exogenous intake, the dose makes the poison.
[03:11:59]  I think that kind of thing often gets overlooked, and it can also reconcile why, like, potentially fructose from, say, having a bowl of cereal with a glass of orange juice, which will saturate this mechanism, it'll overflow, and then you will get more of a fructose assault on your liver, is different and not just like linearly associated with, say, having some blueberries.
[03:12:20]  And it's the same thing with, like, I was asking somebody the other day, you know, do they think fructose is uniquely harmful?
[03:12:28]  Someone with a good physiology background, they said yes.
[03:12:31]  And then I asked them, like, do you think blueberries are harmful?
[03:12:34]  Like, well, no.
[03:12:35]  There's a lot that is in a blueberry that's not just fructose.
[03:12:38]  And what I find interesting is the double standard.
[03:12:41]  Because when we talk about saturated fat, a lot of people say, well, saturated fat is bad.
[03:12:45]  And then extend that logic to dairy is bad, butter is bad, steak is bad.
[03:12:50]  And I just want to show that those leaps of logic are actually very similar.
[03:12:55]  So, like from the whole human perspective, generally there's more to the whole food in terms of how it impacts your body than focusing on like one component that it might be rich in.
[03:13:05]  Anyway, Paul, what were you going to say about the.
[03:13:07]  No, that's a great segue to that point.
[03:13:08]  So, if you look at the research on fructose, I think fructose is a molecule we've been sort of told to fear incorrectly.
[03:13:15]  If you look at the research in fructose, either in animal models or in humans, it's almost always given isolation.
[03:13:20]  Glucose has two transporters in the gut there's SGLT1 and there's glute 2.
[03:13:25]  Fructose is glute 5.
[03:13:27]  But when glucose and fructose are administered together, fructose can use glute-2 with glucose.
[03:13:33]  So what you get when you administer fructose by itself is you get fructose malabsorption.
[03:13:38]  And fructose malabsorption leads to overgrowth of dysbiotic bacteria in the gut.
[03:13:43]  But that doesn't happen with human food.
[03:13:44]  There's no food that humans consume in a whole food form that has isolated fructose.
[03:13:50]  But if you look at the literature with animals or humans, a lot of times people will be given IV fructose, right?
[03:13:55]  Or they'll be given pure fructose.
[03:13:58]  It goes back to kind of what we were saying the difference between an isolated component of a food and the whole food.
[03:14:03]  So, if you look at the studies on fruit, they're invariably healthy for humans.
[03:14:08]  I mean, you look at even fiber, there's all kinds of things.
[03:14:10]  Well, even without fiber, even looking at fruit juices, so orange juice, pomegranate juice, cherry juice, grape juice, watermelon juice, the list goes on and on.
[03:14:18]  These all improve outcomes, whether it's DNA damage, whether it's oxidative stress, whether it's LDL oxidation, endothelial function.
[03:14:27]  You can give someone watermelon juice with.
[03:14:29]  A glucose tolerance test and it improves insulin sensitivity during the glucose tolerance test.
[03:14:34]  So, a glucose tolerance test, you give someone isolated processed sugar.
[03:14:38]  It's called a glucola.
[03:14:39]  It's basically like a sugar drink.
[03:14:41]  And you look to see how well the body disposes of that with insulin handling and sugar handling, glucose handling in the body.
[03:14:48]  And when you give extra, quote, sugar with watermelon juice, it actually improves the handling of that glucola.
[03:14:55]  So, you can improve by giving extra sugar in a whole food form.
[03:14:59]  Cherry juice.
[03:15:00]  Acutely.
[03:15:01]  Yeah, cherry juice, blueberries, all these things, they have great effects in the short term when you're using them.
[03:15:07]  So, fruit, I'm not familiar, maybe Nick knows one.
[03:15:11]  I haven't seen a single study with whole fruit that suggests there's a harm to humans or even a fruit juice that's not like a super, like Sunny D, like a fake fruit juice.
[03:15:21]  So, I think that a lot of it is conflating studies that are misrepresenting fructose by itself as opposed to glucose and fructose co administration.
[03:15:29]  And so, I don't see fructose as a harmful molecule when we're eating it in that package.
[03:15:32]  And this is an interesting kind of.
[03:15:35]  Also, perspective gaze to the difference between fruit and processed sugar.
[03:15:40]  Because if you look at the data, at least observationally and in terms of populations, processed sugar, which is just, technically speaking, it's a disaccharide of glucose and fructose, that looks harmful for humans.
[03:15:53]  But when you give a glucose and fructose together in a fruit or a honey, these have different effects on humans.
[03:15:57]  They just don't look to be harmful.
[03:15:59]  I mean, honey has many, many trials showing improvements in metabolic health with honey, right?
[03:16:04]  Something people think of as pure sugar.
[03:16:06]  And they forget that honey has probably 300 to 350 bioactive components along with the sugar.
[03:16:13]  So I think what's going on here is.
[03:16:15]  At the level of the gut flora, that when you give isolated fructose, you get fructose malabsorption, you get dysbiosis.
[03:16:20]  If you give isolated sucrose, which is this disaccharide of glucose and fructose, you also cause dysbiosis.
[03:16:26]  You cause overgrowth of the wrong type of bacteria in the gut.
[03:16:30]  And that can lead to increased levels of a molecule in the human body called LPS, lipopolysaccharide.
[03:16:35]  And you see this, it's also known as endotoxin.
[03:16:38]  You can give humans sugar and see endotoxin levels rise.
[03:16:41]  Now, endotoxin is another really negative signaling molecule in the human body.
[03:16:46]  It actually tells the mitochondria, like, hey, you're broken.
[03:16:48]  It's a component of the gram negative cell wall, gram negative bacteria.
[03:16:52]  So, you don't want acute endotoxemia when you are eating a processed sugar.
[03:16:57]  And what's interesting is when you give honey or when you give fruit, which contains sugar, you don't get that effect.
[03:17:02]  You don't get LPS rising.
[03:17:04]  You don't get endotoxemia because these compounds in the fruit probably prevent the overgrowth of the bacteria.
[03:17:11]  A lot of the bioactives or these compounds in the whole foods actually affect the gut bacteria by preventing overgrowth.
[03:17:17]  It's incredibly complex, right?
[03:17:18]  That the food we eat affects this delicate balance, this symphony.
[03:17:22]  Of gut microbial populations in our intestines, and that has effects on the human body.
[03:17:27]  So people will say the same thing to me, and I see this from a lot of the keto influencers, not Nick.
[03:17:34]  Nick doesn't say this, but.
[03:17:35]  You're like a little like, not Nick, but he's thumped up.
[03:17:38]  Not this guy.
[03:17:39]  No, but like other keto influencers will say, honey is the same as Coca Cola, or orange juice is the same as Coca Cola.
[03:17:46]  I mean, there was a popular influencer saying that recently.
[03:17:50]  Glucose Goddess was saying that.
[03:17:52]  This French biochemist.
[03:17:53]  Glucose Goddess.
[03:17:54]  Oh, wow.
[03:17:55]  She was saying this, and you think, well, that's not.
[03:17:57]  True.
[03:17:57]  Like you look at the actual effects on human physiology at multiple levels, you get completely different effects.
[03:18:01]  I mean, orange juice improves endothelial function, sugar worsens endothelial function, which is sort of reactivity.
[03:18:08]  Yeah.
[03:18:09]  And I think that one of the main parts of the mechanism here has to do with the overgrowth of bacteria in the gut and then this attendant increase in these molecules in the human body, LPS, also known as endotoxin, and the negative effects those have.
[03:18:23]  So the idea here is just like, and Nick mentioned this.

=== Empty Calories and Microbiome Effects (06:32) ===

[03:18:27]  In this sort of population study, when sugar rations changed, you saw an increase in sugar potentially affect the epigenome, right?
[03:18:36]  The way that humans are programmed.
[03:18:37]  And I think that like an increase in fruit rations probably wouldn't have the same effect.
[03:18:41]  So when we're talking about carbohydrates and humans, the quality of the carbohydrate, like we've talked about throughout this podcast, matters massively.
[03:18:48]  I don't think humans need to fear fruit.
[03:18:50]  There's probably some inter individual variation.
[03:18:53]  But these foods look to be delicate in the way that they affect the human body and the microbiome and the way it all connects.
[03:18:59]  It's really interesting stuff.
[03:19:01]  I, Agree with Paul mostly.
[03:19:04]  The thing I really agree with is the package matters.
[03:19:07]  We're talking about compounds in blueberries, honey, or like we were talking about walnuts earlier, like the effect of elagitanins on, you know, is it urolithin A or hypocuric acid?
[03:19:16]  I think it's urolithin A is the downstream product.
[03:19:18]  But basically, like your microbiome will interact with components that are in your food and generate compounds that can have more powerful metabolic effects than the macronutrients or subgroups they're in, like fructose, you know, than we give it credit for.
[03:19:34]  And other factors actually just.
[03:19:35]  Quick tangent.
[03:19:36]  You're talking about like the basically leaky gut and toxemia.
[03:19:40]  There's also new data showing that you can manipulate your mucin lining and change the gut flora with stress.
[03:19:48]  So, stress activates, it changes signaling in a region called the amygdala, and there's a signal to glands in the gut called Brunner's glands that change mucin production.
[03:19:57]  So, like, another way where all of these things converge.
[03:20:01]  We're talking about like psychosocial things, they're not isolated, they converge on these metabolic pathways.
[03:20:05]  But, getting back to my point on fruit, I totally agree.
[03:20:08]  Like, a soda.
[03:20:10]  And like a honeycomb are two entirely different things.
[03:20:13]  Fruit is not bad.
[03:20:14]  Fruit requires context.
[03:20:16]  But to that end, one of the things I really hate, and I think you probably feel the same way, is platitudes.
[03:20:22]  So I hate the things of like, get your five a day, eat the rainbow, fruit is always good.
[03:20:27]  Cause it's like, well, hell, I'm not gonna say a mango is bad per se.
[03:20:32]  But if you have metabolic syndrome and your choice is a mango, blueberries, or hard boiled eggs for breakfast.
[03:20:41]  I'm going to go with first the whole board of legs, then the blueberry.
[03:20:43]  And I don't know.
[03:20:44]  I'm like, I'm nicking on the mango.
[03:20:45]  Yeah.
[03:20:46]  Yeah.
[03:20:46]  Makes sense.
[03:20:46]  Can I add some context there?
[03:20:47]  Yeah.
[03:20:48]  So I think that in the setting of metabolic syndrome, my perspective is that you have essentially broken mitochondria, right?
[03:20:55]  You have broken energy partitioning, you have broken signaling in the cell that's creating this insulin resistant signal.
[03:21:02]  And so in the setting of metabolic dysfunction, you don't process carbohydrates well, but the carbohydrates didn't cause the problem per se.
[03:21:10]  So I don't think a mango.
[03:21:12]  If you have metabolic syndrome, you're not going to handle the mango well, but the mango didn't get you there.
[03:21:17]  I don't think you became metabolically unwell or insulin resistant eating mangoes.
[03:21:21]  I think you became metabolically unwell.
[03:21:23]  This is my hypothesis.
[03:21:25]  Eating processed sugar affecting your gut flora negatively and potentially packing the membranes of your cells and mitochondria with too many seed oils and the derivatives.
[03:21:34]  So, I mean, these are the two greatest movers that I see.
[03:21:37]  In terms of the actual metabolism, I mean, like fructose does have unique metabolism.
[03:21:40]  So, in the early stages of glycolysis, that is a unique enzyme from glucose.
[03:21:44]  This enzyme actually doesn't have a positive feedback loop.
[03:21:46]  Sorry, a negative feedback loop.
[03:21:48]  So it can go kind of unchecked, deplete intercellular ATP.
[03:21:52]  This has been shown, lead to activation of, I think it's NAPDH oxidase 4, and cause mitochondrial dysfunction.
[03:22:00]  That's what we talked about.
[03:22:01]  It's so small.
[03:22:02]  You talked about this earlier.
[03:22:03]  The amount of fructose that you absorb, it's so small.
[03:22:05]  Well, depending on what you're eating, it's all just converted to different things.
[03:22:09]  I don't think all that mitochondrial.
[03:22:10]  So a cup of blueberries couldn't do that.
[03:22:13]  No.
[03:22:13]  But could the fructose.
[03:22:16]  From, and this is the difficult hypothetical because I said, like, the bowl of Rice Krispie, you know, cereal and orange juice, there's going to be too much fructose in that for the pathway is going to be saturated.
[03:22:29]  So I'm saying put a component.
[03:22:30]  Yeah, I don't know about that.
[03:22:32]  Because if you look at it, I mean, in diabetics, there was a study where they had increasing amounts of honey and they went up to 125 grams a day.
[03:22:40]  125 grams a day of honey in a diabetic.
[03:22:42]  I think it's about 50% fructose.
[03:22:45]  And granted, maybe it's not enough in one single bolus, but that actually improved.
[03:22:49]  Glucose handling.
[03:22:50]  Acutely.
[03:22:51]  Yeah.
[03:22:52]  Well, but I mean, like, I can eat Oreo cookies acutely and drop my LDL.
[03:22:55]  Does that mean Oreo cookies are good for long term?
[03:22:56]  Well, I mean, it's just speculative, you know?
[03:22:59]  I think a lot of this is speculative.
[03:23:01]  I think.
[03:23:02]  I think it was an eight week study.
[03:23:04]  I think the human study, the saturation started to kick in around like half a gram per kilogram or something, which you can saturate in a meal.
[03:23:12]  I'm not being definitive on this.
[03:23:15]  I just don't like the idea.
[03:23:17]  How's another way to put this?
[03:23:18]  People say like empty calories.
[03:23:20]  This is something that we can probably agree on I think the term empty calories is stupid because it suggests that the macronutrient cargo, the carrier, is itself inert and just energy.
[03:23:33]  But the macronutrients, you know, the things that give you energy, the stearic acid, the pulmitic acid, the meristic acid, short chain fatty acids, you know, fructose, sucrose, whatever, they're each unique biomolecules with unique effects.
[03:23:45]  Of course.
[03:23:46]  So, stearic acid, you know, probably can improve mitochondrial function.
[03:23:49]  We know it does.
[03:23:50]  Yeah.
[03:23:50]  So, I mean, like, that's the broader concept I'm getting to.
[03:23:55]  I guess coming back and probably bringing it to the end because I want to not miss my plane.
[03:24:00]  Yeah, you got to leave soon.
[03:24:01]  Is that.
[03:24:04]  Context matters, and what I mean by that is this is difficult to explain without just coming off as this is so hand wavy to be useless, but I think it's useful, and I'll try to explain why.
[03:24:16]  When we're talking about, like, say, macronutrient groups, this is a very diverse set of molecules that is then packaged in foods that have been processed differently and have different bioactive effects.
[03:24:27]  They go into a system that processes it in many different ways.
[03:24:32]  Does it get bio converted in the small intestines?
[03:24:34]  Is the linoleic acid it?
[03:24:36]  Acid, you know, oxidized by myeloperoxidase because you have, you know, excess fat tissue, or is it converted to 4 HNE or 12, 13 Dihome, et cetera, et cetera, et cetera.
[03:24:45]  It gets so complicated that when you look at the platitudes that we hear bandied about, get your LDL down, eat less saturated fat, butter bad.
[03:24:59]  It's comical.

=== Overcoming Nutrition Overload (05:30) ===

[03:25:00]  Yeah.
[03:25:01]  It's comical.
[03:25:02]  It's useless.
[03:25:04]  And it is the basis.
[03:25:07]  For why nutrition is so frustrating and confusing for people.
[03:25:12]  So, I've thought about this a lot and what my solution is to that problem because people gravitate towards it, they want simple, they want the to do.
[03:25:25]  I think there's a way, I want to see if you agree, that we can inspire curiosity and awe in the physiology of all of this.
[03:25:34]  It's not about understanding, like, I don't need to write a post and somebody reads it, like, I got all of this.
[03:25:40]  You get 20% of it, great.
[03:25:41]  Provided you went through the process and enjoyed it.
[03:25:44]  Like, finding the awe in learning about science, metabolism, physiology is a gift that I think we can give to people.
[03:25:54]  And with that humility and the curiosity that I honestly think curiosity can save lives.
[03:26:00]  It's a difficult task, but I think it's one that can be accomplished.
[03:26:04]  Maybe I'm just naive.
[03:26:04]  The more I know, I realize the more I don't know.
[03:26:07]  After the last three and a half hours, I realize I don't know jack shit about any of this stuff.
[03:26:11]  But it's fun, right?
[03:26:11]  It's like, of course, this is an interesting idea.
[03:26:13]  Yeah.
[03:26:13]  And then you grapple with it.
[03:26:15]  And, you know, what I want to applaud Paul for, not just here, but like offline, is you're someone who I feel like I can have a genuine, open, intellectual conversation with.
[03:26:28]  And where we can start like a public conversation and we didn't actually get to like nailing down the numbers.
[03:26:32]  But like if I said, what is your opinion on a zero to 10 scale and you start at X point, you'd be fine saying, hey, I kind of shifted on this in a very non defensive manner.
[03:26:43]  And I think genuinely, some people are like, Virtue signally about it, but I think we need more of that, and it's hard because I keep pulling it back to but incentive structures.
[03:26:55]  The incentive structure doesn't always favor saying, hey, let's sit down and have a nuanced conversation between people who have differing ideas and see what evolves from this conversation.
[03:27:07]  We can both think of examples of people who might be a little bit negative on having open discussions or representing things honestly.
[03:27:16]  Thank you guys for doing this, man.
[03:27:17]  Thanks for having me.
[03:27:18]  This has been super fun.
[03:27:20]  Paul, where can people find you online?
[03:27:22]  It's Paul Saladino, MD, everywhere.
[03:27:25]  All the socials, website.
[03:27:26]  Yeah.
[03:27:27]  Amazing.
[03:27:27]  Yeah.
[03:27:28]  Nick.
[03:27:29]  My name is Nick Norwitz, N O R W Y T Z.
[03:27:31]  I don't think there's another Nick Norwitz around.
[03:27:33]  And I'm really having fun on my sub stack right now, staycuriousmetabolism.com.
[03:27:37]  So you can check it out there.
[03:27:40]  And thanks for having us, Danny.
[03:27:42]  Beautiful.
[03:27:42]  Thanks for having us.
[03:27:43]  Can I just add one more thing?
[03:27:44]  Of course.
[03:27:45]  I think that we've talked about a lot today.
[03:27:47]  And I appreciate Nick having this conversation.
[03:27:49]  It's fun to talk to somebody as smart as he is about all these kind of ideas and share things and learn from each other.
[03:27:54]  I think that a lot of this probably is overwhelming for people.
[03:27:57]  Maybe you felt a little overwhelmed at times.
[03:28:00]  But in my mind, this is just how I conceptualize it.
[03:28:03]  If you just take a step, if you can move one step beyond a calories model and start to think about a theme that we came to a lot of times in this podcast around food quality and the difference between food components and whole foods, you're going to be light years ahead.
[03:28:19]  It's like, look, you said at the beginning of the podcast when you don't eat carbs, quote unquote, which I'm imagining is processed breads and things like this, cakes, you feel much better.
[03:28:27]  That's about all people need to know.
[03:28:31]  If you move away from energy balance, which is probably a psyop started by Global energy balance and Coca Cola, along with many other nutritional psyops.
[03:28:38]  I just think that there's actually potentially an active movement to confuse the consumer.
[03:28:45]  And then we throw our hands up and we think, oh, calories is the simplest model.
[03:28:48]  I'm just not going to eat too much.
[03:28:50]  And I think that's exactly the wrong decision, right?
[03:28:52]  I think that if humans just focus on food quality and whole foods, as overused as that word is, from animal and plant origins, you are going to do better.
[03:29:04]  You're going to get healthier.
[03:29:06]  And that's really all you need to know.
[03:29:08]  And it doesn't need to be overly complicated.
[03:29:10]  You can dive into the little things that we went down the rabbit hole on this podcast.
[03:29:13]  But I think that if you move away from calories and you move toward the idea of food quality, you're on the right track.
[03:29:19]  Just keep following your notes from there and you'll do good.
[03:29:21]  I also want to just add you use the word overwhelmed.
[03:29:24]  And I love that because I hope people feel that.
[03:29:28]  I hope people feel that.
[03:29:28]  And the reason being is like, if you go to the gym, you want to have a good workout, feel exhausted, and then what's the term?
[03:29:36]  Progressively overload.
[03:29:38]  Why should learning be any different?
[03:29:39]  So, yeah, we're not going to go gentle on you because this conversation had a lot of chapters.
[03:29:46]  And I think we went into the weeds and then pulled back.
[03:29:48]  You don't need to get everything.
[03:29:50]  But if you're willing to engage with these conversations and progressively overload your learning, just like going to the gym, that is awesome.
[03:29:56]  That is the journey.
[03:29:57]  And yes, the big picture of if you just kind of go back to basic principles, eat whole foods, that's great.
[03:30:05]  But I do feel that learning about it gives you the insight and excitement to engage in that.
[03:30:12]  You know, be quote unquote compliant with that and then evolve and tweak the way you live indefinitely and enjoy that process.
[03:30:19]  That's how I live.
[03:30:21]  I think that's how Paul lives, how you have evolved your diet so many times.
[03:30:24]  And that will make your nutrition journey not a chore, but a hell of a lot of fun.
[03:30:29]  And you'll inevitably end up in a good place.

=== Basic Principles for Fun Eating (00:31) ===

[03:30:31]  What are you going to eat for dinner tonight, Danny?
[03:30:33]  That's a good question.
[03:30:34]  I'm thinking about probably a steak.
[03:30:35]  That's a good choice.
[03:30:37]  Safe.
[03:30:38]  Safe.
[03:30:38]  No sides.
[03:30:40]  But tomorrow, I think I'm doing a fruit bowl.
[03:30:42]  You're good.
[03:30:43]  I'll be snacking on some.
[03:30:45]  Dried steak on the plane.
[03:30:46]  Eat some of that lineage on the plane, bro.
[03:30:48]  Hell yeah.
[03:30:48]  Oh, dude, that stuff's amazing.
[03:30:51]  That lineage stuff, those dried steak chips.
[03:30:55]  It's good, right?
[03:30:55]  Fantastic.
[03:30:55]  Hair dried steak.
[03:30:56]  Yeah, thank you.
[03:30:56]  Thank you for all that stuff, dude.
[03:30:57]  I really appreciate it.
[03:30:58]  I'd appreciate it if you could have some for the plane, too.
[03:30:59]  Yeah, yeah.
[03:31:00]  All right, man.
[03:31:01]  Thank you guys.
[03:31:01]  Thank you for having us.
[03:31:02]  Good night, everybody.
[03:31:02]  Thank you.