Dr. Nick Norwitz PhD challenges lipid dogmas by revealing that lean individuals experience high LDL due to the "Lipid Energy Model," not genetic defects, as proven when 12 daily Oreos dropped his cholesterol 71% versus statins' 32%. He critiques "eminence-based medicine" and defends allulose over artificial sweeteners while highlighting DARPA's $10 million "Metabolic Dominance" project. Ultimately, the episode argues for nuanced nutrition research over pharmacological defaults, suggesting carb reintroduction safely reverses metabolic strain without ruining ketosis. [Automatically generated summary]
Transcriber: CohereLabs/cohere-transcribe-03-2026, WAV2VEC2_ASR_BASE_960H, sat-12l-sm, script v26.04.01, and large-v3-turbo
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Explaining Science On YouTube00:03:57
When did you come up with the idea to start talking about all these studies that you're doing at Harvard and Oxford on YouTube and making them public?
I've always just been a total dork and liked explaining things.
So it was a matter of me reading a paper and being like, this is cool.
How can I translate this to something that is engaging for other people?
So it could be like, you know, a paper, the title is long and complex.
It wouldn't catch the average person's attention.
But I'm like, basically, what this is saying.
Is that, you know, what is a catchy way to put it?
So, for one example, it could be Diet Coke causes anxious sperm.
You're like, what's up with this?
I'm like, well, actually, there's this really cool study where you take, you know, aspartame, the sweetener in Diet Coke at pretty low doses, and you can induce anxiety in mice that can cause anxiety in future generations.
And then you kind of go through the data, try to break it down.
When you explain it to people, I think the average person's actually pretty intelligent.
You say, look, this is how you look at this kind of graph.
And it's something that I just ended up doing because I like explaining science.
It was a fun exercise for me.
And it was pretty easy with, um, I just pull out my iPhone after I read a paper, record something, and that's been all it's been.
Being public on social media, that kind of like, well, having more of a presence just evolved.
I never really intended for it to happen.
So it's something I'm kind of exploring now because it's kind of fun.
I was trying to actually decide on a topic to talk about at an upcoming conference in March.
And what I think I'm going to go with is something about when worlds collide, when Jade Tower academia and the lay public kind of, you know, Those worlds collide because we're living at a really interesting time, in my opinion, in 2024, where for the first time ever, the lay public has tons of access to information through the internet, through social media, and the academia is forced to interact with the public.
Now, I think there are a lot of negative things that come out of this, but also a lot of potential positives.
So, for me as a young scientist and a clinician to be, being in medical school, it's really interesting to see how this will fit into my future career.
What good can it be leveraged to execute on?
So I'm just playing with it a little bit.
So, for people who don't know who you are, explain your educational background and what you studied and where.
I did my undergraduate degree at Dartmouth, where I studied cell bio and biochem, graduated valedictorian there, and then went to Oxford University in the UK to do my PhD in metabolism.
And now I finished that up, came back across the pond, and I'm doing my medical training at Harvard.
And you are, how many years have you been at Harvard Medical?
This is my third year.
And you, but you got a PhD from Oxford?
From Oxford, yeah.
Okay.
So.
And the PhD is in what again?
I always have a different answer for this because it's in neuro, but I did a lot of metabolism work.
It's in the Department of Physiology, Anatomy, and Genetics.
I like to say human metabolism.
Human metabolism?
Yeah, metabolism, how the body uses energy, basically, is how I break it down.
I could also say it's in neuroscience because I did a lot of neuro work or just physiology.
So, the thing is, people think what you do your PhD in is what you are an expert in, which I mean, kind of makes sense that you conclude that.
But a PhD is a training process.
So, it's not necessary that what you do your PhD in ends up being your research career.
I gained tools and expertise by going through the process.
But by virtue of even just personal life events and where things have taken me, my actual research interests have shifted from what I did my PhD on to.
Other things now, things that we're studying about.
In particular, my research interest now is how lipid metabolism changes, cholesterol metabolism in low carb diets.
Diet Shifts From PhD Research00:14:21
I'm a practitioner of a low carb diet.
I adopted a keto diet back in 2019 for inflammatory bowel disease.
I was finishing up my time at Dartmouth and started developing really bad ulcerative colitis.
And then when I moved to Oxford, things got really, really bad.
So I was in the ICU, I was even in the palliative care ward for a while, and nothing was really working.
So I started to dabble around with my diet.
Not out of expectation, but out of desperation, and then stumbled upon trying a ketogenic diet, which not only put me into like, you know, improved my symptoms, my inflammatory markers went down, but put me into like histologically biopsy proven remission.
So I've been keto now for almost five years, and it's what's allowed me to live my life.
What was your diet like before you came down with these diseases?
I would say it's a pretty standard American diet.
I grew up in a household that was, I would say nutritionally aware, but not nutritionally intense.
So, both my parents are physicians themselves.
So, it's not like we were eating McDonald's for every meal, but you know, being like a young kid in what the early ish 2000s, you know, you eat like breakfast cereal and you eat your fruits and vegetables, but then you'll go to Subway, you'll eat ice cream.
So, it's like pretty standard fare.
And I never had trouble with weight or anything.
So, when you're a skinny young kid, nobody cares what you eat.
They'll give you pizza, give you French fries or whatever.
So, I just kind of grew up.
Eating like that.
And then again, never really had trouble until my early 20s.
And then that's usually when inflammatory bowel disease, at least ulcerative colitis, develops.
And it just happened to hit me.
Yeah.
I was, quick aside, I was, before you got here, we were recording a little like Patreon pre show.
And I was showing everybody photos, a photo of your breakfast that you sent me this morning, which was like 11 or 12 eggs and salmon.
And then there was like two little biscuit cookies or something next to it.
I think they were frittatas, actually.
That is a, oh, so.
It was, yeah, no, I don't always eat like that.
But when you take a, you know, you don't always eat 12 eggs in the morning.
I mean, here's the thing I'm a medical student with medical student income, which is not much, i.e., zero.
And I have a company, you know, sponsoring me to come down to this conference and an all you can eat buffet.
What do you think I'm going to do?
Yeah, right.
I mean, I don't blame you.
This is less, you know, standard low carb behavior, more 28 year old getting free food behavior.
So, yeah, then I went for the eggs.
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Now back to the show.
So you say in your mid 20s, you transitioned to this low carb, ketogenic diet.
Yeah.
What?
Exactly, like what specifically were you eating and what did that diet look like?
Yeah.
So, keto people often think of like, oh, you must be eating lots of bacon, beef, butter, and eggs, like high saturated fat foods, very little vegetables.
Keto is defined by a diet that puts you in a metabolic state where you're making ketones.
That's where the term comes from.
And to achieve that, your carbohydrates need to be low enough and your protein moderated so that your body is burning a lot of fat for its main fuel.
And then some of those.
Circulating fats get turned into these things called ketone bodies.
The reason we make ketone bodies in part is to fuel the brain.
The brain can run on glucose, but it can also run on ketones.
So, if we were evolving as early man and our brain could only run on glucose, what would happen is you're fasting for any period of time, your body would basically break down all its lean tissue and you'd starve to death in a couple weeks.
But we know that doesn't happen.
We can go a long period of time without food because our brains can run on ketones.
As an aside, I will point out that they kind of have two faces.
These molecules, they're really cool.
It's what I studied for my PhD.
They're energy molecules.
It's true.
So they can be burned as fuel, but they're also signaling molecules.
They're basically hormones.
They have receptors on cells and in cells.
They can change the way that your DNA is read into proteins.
They can modify proteins, like literally go on.
They're called post translational modifications.
So after translation, which is where you have like RNA turned into a protein, you can tag them with different things.
There's lots of different molecules you can tag them with, and it changes their function.
And ketone bodies, beta hydroxybutyrate, can be tagged onto proteins about 1,400 times.
At least different proteins change their function.
So, all the jargon aside, the point is yeah, they're fuels, but they're also these potent signaling molecules that really can change the way our body processes energy.
I feel a million times better when I am on a low carb diet and I'm not eating processed shit.
When I have ketones, whether they be from fasting or just eating low carb, or whether I take Dom's Keto Start, I don't know if that's the same.
It's exogenous ketones.
I don't know if that puts you in ketosis, but I feel a million times better.
I can think better.
I have way more energy.
And it's astounding.
It really is.
It's kind of crazy how much, well, it's not crazy.
I was going to say it's crazy how much our diets can impact our physical function and mental health.
But if you step back, it's just obvious.
It sounds stupid to say it's crazy because this is what our body is running on.
And this is what our body is effectively made of.
But people don't tend to think of it.
And yet there is this awakening when people really start to play with their diet and then are reflective on how it impacts them about how much better they can function, even if they're healthy people.
The issue is, And this is the way it was for me people tend not to take their diet seriously until they're forced to.
Right.
They're dealing with a serious health issue.
And of course, that's not what we want.
Well, that's what happened to you, right?
That's what happened to me.
And I don't want that to be the way of society.
So for me, I was forced into it.
You know, if I hadn't had ulcerative colitis, I wouldn't be keto right now.
I probably would just be eating pretty standard fare, you know.
But so a question is this is, I guess, a career mission for me.
How do you make people?
How do you make society shift their mindset so they see how impactful food is and that we make better choices?
I think we do need a societal shift because right now, people aren't just, they just aren't awake to how important this is.
Even in hospital settings, you go into a hospital and you see what patients are served.
Or let's just even, let's not even bring the patients into it.
You walk into a hospital, like what's the first thing you see?
It's not a gym, it's like a Starbucks.
Yeah, a coffee shop or a pastry shop.
I walk into the hospitals that I'm working at and the first thing I'm hit with is the smell of like, Croissants and 12 different types of Danishes.
This is a hospital, and people don't really think twice about it.
It's just the way we go about things.
When you see a patient with diabetes being fed chocolate cake, it's just like that's the way things are.
When you pin anybody down, nobody gets defensive about it.
If I ask a senior doctor or a resident, isn't it just a little weird if you just stop to observe that this patient with a glucose or a carbohydrate intolerance disorder is being fed chocolate cake in a hospital?
Well, yeah, it's weird, but it's on the menu, and they're, you know, an autonomous patient.
They can make their own choices, which is such cognitive dissonance.
There's a point there.
I mean, adults need to make their own decisions.
I have my, you know, it's a complex topic.
The point is, I think we can agree it's dysfunctional.
There's a lot of things we do that are dysfunctional.
Another example would be, you know, bribing people with free Krispy Kreme to get vaccines.
Like whether your opinions on vaccines aside, we can agree on the fact that, you know, diabetes and obesity are risk factors for poor outcomes in COVID.
So why are we permitting people to be bribed with donuts?
Like this is a weird incentive structure.
Again, it sounds controversial just because I'm talking about food and vaccines.
I'm not putting a value statement on vaccines.
I'm just saying this is a weird dysfunctional quirk of our society that we would do this and that we would permit this and not think twice about it.
It is astonishing the cognitive dissonance that exists.
And a lot of primary care physicians don't know, they don't follow up with the cutting edge research that's happening.
Like I told you, when I went in, I had my cholesterol, my LDL was like over 200, maybe like 210.
Was about to have a heart attack for my cholesterol.
He's like, you need to get a calcium score.
Well, to your doctor's credit, I mean, he's keeping up on some of the literature if he's asking you to get a functional test, which we can get into in a minute.
I mean, I am very cautious being someone who I hear the frustration in your voice.
I hear the frustration and I see it and interact with people on social media.
My doctor doesn't get it.
They're not up to date on XYZ.
At the same time, being someone who's training clinically, I understand the pressures of the system and also kind of the level of evidence you need to recommend a certain.
Intervention.
And the fact of the matter is, there are lots of layers here.
And one of the layers is that the research that we need to recommend certain things as standard of care needs to be pretty rigorous.
And these rigorous trials take investment.
And nobody's investing lots of money in good nutrition research.
There are big problems in nutrition research.
And all the money is going to pharmacological interventions because of the incentive structure around.
Our research ecosystem.
So, what was the, there was in the 50s, the sugar industry bribed a couple of Harvard scientists to basically perform a botched study analysis on saturated fats, saying the saturated fats were the cause of heart disease.
Yeah, they were like, I'm not a nutritional historian.
I try to, you know, I think it's important, but quite honestly, I don't know.
Yeah, they bribed them.
They paid them the equivalent of like $50,000.
I've read those releases.
I know about that episode.
What I'm saying is, How that created a domino chain to today.
Right.
And what weight that event actually had on what's going on today is probably something that I don't feel educated enough to comment on in a productive way.
But yes, that did happen.
If it happened in the 60s, I would imagine that some of these companies have way more power today.
They have way more money and they could throw their influence around way more.
I don't know if it would be more effective in today's age with the internet and.
People being able to communicate better, but I don't know.
Yeah, it's definitely still happening.
There was actually a publication talking about how the American, what is it, AND, American Association of Nutrition and Dietects or something, it was called like the corporate capture of.
And it went through about how they've gotten like $15 million from the food industry.
And that's obviously going to affect, you know, and they, again, they release emails saying this is how it's probably affected what they do.
I think that the real problems are a lot more insidious and have to do with incentive structures that are.
Built into the system.
And those are a lot harder to break because you can't just have a whistleblower saying this thing, which is clearly unethical, needs to be called out, these people need to be fired X, Y, or Z.
It's like a faulty incentive structure that pervades the system.
And that's not legal, but, and it's much harder to solve too.
And in the media as well.
The media is very polarizing when it comes to this topic.
If you go on Netflix, all you see is documentaries about how the vegan diet is the way to live forever.
Do you see that, the new one?
That was, what was it?
You Are What You Eat?
Did you see that?
That was a new one.
I haven't seen that one, no.
I try to avoid these nutrition documentaries.
I think I sold Forks Over Knives, is the one I saw last.
Yeah, it's so embarrassing.
I mean,.
So, the recent one was about a Stanford twins study.
It was done out of, yeah, that one.
So, they took, I think it was 20 pairs of twins.
And the idea was we're going to feed them two different diets, right?
A vegan diet and an omnivorous diet.
And I think it was an eight week with two parts.
One was a feeding portion.
And then they actually transitioned to having them kind of cook their own food.
And the idea is well, this is cool, right?
We can take twins and feed them different diets.
And that should be a really rigorous study because these are genetically identical.
Right.
Here's the thing though.
I tried to avoid watching the documentary because obviously they're translating it to a Netflix audience, but I got so many DMs to review it.
I just figured, all right, it's going to save me time to watch this.
What was it, something three ish hours?
There were four episodes that were like 45 to 60 minutes each.
And I was so freaking frustrated because I'm finishing the last episode and I went there to review the data.
I try to be pretty open minded and even handed.
I went there to review the data.
We're three episodes through with the four episode series.
They haven't talked about any of the data, not any of it.
It was a propaganda piece, it was a bait and switch.
And even the things that they talk about, like, oh, look at these like Stanford students making fake eggs.
And then you look in the supplement of the paper, guess how many fake eggs the participants ate?
Zero.
What were the fake eggs made of?
I don't know.
They were like, it was cute.
And I actually think it was kind of cool.
They have, you know, these Stanford students doing like meat alternative, like a meat alternative class in chemistry.
And it's like, this is cool.
I'm all for this, but don't tell me you're going to be doing a documentary about the Stanford twin study and reporting on the health results, then go through three of the four episodes, report none of the results, and then be trying to sell me beyond meat and fake eggs that the participants didn't even eat.
Like this is a just, again, it's where the media just takes the opportunities that they can in order to generate propaganda.
And, you know, I, it's a game and it's a game that rather than be entirely cynical about.
The LDL Paradox Explained00:15:52
I kind of want to learn to play because it is the landscape we're in.
So, you know, you know what's coming in this conversation and what I've done recently.
This is my first attempt to kind of play this game with the resources I have because, you know, you can sit in the sidelines and kind of moan about the system, or you can, you know, start to use it to your advantage and, you know, in a way that you feel is ethical and transparent.
So, I don't mean to be trying to be wise here.
I mean to be.
You know, speaking to you as the guy who is trying to figure it out right now.
Because, like I said, I'm in a very weird place.
I'm a scientist by training.
Now I'm training to be a doctor.
I like to communicate.
I've also been the frustrated patient.
And now, for better or worse, I have a social media presence.
And it's just like, how do all these things meld and how can I use the resources I have to maximal effect?
So, yeah, it's, it's, It's fun.
It's interesting.
It's a little bit scary because I'm always trying to really reflect on whether what I'm doing is having a net positive or net negative benefit.
I think there's a tendency to be like, oh, but I meant X, Y, Z.
We always have intent.
But something you definitely learn in clinical training, if not other places, is that your intent does not necessarily match perception.
And when push comes to shove, perception and impact are really what matter.
So it's worth being reflective about is what I'm doing actually benefiting people or is it having harm?
And try to leave ego at the door when you're reflecting on that.
So, When you first went to the ketogenic diet, your cholesterol was like above 500, right?
It started.
So I actually didn't describe what my diet was when you asked.
So I'll get to that in a minute.
But so we, yeah, my point was like that's the biggest concern I feel like with people that are ketogenic or on carnivore is that the cholesterol is through the roof and people don't want to die of heart disease.
Right.
So when I went low carb, before I went low carb, Mike, just for a baseline, my LDL cholesterol, that's what people call like the bad cholesterol.
So When I talk now, I'm going to be talking about this LDL or LDLC primarily.
It was 95, which is pretty normal.
I went low carb.
And on my first repeat test, my levels were well above 300.
Now, I said I didn't describe my diet.
I now want to describe it because when I started low carb, the way I did it was very low saturated fat, like lots of vegetables and fish, very little red meat, because that's what I thought was healthy at the time.
Very little butter?
No, I didn't use butter at all.
Olive oil?
Lots of olive oil, avocado, olives, lots of leafy greens and fiber.
And I designed it that way just because if I was going to try keto, that's what I thought was healthy at the time.
Now, I want to emphasize that because despite that, my LDL levels more than tripled.
So it wasn't like I was guzzling butter here.
People like to try to boil it down to, oh, they're just eating a lot of saturated fat.
That's a lazy explanation.
And I'll repeat that.
That's a lazy explanation.
It doesn't describe the phenomena we're seeing.
On a lot of levels.
Remind me to get back to why saturated fat is such a bad explanation.
I can come up with a bunch of reasons.
But the first reason is there's no suggestion in the literature that saturated fat can have this kind of impact on people in general.
Like when saturated fat increases your LDL in the general population, it can have a little blip.
But it's not going to increase your levels from 90 to over 300.
The only thing that people think can make your LDL that high, 300, and then eventually mine ended up continuing to climb to the highest it's been my LDL, not total, my LDL was 545.
Which, again, you show that to a doctor and they think one of two things.
They think this is a lab error and a fluke, or you have a terrible genetic condition and you probably should either start a medication or go coffin shopping.
Those are your options.
So, that is now very clear that that is an event that happens for a lot of people that go on low carb, where they have their LDL skyrocket and then they are stuck between a rock and a hard place because They love this lifestyle.
It can often be very therapeutic.
So, for someone like me, I need it.
But then their LDL goes through the roof.
And how do you manage these things clinically and as a patient?
How do you walk the line between them?
And what is actually the risk profile of this particular LDL rise?
And we're going to get into why it's unique, I'm sure, in a minute.
But the interesting thing about it, and I'm going to give a hat tip to my good friend and colleague, Dave Feldman, he noticed when this happened to him, This happened to him in 2015.
And he was looking around and seeing who else it happened to.
And he's like, huh, this is weird.
The people who have this response, who there's a lot of them, but they're actually the minority.
The people who have this response.
Let me ask you this.
Would you think if we consider the LDL bad and high cholesterol bad, that the people who would see the LDL increases would be the healthy, lean people or the people with obesity and diabetes, the unhealthy people?
What would you just intuitively think?
I would imagine it would be the unhealthy people, fat people.
Right.
We see the opposite.
So what we see is actually the people with obesity.
And insulin resistance disorders, they don't have LDL increases.
The people who have increases are the lean, healthy, athletic ones.
So Dave observed this.
This was back in 2017.
We didn't have hard data.
He didn't have hard data.
I wasn't doing keto at the time, I was smashing cookies at the food court.
And he coined this term in 2017, lean mass hyper responder, a term to distinguish these people who go low carb and see the increases in their LDL along with high HDL and low triglycerides.
And we can also get into the mechanism behind it because it's really, really interesting.
But he observed this and said, okay, but these people are usually lean.
So he turned them lean mass hyper responders, hyper responders to low carb, where they're, you know, hyper responses, the increase in cholesterol.
So lean mass hyper responders was the term.
He put it out in a blog post, not a scientist or at least not trained in medicine.
And the response was a lot of people coming forward and saying, hey, that's me.
Hey, that's me.
Hey, that's me.
So he started a Facebook group.
It now has over 11,000 members and a community has arisen.
It's very clear now that there's a population of people.
Who are lean and healthy, who go low carb, or lean and metabolically healthy.
They might have inflammatory disorders, autoimmune disorders, neurological disorders, mental health disorders, but for whatever reason, they go low carb and their LDL then skyrockets.
And then they're freaking out, or their doctors are freaking out.
Anyway, fast forward a little bit.
I go low carb.
This happens to me.
And I joined Dave when we started doing a little bit of research saying, okay, there's something here.
Let's try to figure out what it is.
Then our first paper was published near the end of 2021, early 2022.
With a team at Harvard in Mexico, with my friend Adrian Sotomoda, who's an MD PhD.
He trained with me at Oxford.
And then, senior author on that first paper was an MD PhD endocrinologist at Boston Children's in Harvard.
And what we showed was actually, yeah, there are lean mass hyper responders.
This is a phenotype that exists.
And as it happens, there is an inverse association between body mass index and LDL and low carb diets, which means the leaner you are, the higher your LDL goes.
So.
Now.
To interrupt you real quick, when it comes to BMI, is there a difference between body mass with fat or body mass somebody who's really muscular and has a lot of muscle mass?
So, yes.
What I'll say is our studies are limited in that BMI is typically what's collected.
So, for example, we did a meta analysis of randomized controlled trials where you just analyze a bunch of trials that pre exist, and people only collect weight and height because it's easy, right?
So, you get a BMI.
So, if we're looking across these 41 trials, they just aren't getting DEXs on every people, which goes at body comp.
We are limited by the tools that we have, but you're right.
There's going to be a difference between someone who is, you know, their BMI is 28, but they're shredded, and then someone whose, you know, BMI is 28, but they're, you know, floppy.
Right.
An example, I mean, a good example would be Dom, right?
He's a big guy.
Huge, yeah.
But he had this response.
Now he's BMI over 25, I presume, but he has very little body fat.
So Dom's a monster.
Google pictures of, type in Dom D'Agostino bodybuilding.
Yeah, absolutely.
This will be fun.
You can definitely have people who are over 25 BMI who have this response, particularly if they have low body fat.
There is an extra.
Look at that one on the left, top left.
Sorry to interrupt.
No worries.
Just want to give people some context for Dom's body mass.
And an incredibly sweet man as well.
Oh, Dom's the man.
Yeah.
Look at him.
Yeah.
No, it's a good question.
I'd sum it as we're limited by the data we have.
We have one study that came out by Cooper et al. where we did actually look at fat free mass and did find an association.
But right now we're using BMI as a proxy, which.
On population levels, like you have a cohort of like 500 people, it's going to be decent.
Right.
So it works for our purposes.
But no, it's a good question.
But what we found in this first study was there was an inverse association between BMI and LDL.
Basically, the leaner you are, the higher your LDL goes in a dose response manner.
Right.
More lean, higher LDL.
Okay.
Leaner, higher LDL.
Now, this initial study was limited in just the way the data was collected.
But the research has evolved.
So we've had multiple studies confirming this finding.
And the most recent one, Confirming it was actually this meta of RCTs that I mentioned.
Now, if you think about the hierarchy of scientific investigation, at the bottom you have things like case studies, and then you go up and you have randomized controlled trials, right?
You take people and you randomize them to different groups.
That's supposed to be the gold standard.
But above that, you could say you have the meta analysis of randomized controlled trials, where you take a bunch of randomized controlled trials and you group them and you analyze them as a group.
So that's a very rigorous study type.
Now, we did this and we published it in the American Journal of Clinical Nutrition, the first author, Sota Mota et al.
And basically, what we found was if you look at all the low carb trials, low carb defined as carbs under 130 grams, those, the only category, only BMI category that had increases was lean, under 25 BMI, did have an increase across the studies.
All studies had an increase in cholesterol, in LDL cholesterol.
It was like 41.4.
Across all of these meta trials.
Across all, in lean people.
But then if you analyze the ones in overweight or class one obesity, There was no increase.
Then, if you analyzed in class two obesity, there was a decrease.
So, and then we looked across all of them, and again, there was an inverse.
Class two obesity, meaning very obese, their cholesterol went down.
Their LDL went down, yes.
Wow.
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Now back to the show.
So, again, what we're saying is it's the lean people that are at risk for the increased LDL.
In fact, we also did an analysis in this study because we could have individual participant level data of, oh, how does this compare to saturated fat?
You know, what's the impact?
So, you can see even in the supplement, this analysis, and being even in the top quartile of saturated fat intake had negligible effect as compared to being lean.
Being lean, just having a BMI under 25, was over five times as powerful as having top quartile saturated fat intake.
Bottom line is the low BMI being lean in terms of factors that are explaining why people go with why people see increases in cholesterol and low carb.
It's being lean and metabolically healthy, it's that's a risk factor, not eating a lot of saturated fat, and that seems counterintuitive and paradoxical.
So, the question is, why would this occur?
Um, and how can we test it?
So, the um, do you want to talk about?
The most recent stunt or the model behind it first?
Let's talk about the most recent stunt and then we'll tell them the model.
All right.
So, do you want to break the title or should I?
The title, the legit bait title.
Yeah.
Which will be pretty close to the title of this episode, but let me see if I can recall it.
Harvard Medical Student Uses Oreo Cookies to Lower His Cholesterol.
Is that about right?
Something like that.
Yeah.
So, you did a study.
Basically, you ate Oreo cookies, 16 Oreo cookies a day for almost a month.
And then you did a washout trial, and then you did the same thing with statins and you compared your cholesterol, which is.
It was 12 per day for 16 days, but otherwise, yeah.
So we'll get into the model in a second.
But my thought process here, again, going back to translating science to a broad audience, is look, what I'm studying, this phenomenon that we just described, if you're following along, you might have had that, like, huh, this doesn't make sense response.
I think that's an appropriate response.
But it's hard to get people engaged when I say lean mass hyper respond to lipid energy model.
cholesterol this, cholesterol that.
And when I try to explain the intricacies of the model without some sort of hook, people often get lost.
And in particular, actually, I'd say there isn't much traction in academia.
I would say there's even suppression.
And suppression, I'll just be clear.
I'm not a person who uses hyperbolic terminology flippantly.
I'm very particular about my words.
So when I say suppression, I mean suppression.
And we can talk about that as well, including things that have been published that I think are just I am astonished that they got published.
Are you talking about this specific study you did?
You experienced suppression?
Suppression In Academic Discourse00:02:46
No, no, beforehand.
So, what I'm saying is, I'm building up to why I did this.
And what I'm saying is, what we're studying, I think, is very important, but it's not being talked about enough.
It might be the most important.
You can say that.
I won't reject that statement.
But anyway, I think it definitely has importance for progressing the science and also providing patients and clinicians with information that can be immediately clinically useful.
So, point being, We'd actually shown before that adding back carbs in these lean people can lower LDL.
We've even shown it in a case series that the most dramatic response we had was adding about a sweet potato per day, lowered the guy's LDL by 480.
Wow.
So lowered it by 480.
As in, it was 665, it dropped to 185 with about a sweet potato.
But one sweet potato a day.
It was, I mean, 50 to 100 grams of carbs.
So, sweet potato I'm using as a comparator of that carb dose.
That was in a case series of five patients.
Average drop was over 200.
We had a recent interventional trial, also again, drops.
But people aren't talking about these.
And that's a shame, not only because I think the science is important, but because there are so many thousands of patients going to their doctors with this response.
And if the doctor's first thought is, this must be a genetic disorder, you definitely need medications for this, then somebody could end up being signed on to statin therapy or rapatha or some other medication for life rather than trying an intervention that actually might be more potent with less side effects, eating a sweet potato.
Now, if you need it for therapeutic reasons, a ketogenic diet, we have a different discussion.
But bottom line is, this is important and needs to be talked about, but it's not being talked about.
Can you stay in ketosis if you eat a sweet potato every day?
Or 100 grams of carbs from anything every day?
The idea, not without exogenous ketones.
Okay.
So, we can talk about patients who need it therapeutically, but just the idea that you could reverse this phenotype with carbohydrates, which is consistent with our explanatory model, I think is important.
So, I want to get the word out about the model and the phenotype.
That's because I think people should know.
I also think that we need more resources to do the rigorous research.
And I'm not a professor emeritus with millions of dollars in funding, but I can be creative and I can, you know, stimulate grassroots enthusiasm for this and create pressure and interest that hopefully can drive the research forward and get us more resources.
So I engineered something that I thought would get some headlines, which was Oreo versus Staten.
The idea here is if this is a phenomenon, That is an adaptive response to carbohydrate restriction.
Promoting The Lipid Energy Model00:15:39
So, basically, what happens is when your carb stores in your liver go down, it kicks off this fuel trafficking cycle that causes your LDL to go up.
We'll get into the nitty gritty in a minute.
Steve, you have a whole PowerPoint with some of the graphics that really illustrate this well.
Yeah.
So, basically, when you're eating carbs, your liver stores glycogen, right?
Yeah.
So, glycogen is the stored form of carbs in your liver.
It's used to, you know, it's.
When your blood glucose starts to go down, you'll release some glucose and it keeps it at a steady level.
Now, you can obviously create more glucose from things like proteins, and so it's called gluconeogenesis.
But bottom line is the cycle here kicks off.
And I just want to first give a hat tip to my friend Dave Feldman, who came up with a model initially.
It's called the Lipid Energy Model.
This is a figure one from our paper we published on it a few years ago.
But the idea is your carb stores in your liver go down.
And when you're lean and metabolically healthy, you're really good at burning fat.
So what happens is Fatty acids get released from your fat cells, which you can see here is the little jaggedy lines, and they circulate around to fuel your tissues.
But some of them get picked back up by the liver.
And then to continue the trafficking process, they get repackaged into a storage form of fat.
The storage form of fat is called triglyceride.
So you take three little fatty acids and you stick them on a backbone called glycerol, and you end up with this molecule that kind of looks like an M.
And then to ship them out, because fat doesn't like sitting in water, if you pour like oil and water, you know they don't like to mix.
You need to carry your boat.
Let's call it.
And that's called VLDL.
So that's the big sphere there that's in orange and green.
And the liver ships out these VLDL, very low density lipoprotein that's carrying the fat.
And then the VLDL are going to go to your fat cells, the little yellow cells there, and your muscle cells, where they're going to drop off their cargo.
They're going to drop off the fat.
So it's going to replenish your fat cells and it's going to fuel your muscles.
So what's happening there is a protein called lipoprotein lipase is kind of sucking the fat out so that they can go back into the fat cells and the muscle.
In this turnover process where the VLDL is being turned over, the fat's being sucked out, the fat goes down.
So, fat and your blood's called triglycerides.
And I'm highlighting these because these are the terms that are going to define the triad.
You'll see how it does it.
So, you know, there's the VLDL being shipped out, it's being turned over.
The triglycerides are being sucked out, going back to the fat and going to the muscle.
So, your triglycerides are going down.
Right.
And then what happens when you take this big VLDL sphere, this boat, and you suck out the core, the triglycerides, the triglyceride goes down, then the sphere shrinks.
So, when a VLDL shrinks, it becomes an LDL.
That's what an LDL particle is.
So, then, you know, because your VLDL is being shipped out so fast and turned over so fast, your triglycerides go down.
And your LDL goes up.
And then the last part of the puzzle is what happens with the HDL?
Well, you can imagine if you shrink a sphere, you have to shrink the rim, you have to shrink the surface.
And so surface components come off of the VLDL as it's shrinking and get picked up by HDL, and that causes the HDL cholesterol to go up.
So you can see through this cycle that your triglycerides will be low because they're being pulled out of the VLDL quickly.
Your LDL is high because you're producing a lot of VLDL that's getting turned over really quickly.
And then as it's turned over, it generates LDL.
And HDL as well from the surface component.
So then you end up with this triad, three markers, which you can see on a basic lipid panel very high LDL, very high HDL, and very low triglycerides.
And that is what defines a lean mass hyper responder.
And if you increase trafficking through this cycle by being very, very low carb and lean, then what should happen is this triad gets accentuated, particularly the LDL goes up because you have to traffic more fat around.
So that's the gist of it.
And the cool thing about this model, no model explains everything, but models should be useful.
So this makes predictions.
We can go through some of the predictions, but one prediction, oh, and if you go forward or go backward one slide, actually.
Yeah, so this is the triad that I was explaining.
This is what results.
When you get a basic panel, you see the high HDL, the high LDL, and the low triglycerides.
So this is the definition of lean mass hyper responder.
Right.
Actually, the lean mass hyper responder doesn't even have a BMI criteria.
This is the only definition.
The lean mass comes from the idea that this tends to occur in lean people.
Got it.
So, question What happens after the triglycerides are sucked out of the VLDL and then it shoots out regular LDL?
What happens with that regular LDL?
Eventually, it'll get taken up by the liver or potentially other tissues, which is a whole other topic.
But let's say it's taken up by the liver.
But VLDL has a much shorter timeframe where it's sitting in the bloodstream than LDL.
So, you end up with LDL sitting in the blood for something like three ish days.
And then it gets taken up by the liver eventually.
So, that's actually a really, really important distinction.
Because if you have a functional lipid metabolism and your LDL is being trafficked really quickly but also taken up, then you have a lot of flux through this system, which is different than a condition like familial hypercholesterolemia, which is this I kind of alluded to it earlier this terrible genetic condition where you have a broken receptor because then the LDL isn't being taken up.
And those are two hugely different things.
By the liver.
By the liver.
Got it.
So those are two hugely different things because it's kind of like, you know, water, you know, say there's rain and then there's water.
Flowing down a river and then the levels come up a little bit because it's just rained, versus you dam a liver at the other end, I mean, not a liver, a river, a river at the other end, and then the water levels rise.
The water levels can rise for two very different reasons.
And understanding those reasons is, you know, they have different consequences.
So, with a lean mass hyper responder, the LDL has a place to go.
Yes.
And is there a distinction between plaque buildup and cardiovascular disease?
Like, why, even if there's more LDL, even though it's getting taken up by the liver, it's still circulating through your arteries and your bloodstream, right?
So, why wouldn't that cause cardiovascular disease in a lean mass hyper responder?
Let's go to the Oreo versus statin thing.
Okay.
And then we'll talk about the risk later because when we're talking about mechanism and risk, I do like to separate them just so that they don't get conflated.
Like when we're talking about, there's a scientific angle to take on this where I'm like, I just want to understand the mechanism.
And then there's the, we have a patient, what do we do about it?
What is the risk?
And actually, to properly assess that, we need to look in trials for risk, for plaque accumulation, which we're doing.
But that's why I want to table that because that's a whole other study and a whole other discussion.
Okay.
We will have.
I'm looking forward to it.
But bottom line, lipid energy model, it's useful because it makes predictions.
And one prediction is if you add back carbs, what'll happen?
The driving force goes away, right?
So, should any carb work?
I mean, according to our model, the model doesn't distinguish, it doesn't say, oh, you need a healthy carb.
So, should I be able to do this with Skittles or French fries or Oreo cookies?
In theory, it should work.
In theory, in a lean mass hyper responder, according to the lipid energy model, if the driving force is.
Completion of carb stores in the liver, all I should have to do is add back carbs.
And again, like I said, we've seen this in other settings, and it should lower my cholesterol.
So I decided I was going to test that, but I didn't think that was enough.
I wanted to test it with a comparator, and I wanted that comparator to be standard of care therapy, in particular statins, which most people over 40 listening to this probably will know what a statin is.
If you don't, Google it.
But it's a common medication for lowering cholesterol.
So I thought I'd use a high dose statin at that, 20 MIGs for Suvastatin specifically.
And I did all the appropriate things.
I went to the IRB.
They gave me exemption because it was an N equals one study.
A PCP was ordering labs.
So she was getting all my labs.
They were going straight into my electronic medical record.
And I got a lipidologist to consult, an expert, Professor William Cromwell, who was consulting on study design and ended up being senior author on the paper.
He's been brilliant, really open minded, and really a great mentor in this process.
Is he at Harvard?
He is not at Harvard.
Okay.
He's in North Carolina, if I'm correct.
And, um, Anyway, so I came up with a study design, which was I was going to have a run period with my normal diet for two weeks and have blood labs and then do Oreos for about two weeks at 12 cookies per day, 12 cookies chosen because it's 100 grams of carbs.
And then I was going to do a washout period, meaning I go back to like a keto diet, let my cholesterol levels, excuse me, return to their higher, you know, normal status, normal for me, and return to my normal body composition because this was an addition.
I didn't want to swap out because I don't want to be like, oh, but you reduced fat because you added Oreos.
Like, no.
I added Oreos.
I didn't swap anything out.
I didn't reduce my saturated fat intake.
Actually, it went up because I'm eating Oreos and they have saturated fat.
You maintained your ketogenic diet that you normally follow.
Yes.
In fact, if you go to in the paper, table one, it goes through the macro breakdown.
And what you'll see in table one is that my Oreo diet was basically just the macro equivalent.
Yeah, sorry, I didn't put it in the slide deck.
It would actually be in the actual paper.
But what you'll see if you actually go to the paper, which I encourage people to do, is that.
For the statin arm and then the run in, I had the same diet.
And the only difference in the Oreo arm is the difference that would be the macros of Oreos.
They just get added on.
It's a pure summation.
So I added 12 Oreo cookies to my diet for initially, I was going to do it for two weeks, then a washout, and then receive a statin for six weeks.
People ask why different phases.
I mean, sorry, why different durations for the two phases.
For statin therapy, just given the kinetics of the drug, I was advised by multiple cardiologists and a professor.
Cromwell, that a fair trial of this medication to give it its fair due, fair trial, would be six weeks.
So that's why the statin phase was six weeks.
The Oreo phase was two weeks because I thought it would be enough time, quite honestly.
And also eating a whole sleeve of Oreo cookies in addition to my diet when I have a background of gut issues was I wasn't going to be able to pull it off for six weeks.
Yeah.
Anyway.
Why did you choose Oreos, by the way?
Why not something else?
Can you think of one food that has better branding and just acknowledgement that it is a delicious, hedonic, unhealthy, Can you think of a better brand?
No, probably not.
Yeah.
Maybe Krispy Kreme.
I don't think so.
I think more people know Oreos than Krispy Kreme.
Yeah, you're probably right.
Yeah.
So that was it.
That was the reason.
That was like, again, sweet potatoes aren't going to catch the headline.
What is the thing that is the most provocative that if I said this thing, this food, lowish cholesterol, what would that thing be?
What shitty food has the best SEO?
Yeah.
And it's Oreo cookies.
It's probably Oreos.
You're right.
I couldn't think of something better than an Oreo cookie.
Um, And so we went with Oreo cookies, or I went with Oreo cookies.
Did all of your underlying issues that you had previously flare back up?
No.
There was actually one additional element to the methods that I have not mentioned, which I will mention now, which is I actually did use exogenous ketones during the Oreo phase.
And I'll tell you why.
There were two reasons.
One was it, I think, is therapeutic for me, ketosis.
It did irritate my IBS, which is different than IBD.
Inflammatory bowel disease and irritable bowel syndrome are two different things.
So I had GI upset.
But I didn't go into a flare.
And I have reason to believe that ketosis is actually protective for me.
So exogenous ketones might provide a buffer.
But actually, the main methodological reason I wanted to do exogenous ketones is because while it seems like, in addition to the intervention, like you're changing multiple variables, you're actually not.
You're controlling for ketosis as a variable.
Some have speculated without evidence, actually contrary to evidence, but including lipidologists on Twitter, prominent lipidologists.
We can name them if we want.
Sure.
Thomas Day Spring.
I might get in trouble for saying that, but nevertheless.
Why?
Is he a big shot?
He thinks he's a big shot.
Oh, okay.
I'm going to give him.
I've never heard of him.
I'm going to get into even more trouble for saying that.
But anyway.
Stir it up.
Yeah.
So that aside, he has said, and the only reason I feel comfortable saying this is because he said, like, ketosis downregulates LDL receptors and things.
And then I was like, this isn't evidence based.
And then you ask for evidence, and he's not willing to actually put up any evidence.
The guy that actually called him out, For what it's worth, was a vegan, Plant Chompers, on his channel, who's like, Look, actually, the evidence contradicts you.
We have mouse data showing that ketones actually upregulate LDL receptors in the liver.
And in a human randomized control trial, there was no decrease in LDL receptors despite high saturated fat intake.
So, again, making claims that are beyond the boundaries of knowledge and then not being willing to fess up when you made a claim that was wrong.
Also, if it sounds like I have a bone to pick, it's not just about the data.
He's been a little bit of a bully and unwilling to.
Well, there's been name calling, let's say.
Not on Twitter.
Oh, yeah.
No, I mean, some nasty things have been said from him to other people that are just like, I mean, it's quite unbecoming.
Well, you're going to upset some of the gatekeepers.
There's people that have established big followings and then have made some claims.
I mean, it's got to be so hard in the medical field.
Being a medical or healthcare influencer, when somebody comes up with new data that contradicts shit that you've said that people have actually taken seriously, even though there's all the disclaimers, this is not medical advice, people still watch that and they practice it.
They take that advice seriously.
And then when someone comes up and finds evidence that contradicts it, that's gotta with you.
It shouldn't though.
Why?
Because they're humans.
They're human beings.
But why are you attached to the results so much?
It's like, My dad told me, my dad's a scientist.
He's a clinician as well.
But he's like, you know, when you're doing science, you know, it's really cool when the data confirms what you thought would happen.
But what's even cooler is when the opposite things happen because that's when you learn.
That's when you're like, oh, crap.
Like, what is going on here?
We should get excited about it.
I think, you know, ego and defensiveness in science is really like, well, there shouldn't be shame about your hypothesis being wrong.
What we should do is put your ideas out there.
Be bold about them, be direct about them, and then evolve your opinions as more data arise.
And I try to be open about this.
That's why, like with this Oreo thing, I announced it publicly before I did it on a vegan's platform.
I'm like, I'm going to do this.
And here's the protocol I'm going to do, but have not done yet.
And we'll see what the results are together.
That aside, we got on this track because we were talking about why I was taking exogenous ketones.
Yeah, you were taking exogenous ketones too.
Yeah, because, well, it keeps ketones constant, right?
If I dose exogenous ketones to keep my ketones at the same level, Then nobody can say, oh, it's because you went out of ketosis that your cholesterol went down.
Because if Tom Dayspring were right, and he's not, but if he were right, then the cause of my LDL dropping was that the ketones were no longer down regulating the LDL receptor.
Ah, okay.
Testing Exogenous Ketones Publicly00:08:21
So this was methodologically actually cleaner because I stayed in ketosis the whole time.
Now, how do you take exogenous ketones?
How often, like during a day?
Can you walk me through what it's like when you take them and how much you take?
So I was taking a free beta hydroxybutyrate supplement and I was dosing it.
Actually, four times daily with blood ketone measures to keep it in the same range that I normally had endogenous ketosis.
So it wasn't just like I took five grams.
It was like I'm actually targeting blood levels.
Do you do the blood prick thing or do you use the blower?
You use the blood prick thing?
The blood prick, yeah.
Okay.
So anyway, so that was the methodological addition.
And we can get back into.
And what sort of ketone range did you aim for?
1.2 to 2.2 millimole.
Okay.
So anyway, that was the design.
I had a washout, then I tried the statin.
And you can see the results here on the slide.
It was in 16 days, the Oreo cookies lowered my cholesterol by 71% from 300.
That is astonishing.
Oh, it's bananas.
Like, it's.
So, if you want to know, so you see the three dots over near the right end of the Oreo graph.
Yeah, you got three tests back to back.
Right.
Because originally it was going to be two weeks.
But then on the two week mark, the drop was so low that we're like, wait.
Is this really like I'm pretty sure it was real, but it was like we just need to repeat it, we need to confirm it.
So, let me get a test tomorrow.
Yeah, this must be tomorrow.
And the next day, it was even lower.
And the next day, it was even lower.
So, it was actually downtrending still at the end.
It might have gone lower if I continued, but at that point, we had confirmed the effect.
So, in 16 days, 12 Oreo cookies per day lowered my cholesterol 71% from 384 to 111.
And that's the LDL.
That's crazy.
No drug does that.
Not even so, like Rapatha, PCSK9 inhibitor, which is right, right.
That's what Peter Artia talks about.
That can reach steady state in, you know, like five days.
And that maybe has a 50% effect.
This is stronger than any drug I know.
Oh my God.
It was cookies.
It was so it's like you see this headline, and everybody's like, This must be a joke.
It's clickbait, but it's legit bait.
I this happened, and even if you just say it's one patient case, yeah, but it's a patient case that was predicted by our model, and that's consistent with all the other literature we have on this topic.
So take that as you will.
Now, let's compare it to statin therapy.
Statin therapy at a I wanted to make it look as strong as it could, so I chose the lowest point, which actually wasn't the endpoint.
I'll tell you why in a minute, but it dropped to 284.
So, the reduction for the statin was 32.5%.
So, you started when you started the statin therapy, your LDL was at 421.
And the lowest point it got was 284.
It was 284.
So, the relative effect was half as much as the Oreo cookies and about three times as long, six weeks.
Why do you think it went back up towards the end, the last two weeks?
So, if you actually look very carefully, what you'll see is that weeks three, four, and five, it's very stable.
It's in the 280s and 290s, it's within like three or 4% of each other.
So, consider that stable.
So, say it took me three weeks to get kind of to a steady state.
And my initial plan was to go all six weeks and keep everything as consistent as I could.
But when you have stable levels for three weeks, it actually presents okay, I'm at steady state.
We kind of have the result.
Let's test one more, do a subtest of the lipid energy model, which was all right, one prediction is adding back carbs should lower LDL.
We've demonstrated that, and we've demonstrated that Oreo cookies are more effective than statin therapy in this crossover.
Another prediction of the lipid energy model is if this is an energy trafficking system, if you're keto, which I was on the statin phase, what should happen if you need more energy?
If my LDL is going up because it's trying to traffic fat fuel, and then I need to traffic more fat fuel, should my LDL go up or down?
Up.
Right?
It should go up.
How do you increase energy?
I just exercise.
So, what I decided to do is I'm just going to add 10,000 walking steps per day.
So let's see what happens to my cholesterol if I just walk a little bit more.
And in a week, my LDL jumped by about 50.
Wow.
That was the blip at the end.
So that is pretty cool.
That's a little like, again, that's an Easter egg in there where an observing person looks and they're like, wait, why is it going up later?
And I'm like, because I walked more.
No way.
So, again, a prediction of a model that you can test.
And just, you know, on the axes, it looks like a small increase.
That's just because the Oreo effect is so gargantuan.
But if you see a 50, if you went to your doctor and in one week your LDL went up 50, they'd flip the.
They just flip.
By just walking.
Yeah, because I needed more energy.
So there was more energy flux.
I mean, that's the explanation.
That was the basis of the prediction.
And then we executed on it.
And other people have done this, it isn't just me.
Other people have done similar things.
It's just other people haven't published on it because people are doing this in this kind of citizen scientist ecosystem.
Right.
So there's actually now a sub experiment there testing another postulate of lipid energy model.
So the punchline here is.
Yeah, I could lower my LDL with 12 Oreo cookies per day by twice as much as I could with a statin over a longer period of time.
Which, you know, that's something that everybody just, I hope everybody can stop and think about how bizarre this is.
And I'll be very clear in case it's not obvious.
I'm not recommending Oreos as a health food.
I would hope the average American adult or average adult in the globe, you know, has the common knowledge to figure out that's not the case.
And I've made this joke before, so I'll lean into it.
You know, if somebody's actually tricked into believing by this that Oreos are a health food, then you can thank me for helping out natural selection.
But that aside, I don't know if that joke would get me in trouble.
I think it's kind of fair game.
It's tame.
Anyway, people want to put a value judgment on this.
What's up, guys?
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Back to the show.
They want to say, Nick, now you're saying statins are bad or LDL is fine.
Provoking Curiosity And Response00:10:54
I'm not saying any of these things.
Where do I say this?
I'm actually very cautious with my language.
What I'm doing here is I'm presenting an implicit, uncomfortable tension between two observations.
You had a bad intervention, Oreo cookies, that had a good effect, lowering LDL.
So, how do we reconcile these two things?
I'm not here to tell you what the answer is.
I'm here to put that question forward to science.
To everybody, really, and say, here's the uncomfortable question that we have to grapple with here.
Now, give us resources to pursue it and collaborate with us in pursuing it.
It's that uncomfortable question.
And I think people are, you know, not, well, obviously they're uncomfortable sitting with this uncomfortable question, but I think that's very cool.
I think it's, again, it's meant to be provocative, it's meant to make you look and have a little bit of a gut emotional response because honestly, that's what's going to capture attention.
Provoke future research that we need.
This isn't going to change any policies, nor should it.
I'm not trying to make any claim other than this is curious.
We need to study it more.
And I find this so fascinating.
When did you publish this online?
Monday.
On Monday.
On Monday.
So, what sort of response have you gotten?
Oh, psh.
The last four days, I mean, day two, I woke up and there were 2,000 emails in my inbox.
Cool emails too.
Like one email was from a physician who was a lean mass hyper responder.
She's like, I want to replicate it.
Can we write a protocol for me?
And this is a doctor saying, I want to do this on myself because I'm a lean mass hyper responder.
For the record, there are a lot of lean mass hyper responder doctors.
I've met at least a dozen.
Like these people, it's like atheists and the clergy.
You walk through the hospital and it's like, hey, Nick, so I'm a lean mass hyper responder.
So, yeah, anyway, that aside.
And then on Twitter, there was a strong response.
YouTube, there was a strong response.
I'm not big on YouTube.
I mean, thank you for listening to my channel, but like I literally.
Your YouTube's amazing, man.
You do a great job.
Historically, I've just pulled out my iPhone and just kind of broken down a.
A paper or two.
I'm trying to level it up with some.
Like, I've now, I'm outsourcing editing via Fiverr, which is going to be a game changer.
So I'll drop some videos.
But the video abstract just jumps to a quarter million views, which for someone that with like, you know, a month ago I had 7,000 subs, a quarter million views is a relatively big response.
And then there's like paper tracking metrics.
So you can actually get a holistic score for your paper attention.
It's called an altmetric score.
And get this within a day.
Of publication, 24 hours, literally 24 hours, our paper had jumped into about the top 0.05% for all time.
For comparison, so Nature is like a prestigious journal.
They talk about the big three cell, science, nature.
Nature, the average score is 102.
The highest impact factor journal in the world, I think, is the New England Journal of Medicine.
Its average altmetrics are 128.
These are lifetime scores.
In one day, our paper had hit over 1,100.
And, you know, this isn't like by any means like a world record.
I mean, I think now we're in the top 10,000 for 25 million of all time.
But, point being, like for what it was, which is kind of a dinky little case study experiment, the response has been dramatic and this has only been a couple days.
So it's been fun.
I have had a lot of very interesting discussions.
What I will say is that sometimes it's fun to highlight the trolls just because it actually acts as a little bit of a trampoline for engagement.
And if your goal is engagement, it can be beneficial.
But, 99.9% of the responses have been incredibly curious and respectful.
And just as I wanted it, wow, this is cool.
I want to learn more.
For anybody that actually does some digging, somebody might say something like, oh, you're just trying to create a excuse to create, you know, eat Oreo cookies.
To which I say, if that were the case, you kind of have to give me props for commitment there.
But it wasn't the case.
That aside, no, especially in academia, I think I've heard from so many doctors who are like, either I wasn't aware of this before and now I'm aware of this and actually it's going to help me treat my patients.
I've gotten that response.
Or, this is so cool.
Like, how do we learn more about this and how can I help out in the process?
Including from people like, look, this isn't a carnivore versus vegan, low carb versus low fat kind of thing.
This is just science, this is curiosity.
So, I've had great discussions with plant based scientists who are interested in this.
And they've been really open to having these discussions.
So, this is provocative, but I don't think it needs to be the kind of provocative thing where we're sniping at each other.
It's the kind of provocative thing where it's just, this is something curious.
Let's come together and figure out what the heck the answer is.
We have some ideas, but we need to rigorously test them.
So it's been a fun few days.
It's definitely.
What sort of negative feedback have you gotten?
Have you gotten any negative pushback online or anywhere?
Nothing really significant.
I mean, having been somewhat public for a little bit of time and having certain brands on my back, like just being Harvard branded, for better or for worse, people like to hate on you.
So they come up with caricatures and they say stupid, stupid things, but nothing really serious.
Some will say, like, oh, this just shows.
And when I quote people, I'll try to quote for people that have some degree of relevancy.
The chief medical officer at Weight Watchers commented.
His name's Spencer Nadalski.
He's a little bit of a douchebag.
You said it.
Sorry, Spencer.
I don't know who Spencer is.
That was just a joke.
Effectively.
So, I mean, something like, this just shows Nick's diet was so bad before that Oreo cookies improved it, which too I'm like, all right, dude.
Like, is that your lipidologist insight?
All right, fine.
Leave it like that.
Again, I think I used to get more touched by.
Negative comments on social media.
But the thing is, if you're putting out scientific work, even if it has a funny title or a headline, if you're putting out scientific work and somebody attacks it in a very, very weak fashion and tries to troll you, then they're not providing the speed bump they think they're providing.
They're providing you a little trampoline off of which to contrast yourself and your response and push forward.
So the trolls that are going to put forward their signal.
Yeah, exactly.
Keep it coming, please.
And if you actually have constructive criticism, I want to hear that too.
So I found that, you know, they say like, You know, all attention is good attention.
I never used to believe that.
Now I believe all attention can be functional if you see it in the right light.
So, again, I stand by the data we have.
And it's not that I stand by this n equals one as a solo n equals one.
I'm standing by this framed by meta analysis of RCTs, eight other publications we have.
There's a waterfall coming out.
It's just that it's not being talked about.
And so I needed something to kind of poke people, say, hey, check this out.
And so that was.
Oreo versus statin, which, you know, it was an experiment.
I have to say, it was a two part experiment for me.
One was actually testing the lipid energy model.
Another one was a sociological one, which is I'm playing with fire here a little bit, obviously.
Social media fire, media fire.
And, you know, that fire could get out of control and get away from me.
I have a goal.
I don't know if I'm going to be able to achieve that goal of mobilizing people, starting this like grassroots enthusiasm for this topic that I'm really passionate about.
So, I'll see how it goes.
I'll see how effectively I can control the narrative, incite excitement for science and this topic.
Like Andrew Huberman always says, you know, thank you for your interest in science.
Like, that's what I want to be the punchline here.
Not Oreo cookies are healthy and I don't want to stir confusion, certainly.
So, I try to be pretty clear in my messaging.
I don't know if I'm going to be able to hold on to the narrative.
But again, as someone who is looking forward at his career, trying to figure out what he wants to do, these are useful data for me in figuring out, like, you know, how can I use the resources available to me in 2024?
To promote a dialogue in a productive fashion.
This isn't something that anybody else I can think of has been in the particular position to do, right?
I'm a weird guy.
We're living in a time of social media.
I happen to be someone who has a pretty potent patient history, so I get that point of view.
I'm trained as a PhD scientist, I'm active on social media, and I'm training in medicine.
I wear a lot of hats.
And so I find myself at like the center of like a four way Venn diagram, and I'm kind of just, you know, exploring from there what things I can do, how I can educate, teach, have a positive impact.
I'm not always going to, you know, let's say, point the ship in the right direction, but this was, again, at some levels, a sociologic experiment, which is going on now.
It's been literally four days.
So we'll see how it rolls out.
We'll see, you know, I would love, like, You know, Harvard to cover it.
I'd love major news networks to cover it.
I'd love to have chats with people with big platforms like Peter Attia or Huberman or Rogan if those opportunities arose.
I, you know, not to be presumptuous, but this is at least a topic that I think that all of those people named and, you know, people like Derek and a lot of other people would really be interested in having this conversation because it's cool.
It's good science and it's provocative, but it definitely doesn't need to be polarizing.
So I want to talk with as many people as possible about it.
So if you are somebody who follows a ketogenic diet, mainly not, you know, Say it's not for a medical reason or not to control some sort of disease or metabolic issue, and your cholesterol is through the roof.
I guess the main question is: is it a two-fold question?
Is super high cholesterol above 200, maybe above 300, is that bad?
Or is this something that if you don't have to rely on a ketogenic diet, Maybe something you should think about when it comes to adding back carbs.
Yeah.
I would say this point in time, given the data, the latter is a more logical thing to do.
So let's, you know, if it were me and I didn't eat a ketogenic diet therapeutically, right?
Lean Mass Hyperresponders Defined00:14:50
Would I eat a sweet potato to lower my LDL from the 400s to 100?
Yeah, man, I like sweet potatoes.
They're delicious and they wouldn't have any real negative impact on me.
So, in a Status where we have lots of unknowns, and the data that we do have, albeit on other populations, not lean mass hyper responders, and again, we it's really important to talk about those distinctions.
But the data we do have say high cholesterol like that is dangerous.
So, if you don't have a compelling reason to be keto, at least cycle in carbs, like what's the downside?
Really, I can't think of any downside, even if you're using it for well, here's the thing the people that would be playing with that probably won't be using it for weight control, or they've already been very successful and can maybe add back a lot of low glycemic carbs.
Because if you're using keto for You know, obesity treatment, then you're not going to have this response in the first place.
Is a sweet potato the best kind of carb?
Oh, I'm just using that as an example.
Let's go to what's your favorite carb?
My favorite carb?
Fuck, man.
What's your favorite, I quote, healthy carb?
I mean, I love bananas.
I love fruit.
Bananas would work.
Really?
Have a banana smoothie.
I've literally seen people do bananas, mangoes.
I don't give medical advice, right?
But like, I've had a lot of lean mass hyper responders come to me and in this situation where they don't need it.
And I'm like, you know, I can't tell you what to do, but.
If I were you, I might play around with carbs.
A lot of people who follow carnivore diets, they like to add fruit before workouts.
Yeah, if it works.
They said it gives them more energy or gives them more power when they're trying to get through a hard workout.
I think a lot of these things are empiric.
You just have to toy around with what works for you.
And I'm definitely not anti fruit, I'm not really anti any whole foods.
So if you're carnivoresque and you want to have some banana or mango before a workout, dude, do it.
But for those people, Who are using ketogenic diets therapeutically and have this response, things get a little bit trickier.
There are a lot of options.
One is to try to walk the middle road with carbohydrate reintroduction.
And there are tricky things you can do to kind of create a ketone buffer.
You could take exogenous ketones.
You can switch to a higher polyunsaturated fat diet.
So, polyunsaturated fats will increase your ketones more than saturated fats, all things being ketone.
Can you explain what a polyunsaturated fat is?
Fats are defined, fatty acids, by the number of double bonds.
So, how many, which Creates bends in the tail.
Saturated fat has no double bonds.
Mono, one double bond.
Poly, many double bonds.
Okay.
So, examples of high polysaturated fat rich foods would be walnuts, pecans.
My favorite is tahini or sesame oil.
So, if we're talking numbers for those listening Seed oil?
Sesame.
Sesame.
Okay.
Which is in the seed oil class.
The whole thing with the seed oil look, I wouldn't encourage drinking corn oil, but just because it has high alinoleic acid content does not make it a bad food.
I think it's a little bit overblown.
And in particular, here's something interesting.
When you're low carb and you're burning fat, these fats get burned very, very quickly as fuel.
So you actually might burn them off very quickly, and they will result in pretty high ketone levels.
So I can, with sesame oil, if I take about three tablespoons at night, get my ketones within 20 to 22 hours at 6 millimole.
Oh, wow.
Again, you can.
And I bring this up because it's highlighting the fact that we can be innovative with protocols.
Level of ketones and therapeutic, let's say, is two, then I have a big buffer to play with, more of a buffer than if I had a different fatty acid profile.
So then I can add back more carbs and we can see maybe what happens to my LDL.
Plus, the polyunsaturated fats themselves might lower the LDL a little bit.
Bottom line is there are a lot of things you can play with with respect to diet.
Another option for these patients that are using ketogenic diets therapeutically and have the lean mass hyper responder response will be medications.
That's an option.
But above all, this is really trying to answer the question what is the risk profile?
Of these individuals, which is the question you asked before.
Right.
Now, what your standard cardiologist would probably tell you, and I will, of course, caveat I am a medical student.
This is not medical advice.
And a cardiologist probably, some of them have more years of training in cardiology and lipidology and clinical experience that I have being alive on this earth.
So take what I say with humility and a salt shaker.
That said, I would say that your average cardiologist would probably say, The preponderance of evidence, it's often a term that's used.
So, the body of evidence would say that high cholesterol is really dangerous, really high cholesterol is dangerous, and you should lower it.
And that's not an incorrect statement.
The body of evidence does suggest that.
The problem is that a preponderance of evidence in a population that's distinct from the population you're studying, can you extrapolate from.
If I collected all these data on population, let's make it male and female just to make it easier.
If I wanted to conclude something about, you know, Female hormones.
So I did a study including, you know, 99 males and one female, and they included something about females.
Like, that doesn't make any sense, right?
So the evidence base we have is on people who, you know, aren't low carb and lean.
This isn't a population that's been sought out before.
And this response is incredibly unique.
So I want to highlight a really important contrast, and then I'm going to get some water because my throat's going to die.
Yeah, crack that liquid death open.
Don't be scared.
It's just water.
Yeah.
Anyway.
Murder your thirst.
Good.
All right.
So, the analogy that's often drawn with these lean mass hyperresponders with really high LDL is something called familial hypercholesterolemia.
I mentioned it before.
This is a rare genetic condition, well, rare in its homozygous form.
So, that's the more severe form.
A homozygous form, I think it's something like one in a million, but where there are incredibly high cholesterol levels, LDL in particular, and really early heart disease.
As in Brown and Goldstein, who Yeah.
They were finding heart disease in kids as young as like eight years old.
Yeah.
So, little girl, it's literally heartbreaking.
Like, kids that are eight years old having heart attacks because they have these high cholesterol levels.
And what was concluded out of that, and I'm not saying just out of that, there's a large body of literature supporting the idea that LDL particles, ApoB containing particles, are causal in cardiovascular disease.
That's not untrue.
But in that circumstance, what you have is a genetic disorder where you have a broken lipid metabolism and it's broken from birth.
It's not like manipulated easily by diet.
Restricting carbs, adding carbs isn't going to do anything.
This is, again, that scenario where the LDL receptor is broken.
So, you have inappropriate flux.
You can't take up the LDL particles, they build up in the blood.
Now, I want you to contrast that to what we have with lean mass hyperresponders, which doesn't have any clear genetic link.
It's not congenital, which means you don't have it from birth.
It's induced by carbohydrate restriction.
So, you reduce the carbs, you have the phenotype.
You have bad carbs, the phenotype goes away.
It's part of a triad of markers, not just an individual marker, as part of this metabolic response.
And there are other phenomena like it is inversely associated with, you know, Body mass index, which is weird.
There's typically very, very low triglycerides and high HDL.
Point being, I want to create this compare and contrast.
You can imagine it like a t chart to say these things are different.
They both have high LDL, but they're clearly different mechanistically.
And so it's important to distinguish them mechanistically for a couple of reasons.
One is in terms of treatment options giving a kid with FH a sweet potato is not going to do anything, giving a lean mass hyper responder a sweet potato will.
So there's treatment option differences.
And then the question of risk arises.
And all I'm saying is, it's not appropriate to conclude fiercely that from a genetic disease, Mendelian randomization studies, or studies on populations that are metabolically unhealthy, that we would conclude that there's the same risk profile in someone with a similar LDL, but with a very different driver as part of this metabolic response.
It could be true.
It could be true that lean mass hyper responder is at massively elevated cardiovascular risk.
That's a possibility, but it doesn't necessarily follow.
So, you don't want to gamble with your health.
So, I would, again, as a LEMAS hyper responder without a medical comorbidity, just add some carbs, lower your LDL.
It's the safest thing to do.
But not everybody has that luxury.
So, what do you do going forward?
You want to collect more data to help refine and provide an evidence base for patients making decisions with their doctors.
So, one thing that's going on is a study out of.
The Lundquist Institute in UCLA, where they're doing just that.
They're looking at plaque and lean mass hyperresponders, not just calcium scores, but they're using something called coronary CT angiography, CCTA, which can see soft plaques too.
Oh, so that's way better than a regular calcium score.
Yeah, it definitely provides more detail.
And this study was to follow people with very, very high LDL who are of this phenotype for a year to see how much.
Plaque accumulates or doesn't.
So it's a prospective trial.
The prospective element of the trial, so the follow up will be completed in February and then the results need to get written up and published.
But what we did was a comparison at the baseline.
So when we got the first scans on these patients, these lean mass hyper responder patients, on average they'd already been keto for 4.7 years.
So you consider that 4.7 years of exposure to these high levels, right?
Average age was 55.
So they're not just young, you know.
Like me and you.
So, you know, one would expect maybe they do have some heart disease, especially with these crazy high levels for 4.7 years.
And what we can do is compare them to a control group.
Miami Heart was chosen as the control, matched as well as we could for various variables.
You can't match perfectly just because lean mass hyperresponders are so unique.
Like you can't match for HDL because HDL is just going to be so high in lean mass hyperresponders.
But bottom line, both groups had overall similar risk profiles except for the LDL.
So then we looked at the baseline scans and asked the question is there more total plaque?
Into lean mass hypersponders as compared to Miami Heart.
Now, again, the distinction is one group has a mean LDL of 272.
The other has a mean LDL of 123.
And the.
And the.
Sorry, the one who has the lower LDL, that's the control?
It's a match.
Yeah, it's a match.
Okay.
And so the hypothesis would be, or the common guess would be those with a really high cholesterol, same age, matched as well as we could for other risk factors, would have more plaque, right?
Especially if they've had this high cholesterol for 4.7 years.
The data off the early match, the papers, the data has been discussed at a conference presented by Professor Matthew Budolf on December 8th, 2023, and the paper is under review currently, but showed that there was no increase in plaque, no compared to Miami Heart.
So there was no higher plaque.
Now, you could say, oh, well, it wasn't powered enough to see a difference between the groups.
So then you can ask, oh, what was that?
Was it what?
Powered.
Like there wasn't, so there wasn't, there, Weren't enough people, let's just say, to see a statistically significant difference.
So the p value didn't drop low enough.
So then you can say, like, was there any trend?
Was one group looking maybe a little bit better than the other, even if it wasn't statistically significant?
And yeah, there actually was.
The lean mass hyper responders were trending to have lower plaque.
Again, it wasn't, you know, this isn't conclusive.
Data need to be validated.
But when we're talking about the preponderance of evidence, we're not talking about this lean mass hyper responder population, which is unique.
And this is the first glimpse of data that we do have at this specific population.
Now, these early data shouldn't change any particular clinical guidance, but at minimum, they're interesting and definitely they've been provocative.
So, yeah, with the request of the risk profile of lean mass hyper responders, you might be able to read between the lines and think what my long term guess would be.
But I would say right now that we don't know that it's inappropriate to conclude firmly that they are at high risk with these high levels just because we don't have those data.
But it is appropriate to treat conservatively in the meantime.
How long has your LDL been above 300?
Almost five years.
Almost five years.
And you got a CT angiogram.
What was your plaque?
Zero.
Zero plaque?
Yeah.
Now I'm young, so I wouldn't conclude that.
Still five years.
That's a long time.
Yeah.
I mean, there are people in the trial with LDLs of 591 who are older, and they have no plaque.
So, I mean, the average person in the lean mass hypersponder group had.
The median, I should say, the median person, the median plaque score was zero.
So, wow, dude, that's for what it's worth.
Again, I don't mean to make these data into gospel, they're just a glimpse at what's to come.
Point being, there are a lot of unknowns here, and I think it's always appropriate to delineate what is the boundary of the known and then ask questions further.
So, I do get ticked off when people try to reduce it and say, you know, we know the answer, Apple B is lower.
Lower is better, period.
End of story.
Like these simplifications, I get what you're trying to do.
You're trying to take a conservative stance, but people aren't that dumb.
They're going to call BS and then you're going to lose credibility.
So let's be honest about what we know and what we don't know, and then, you know, practice a nuanced and, you know, appropriately conservative and caveated communication style.
I try to do that as best I can because I think people are pretty smart and receptive to that.
But when you try to simplify it down and provide people with, you know, let's say, patronizing advice or directives, they don't respond well.
We can see this.
Cholesterol Regulation Debunked00:07:59
Now, what about ApoB?
How does ApoB factor into all this?
Because isn't ApoB one of the number one predictors of heart disease?
So, ApoB, apple lipoprotein B, is the, let's just say, the tag, the protein on LDL, the lineage of LDL particles.
So, ApoB100 specifically, if you went back to the lipid energy model diagram, you know there was an orange sphere with a little green squiggle on it.
That green squiggle was supposed to be the ApoB.
So, that lineage of particles is ApoB particles.
The VLDL turns into the LDL.
There are some others like LP delay, chylomicrons have ApoB48.
Point being, these are proteins on the LDL lineage of particles.
They're a better marker, but here's the thing if your LDL is 400, your ApoB is also through the roof.
In people with, let's say, moderate levels, there can be a discrepancy, and that discrepancy can be meaningful.
So let's say your LDL is 150.
An LDL of 150 with lower ApoB is probably better than an LDL of 150 with higher ApoB.
But when your LDL is 400 or 500, your APO B is through the roof.
It just is.
Like my APO B sometimes doesn't even measure on labs because it's too high to measure.
Really?
Yeah.
And what about LP little a?
One of the interesting things about my blood work is my APO B, or whatever you call it, APO Apo, and my LDL were super high, but my LP little a was very low.
LP little a is sort of like a variant of an LDL particle.
It has these things called Kringle repeats.
It's like a little, it's like a LDL with a tail.
Sort of.
And it is an emerging, let's say, interest risk factor.
It's an Apple B type particle.
It's as far as I'm not an expert in it, but as far as I understand, it's largely genetically determined.
So, like, mine is very high.
My dad's is very high.
I used to have low LDL and it's gone up on keto.
Like, my LPLA has been basically stable.
Okay.
It hasn't, like, gone up or down significantly with keto.
So, some people are just, let's say, cursed or blessed with higher or lower LPLA.
Okay.
Diet.
Genetic.
Yeah.
I mean, inflammation and diet can change it, but like, you can have a.
Genetic floor, as far as I'm aware.
I'm not really clear on what the risk profile is, again, in someone who is completely otherwise healthy with low inflammatory status.
I would not be surprised if there weren't a pretty strong interaction between other risk factors and general inflammation and LpA.
As in, there might be circumstances, this is me completely speculating, but where higher LpA isn't super dangerous.
But I don't know.
I've always been warned when it comes to the ketogenic diet, for example, when I first started doing it.
I have kids, so I have like shitty food all around my house, like chips and stuff.
I would go, I would be like very strict on my ketogenic diet for the entire day, and then I'd eat like a bag of chips or like animal cracker cookies before bed.
And everyone would always, you know, all the research and talks that I've seen smart people do, they all say like that is like one of the pitfalls of the ketogenic diet.
Like you really fuck yourself up if you combine, if you follow a ketogenic diet, but you just like eat some.
Treats at the end of the day, or eat a bag of chips, or have some ice cream.
Like, that could be like five times worse than just not following the ketogenic diet at all.
Yeah, I don't really ascribe to that.
It doesn't really make any sense to me.
I will say if you're like ketogenic, say, for a prolonged period of time and you reintroduce carbs, you'll be carbon tolerant for a period of time.
Like, if you do an oral glucose tolerance test, you will maybe even appear diabetic, but it's not because you're insulin resistant.
You're just secreting less insulin.
So, your body, it's not stupid.
So, it's going to, you know, adapt.
And if it doesn't need to burn carbs all the time, it's going to, you know, Adapt to be less efficient at using them.
Now, you can readapt, but it'll take time.
It'll take weeks to readapt properly.
The whole idea with what you're talking about, where you're low carb most of the day, but then eat carbs later in the day, I think the main downside there would mostly be behavioral.
As in, if you're carb restricted and you like carbs, then you might end up binging at the end of the day on carbs.
But I don't think, I mean, I know people who generally eat very low carb throughout the day, but then maybe they like to go out to dinner.
The dinner has a little risotto.
I don't think that's particularly dangerous.
I wouldn't call that ketogenic at that point because to be ketogenic, you need to deplete your glycogen stores so you go into ketosis.
So if you're eating carbs every night, you're probably not dipping into ketosis that much.
But I don't think it's dangerous.
What I would say is if you are keto, if you were to, say, eat a big bowl of ice cream as a one off, that one off would have a larger impact on, say, your blood sugar.
And probably oxidative stress as compared to someone on a mixed diet who had the same amount of ice cream as that one off event.
But that doesn't mean the cumulative, like, would it be worse to eat a ketogenic diet and then treat yourself on Thanksgiving and Christmas or eat a standard American diet all year?
I think the standard American diet all year.
That's way worse.
Oh, yeah.
Right.
I would be confident in that assertion, unless you have a really poorly formulated ketogenic diet.
What is the correlation or the difference between cholesterol, dietary cholesterol, and cholesterol in the blood?
Yeah.
Dietary cholesterol is found in a lot of animal foods, eggs, organs, red meat.
And then the cholesterol in your blood, you can synthesize all the cholesterol you need.
The dietary cholesterol, I mean, the simple way to put it is it really doesn't have much of an impact.
You eat more cholesterol, your liver will make less, and your other tissues will make less.
If you eat less cholesterol, Your body will just make more.
So there isn't much.
If you eat less cholesterol, your body will just make more?
Yeah.
It'll make what it needs.
I mean, there are some people that are hyperabsorbers of cholesterol, but for most people, dietary cholesterol will have very little impact on your cholesterol levels.
Your cholesterol also does circulate from your system.
Like your body can make cholesterol, circulate it into your gut, and then take it back up.
So a lot of it's called enteroopathic circulation.
Mm hmm.
A lot of the cholesterol you take up from your gut is actually cholesterol that you secrete and then recycle.
So, where do you plan?
What's your next step with this whole thing?
I know you're kind of getting it out there, getting the word out there, and getting more attention on it.
The way you're doing it is fantastic.
But do you have any sort of plan on doing any more studies or following up with anything?
Absolutely.
I mean, we have so many things we want to do, a literal wish list, and it's going to depend on resources.
That are available.
One thing I'd like to do, for example, is really prove how generalizable this is.
Take people who have never been keto before.
Like you literally go to a gym, pick out people who look like lean and athletic and try in a metabolic ward to turn them into lean mass hyper responders to see how many can convert.
Because we've not found any genetic links, but I don't know if there is, you know, say a genetic permissibility.
So, you know, could we get, if we had 10 really lean athletic people and we put them in a metabolic ward and controlled their diets, could I get 100% conversion?
Could we get 100% conversion, 90, 80, or would only 20% convert?
I do think it would be upwards of 50, but I don't know.
I'd also like to do things like a crossover trial in a larger group.
Comparing statins, which is one medication, to azetamide, which is another medication, to carb reintroduction, and see in a proper larger scale trial what's more effective.
Genetic Permissibility Questions00:11:34
We want to do tracer studies to assess the lipid energy model, more risk assessment studies.
There are so many things we want to do, more ideas than we have resources to pursue at this point in time.
So, my goal is to do what I can in the coming, say, year and a half while I'm finishing medical school.
And then probably really emerge out of my cocoon thereafter.
So, what you see now is the reserved me because I have the, I don't want to call it a distraction, but a lot of other things pulling on my time in life.
So, it's been, you know, really energizing to be engaged in this.
But at the same time, my focus is largely elsewhere.
So, where's your focus?
I mean, medical school.
Right.
Which is definitely, you know, it.
It's not an easy thing.
Yeah.
What is that like?
What's that schedule like being a Harvard medical student?
I mean, I just got my schedule for my next rotation, which starts Monday, and it's something like six to six, six days a week, except for the six to six nights, six days a week.
And then nights are 5 p.m. to 7 p.m.
Last year was worse because actually I just finished my USMLE step one and step two, but imagine, you know, doing bad hours clinically, but then you have to get back and study and do like 300 flashcards and a bunch of like problem sets.
And then rinse and repeat because you have exams on top of that.
So, and then, you know, you toss in research and you toss in, well, if you're stupid enough like me to toss in social media as well, then you have that.
And then imagine trying to like date and being just an adult 28 year old human being.
Right.
It becomes, you have to pick and choose at points in time.
So, yeah, it's, I'm not unique as a young person trying to figure out their life.
And so, yeah, it's, it keeps me, it keeps me busy.
For sure.
But it's been fun.
It's been fun.
And it really is a privilege to get to study where I'm studying, not just because of who I get to learn from, but who I get to learn with.
I honestly love my class so much and the people that I meet.
They're so amazing.
I think the community does really just inspire each other because everybody's just so energized and passionate about something.
I clearly have my passions, but I also love meeting someone new in my class and hearing about their passions because they're doing things that are like.
Equally, if not more, amazing in the world at this time.
So, I'm really up to it.
I know people are pessimistic about the medical system right now.
Having met my cohort of students, I'm really, really optimistic that, and I came in pessimistic, but I am optimistic that the medical system is going to change because I think we have a lot of young people who are very jazzed up with big ideas about how things absolutely need to change.
Is that something that's talked about at Harvard on campus in classes, like with some of the professors that you deal with, the medical system?
And how broken it is?
I, not in a formal way.
There probably are electives on.
I think there is one AISC on healthcare systems.
But I would say it's an open conversation.
Nobody is trying to defend the system as it is.
But the solutions are very complex.
So you can only kind of bite off one piece at a time.
I think people are very good at listening to each other when one person raises an issue.
So I'm clearly very passionate about metabolic health.
My peers have been very engaged with respect to that topic.
In fact, Probably one of the most touching moments in medical school was in my first year when one of my peers stood up after class.
Now, after class, usually just everybody wants to get out of there.
I certainly know that feeling.
But somebody said, you know, we were talking about metabolism.
They asked the professor if I could just stand up and talk to the class about metabolism.
I had no idea they were going to do this.
I wasn't prepared at all.
I babbled like what I felt like was an idiot, just about my interest in metabolic health.
Thereafter, that class, there were a bunch of us just standing out in the hallway talking about metabolic health, and we started doing cool things.
Like we got.
Continuous glucose monitors, and then did a group project, which we actually published on, where we all wore continuous glucose monitors, had like journal club meetings, and just engaged in the topic of metabolic health because it was something that I was passionate about.
And I shared it with my peers, and they were incredibly receptive.
And these aren't people who, you know, went keto because they had a medical condition.
It's just like they were interested in what I was interested in.
And I try to reciprocate that, being interested in what they're interested in.
And so there are a lot of problems, but I think that there are a lot of really smart young people with big ideas for solutions.
And we talked earlier about suppression of some stuff, and we were going to dig into that a little bit more.
What kind of specific suppression have you seen with whether it be your new study with the Oreos or other things that you're interested in?
Yeah.
So I won't speculate as to like algo, blah, blah, blah, internet suppression, but specific things would be like a prominent lipidologist, including Thomas Datespring, saying falsehoods like this isn't a real phenotype, it hasn't been published upon.
I'm like, dude, we have like eight, nine papers.
We have more coming out.
It's also been published upon by others.
There are definitely papers out there.
So, stop talking this nonsense about there not being.
I think the most egregious example, though, that I can think of was if you can find there is an abstract, circulation, type in statin, ketogenic diet, CAD, rapid progression, or something like that.
So, circulation is a pretty prominent cardiovascular journal.
And there was an abstract published that was presented at an AHA meeting, if I'm correct.
And the title, let's see if we can find the title so we can read it so I'm not misrepresenting it.
At all.
Rapid progression of CAD after stopping statin, starting a ketogenic diet in a phenotypic lean mass hyper responder.
Okay.
So, this is a scenario where they're using our coin terminology.
They're calling out a lean mass hyper responder and rapid progression of coronary artery disease.
So, this guy has coronary artery disease after stopping a statin and starting a ketogenic diet.
So, the title is clearly claiming he went keto and had progression of heart disease.
Right.
It says that directly and he's a lean mass hyper responder.
Now, I wanted to bring this up because what you see here is the entirety of it.
There is no more.
It is not a full paper.
It is an abstract, but it got published in this.
Oh, wow.
It's very short.
Yeah, that's it.
That's it.
What's the conclusion?
So, I mean, the title is kind of the punchline.
Okay, guys.
But what I expected when I saw the headline was this is somebody presenting a case in which there actually was a lean mass hyper responder who had rapid progression of disease on a ketogenic diet, which.
I mean, we have thousands of them.
Of course, there's going to be one person.
You'd think there would be one person, especially with cholesterol levels this high.
So, I think, okay, they found a case and they're presenting it as a cautionary tale, which I'm all in favor of.
If the text supported that title, I would be promoting it a lot because I think it's an important story to hear in contrast to other stories we hear with people with high cholesterol who don't have progression.
But then I read it and my jaw dropped because it was so egregiously mismatched with the title.
The scenario was this there was a man, presumably on a mixed diet because he wasn't keto, who.
At some time, probably in his 40s, they don't give a very good timeline, but had occlusion of his left anterior descending, which is the main left artery of his heart.
So they went in there and did what's called a PCI.
So they basically stented open his artery because it was clogged, his left artery.
While they were in there fixing his left artery, which was clogged via his mixed diet, or while he was on his mixed diet, I'm not blaming the mixed diet, they noticed that there was some moderate disease.
There was already disease in his right.
So his left is clogged up.
They're pumping it open or stenting it open.
Then they look in his right artery.
And there's moderate disease.
So they give him a statin, secondary prevention, totally like.
I'm not clearly, I'm not like criticizing the clinical care of this patient at all, but this is what happened.
Left artery, you know, occluded, stented open, look, has right artery disease.
They put him on a statin.
He's then on this statin for multiple years, two years to be exact, during which time they're not like analyzing the progression of his right artery at all.
It's a couple of years go by.
There can be progression on this medication.
Then they go to.
And then he tried a ketogenic diet and had an RCA STEMI, ST elevation myocardial infarction, heart attack.
So the timeline is such that they say, okay, he has left artery disease.
We have to actually go in there and stent it open, presumably stent it, it's PCI.
And then they see there's right artery disease.
Then a bunch of time elapsed where they're not following him for plaque progression.
They're not looking at plaque progression during which he's on a statin.
Then he tries a ketogenic diet, which they don't define, they don't give a duration, and he's not even a lean mass hyper responder.
And yet they can come off with that title?
What, like, what not?
Like, it could be.
Who is that?
Who published that?
It was the Journal with Circulation.
And here's the thing I actually tried, I had multiple people I was in contact with, including cardiologists, who was like, well, let's put a letter to the editor in.
You can't do a letter to the editor because it's an abstract.
You couldn't even do an e-note or an e-letter because it's an abstract.
And the author's contact information is not provided.
So let's not call them out by name.
I mean, people can look and see what their name is.
We have it up on the screen.
But point being, like, I.
I was very vocal about when this came out.
Nobody replied to the criticisms.
I tried to do a letter to the editor again.
There wasn't the option for that.
And it just stood.
And this is one of those things where it's like, it's not a gray zone.
It's not like, okay, we have interpretive differences, Nick.
This is clearly a propaganda piece.
Take it back.
Who sees this, though?
We literally had to find the exact headline to find it.
Circulation is a major cardiovascular drug.
It is.
Yes.
Okay.
There's more behind the scenes that I can't reveal, but let's just say the fact that the.
So, people that are in academia or in this medical field, they see this stuff.
Oh, I mean, people like Thomas Dayspring were like flaunting this on Twitter saying, get with the science, LDL deniers.
And I'm like, dude, read the freaking thing.
This is garbage.
And again, I'm not someone who uses hyperbolic terminology, I think, most of the time, but this is garbage.
This is like.
It's not even that the bar was lowered, there was no bar.
It's like you like the title, so you ran with it.
They miss cite the criteria for LMHR, and even with miss citing it, he doesn't meet the criteria.
Right.
And again, it's like, so this guy, let's just say he was eating a standard American diet.
They don't define his diet, but like he's eating a standard American diet for most of his life, has left artery disease, multiple years elapse, and then what?
He tries some bacon for a week?
That legitimately could be the case.
Right.
And then you say it's a ketogenic diet's fault because they don't define, they don't give a duration.
It could have, yeah, it's, I mean.
What's this guy's name again on Twitter?
The guy who posted this, he was flaunting it?
Oh, Day Spring?
Day Spring.
What is the incentive for people like this?
Critiquing Bill Cromwell's Claims00:02:19
Is this just a theory or something that he's been talking about for so long?
He just doesn't want to be wrong.
After all these years, because clearly he's an older guy.
Yeah.
I mean, I. Or do you think there's some sort of other.
I think it's ego defense and arrogance.
It's a sinister thing.
No, no, no.
I think he's generally thinking he's doing the right thing.
I think he's arrogant and doesn't want to look at new data and thinks that people like me are just beneath him.
And thankfully, there are other people who are a little bit more open minded, including the guy who trained him, who, here's an Easter egg, is the senior author on Oreo versus Staten.
What was his name again?
William Cromwell.
William Cromwell.
Who, yeah, trained Day Spring.
And, you know, he's so anyway, if people weren't aware of that, there's a little fun Easter egg for you that we snuck in there.
William Cromwell has been amazing.
One of those people that, like, I've worked with a lot of people.
And there are some professors, a lot of them, or some who, like, will rest on their laurels, others who remain engaged throughout their career with the academia, and that's respectable.
And then there's a small group.
Who are very engaged with the academics, but who are also willing to see the new generation not as just the student, but they're willing to sit down with you with humility and listen to your new ideas as equals.
And I can't tell you how good that feels and how much respect that makes me have for those people.
So he's been absolutely phenomenal.
In fact, I think it takes a little bit of time for people to adopt new ideas, and sometimes it takes someone on the inside with credibility.
Cromwell's been doing lipidology longer than I've been alive.
Like he's been around the block.
And for him to come out and promote these ideas with us, like he was with us on Canberry and has been on with us on various channels since Oreo versus Staten came out and can speak about it very well.
I mean, that has a lot of utility for us.
Actually, I call him, I'm trying to nickname him, brand him Lem Jesus or Lipid Energy Model Jesus.
Also, because his name is Bill Cromwell.
So BC and BCE.
It's a perfect pun.
I'm hoping it catches on.
But he's been fantastic.
Engaging With Experienced Critics00:04:42
And, you know, I do have, you know, it's not my brand to take shots at someone when they're not in the room, like now with Day Spring.
But the thing is, his way and his is bullying, including, I mean, you can look at my Twitter because I've tweeted about it when he just, you know, calls some of my friends nasty names without engaging.
And then, you know, he says things that don't necessarily have an evidence base and you ask questions and you try to engage.
He's never replied to me.
Once ever about anything.
Yeah.
Which is just like, dude, if you're actually an academic who's engaged intellectually on this and I ask a direct question multiple times, like if at that point you're not engaging, then I do feel I have a little bit of license to call you on your BS until that point in which you step up and have a conversation.
I have even invited him, including others, to live casts in front of, you know, on audiences with like millions of subs.
I'm like, if you think I'm out of line, call me out.
Catch me out live.
Like, this is your opportunity.
You want to have a conversation?
Let's have a conversation.
And you can denigrate my friends for not being properly credentialed and being, quote, internet babblers, some of the terms he's used, because they haven't had a PhD or X, Y, or Z or publications.
You can try to play that game with me, but I don't think it'll go very well.
So I'm not with 50 years' experience, but I think I'm credentialed enough and smart enough to be worth having a conversation with.
And if you don't want to have that conversation, Well, I just don't think it's going to age well for these people.
Yeah.
I mean, he's not the only guy that does this kind of shit online, right?
There's also that guy, Peter Hotez, the vaccine scientist who attacks Joe Rogan for some of the things he says about vaccines and all those questions about vaccines.
I'm not going to go down the vaccine rabbit hole with you.
I'm sorry.
I'm just not.
I don't want to go down.
I don't care about the vaccine rabbit hole.
I just wanted to point out that there are people like that.
Yes.
That exist.
People like that.
That are surrounded.
By people who have the same beliefs they do.
And I'm not even like, not even talking about financial incentives.
They're just timid people who want to be supported by their quote unquote tribe.
Yeah.
And that could be the case with this guy.
Yeah, I think so.
I think he gets a lot of positive feedback from his community.
That's the annoying thing.
That's why I want to call it out.
It's sometimes like when he said this thing about ketosis.
Downregulating LDL receptors, everybody, including physicians, like, oh, I didn't know that because it's not true.
There wasn't like a critical thinking.
It was like, if you have enough gravity in the space, then what you say then actually gets baked into the common knowledge base and isn't challenged.
It's the eminence based medicine versus evidence based medicine, which I hate.
So at the point where somebody feels the license to make stuff up and isn't held to account, that I think is very dangerous.
And that's what gets me a little bit irked in addition to the.
The bullying.
So, you know, I'm getting a little bit pokey here, evidently.
And part of the purpose of that is I want to provoke a response.
You know, maybe somebody will hear it.
Maybe, you know, Tom will hear it, Tom Day Spring, and then react and have a conversation with me because I'm happy to have that conversation.
I'm happy to leave grudges at the door and learn from him because I'm sure he has something to teach me.
And I'd like to enter that conversation, were it ever to happen, with mutually open minds, me being willing to learn from him, but also.
You know, I think we have some interesting data that he definitely has not looked at.
So let's have those discussions and, you know, act as a team to push the science forward rather than, you know, the alternative.
Yeah.
And, you know, I said earlier, I said, you know, this could be, you alluded to, maybe it's not that important, but I think it could be like one of the most important topics to talk about because literally food and nutrition is the biggest fact, like the biggest or the lowest hanging fruit.
For keeping people healthy.
And when it comes to our whole healthcare system and the amount of people that die from cardiovascular disease in this country, it's like the number one killer, right?
And look at the things people eat, Captain, you know, cereal and grocery stores are full of shit processed foods.
Pushing Science Forward Together00:10:17
And it is a huge problem.
And I personally think it is the biggest problem.
Yeah, I think it's definitely very important.
It also is just a question, you know, a story about like, Pursuit of scientific curiosity.
I think people always want to know what is the significance now?
That's an important question to ask.
But in science and medicine, generally, the biggest breakthroughs come through just pursuing an interesting observation or interesting question.
You know, making weird observations.
The example I've been using, whether or not you like them, or depending on what your opinion is of them, the GLP1 receptor agonists, things like Ozempic, Wigovi, they're definitely a revolution.
It's the GLP1 receptor agonists as a class of drugs.
Okay.
Is that like azetamide?
No, it's like Ozempic.
Ozempic, okay.
So these weight loss drugs, which are now all the rave, and they're very successful.
Is that the stuff Elon Musk was talking about?
Yeah.
He lost a lot of weight on it, I believe.
But where do you think those came from originally?
They came from studying Gila monster venom.
Who?
Gila monsters.
You can Google a Gila monster.
What's a Gila monster?
It's a lizard.
How have I never heard of that?
Have you heard of that, Steve?
Yeah, man.
It's a lizard.
Stop it.
Yeah.
Yeah, it's a lizard.
Liar.
It's like a.
Yeah, it's a Gila monster.
You see him at the zoo, man.
Oh, yeah, I've seen them before.
Google, I forget what the compound was.
Google Gila Monster Venom Ozempic or something.
And it's like Excendin or something.
It's a drug that uses a compound in Gila Monster Venom to help lower blood sugar.
The compound is similar to a hormone produced by the intestines, but it lasts longer in the lizard's body.
The synthetic form of the lizard hormone can help diabetics control their blood sugar levels.
It also slows the stomach from emptying and decreases appetite, which can lead to weight loss.
So, anyway, the point and the reason I brought it up is.
You can study something that seems kind of niche and esoteric and can have major rippling effects that you could never have predicted down the line.
So, people ask about the relevancy of Oreo versus statin.
Yeah.
And the lean mass hyper responders and stuff, I'm like, all right, there is relevance to a small population of people immediately in terms of understanding this, treating it if it needs treatment, understanding the risk profile.
But it's such a weird thing.
Again, going back to that, if this is able to be replicated, which I have every reason to believe it would be, and we've seen very similar things in other people, this just Oreo types.
Or, we have a statin type thing where you have, again, an intervention that seems bad and an outcome that seems good.
And you want to try to understand that.
What we gain when we figure out the answer and provide rigorous evidence to support the model underlying it and the mechanisms underlying it, what could fall out of that is probably something we couldn't even imagine now, like Gila Monster, Venom, and Minozumpic.
Hmm.
That's the way I look at it.
So, I don't need to like rationalize why this is going to be.
Let's say that was how I would rationalize how this is relevant to everybody.
So, how do you control your cholesterol right now?
I assume you're not eating Oreos anymore.
No.
I mean, I'm monitoring.
I am not on any medications.
So, you're not worried about it because you're just getting the CT angiograms, making sure you don't have any plaque?
I wouldn't say I'm not worried about it.
I'm saying it's a complex choice with lots of individual factors.
I do have my concerns about lifelong medication.
I'm not sure what my risk.
Profile is, but I am pretty confident in my individual case, given I've gotten scans after multiple years of having levels as high and have no evident plaque, that I'm not going to drop dead in a year.
So I have.
How often do you get your blood work?
Oh, I mean, more commonly when I'm doing experiments than it's like weekly.
But other than that, I'm not just getting it routinely, but I do a lot of experiments.
So it pops up every now and then.
You know, my options are medication.
Carbs, getting fat, and being sedentary.
All those things would work.
So, yeah, I'm going to try to avoid the.
Well, you know, right now I'm feeling pretty good and I'll do what I need to do to, you know, feel well, finish my training, live a happy, healthy life, and then watch along the way, see if there's any progression.
Hoping there isn't.
I don't think there will be, but also watching for more data to come out.
I reserve the right to change my opinion at any point in time.
I don't go into a doctor's office saying I will not take a statin or I won't take a medication.
It's a discussion.
It's a discussion that we all need to have.
And so I don't want people to hear what I'm doing and say, Nick's doing this, therefore I'm going to be doing that.
I am probably very different than you, whoever you are listening.
So it is an individual choice.
And, you know, I think it's important to just enter, really do try to talk with people with different perspectives on this, with different levels of expertise in different areas.
Yeah.
And then form your own opinion and then, you know, make a decision based on your priorities.
And then in the end, everybody has to respect that.
There is patient autonomy.
And I don't think any of us are going to.
Reject that concept.
Even if a patient has a right to refuse life saving medication, were it to be that, they have that right.
Yeah, I mean, even the smartest people that study this stuff and that know about this stuff, they experiment all the time.
Like Dom, for example, I think he just started experimenting with his Zetamib himself because he has really high cholesterol.
And I asked him, I'm like, what do you think?
He's like, I don't know yet.
I'll let you know how to get my blood work.
Did he say how he reacted to it?
I don't, maybe he did.
I don't remember the text, but he said that he hasn't gotten his blood work back yet.
Okay.
Why?
How did he react to it?
I probably shouldn't say.
I don't know if it was in a private conversation.
Oh, you can ask him.
Oh, okay.
Gotcha.
Well, he doesn't do a lot of cardio.
So, but that wouldn't affect, I don't know if that would affect anything.
So, yeah, actually, that's something that I didn't bring up earlier, but there might be, and this is again, a hypothesis originating from Dave Feldman, but an attenuation of the LDL rise.
So, less rise in people who are heavyweight trainers because of the use of the LDL particles for structural function.
As in, when you're weightlifting, basically they get, let's say, subsumed.
This is speculation, but they get subsumed, and that will drive down LDL.
Weightlifting?
Yeah, if you're like a heavy weightlifter.
Right.
Like, you know, if you're, you know, so somebody came up, it was, I forget who I was speaking with the other day, but we were doing, they wanted to make, oh, it was, I think, Dr. Boss or something.
I think that was her.
A comparison between me, there was like a picture of me, And then a picture of The Rock.
And the point is.
You're pretty shredded.
I saw your pictures.
I have been historically.
He's got some nice shirtless pictures for all the ladies listening.
I'm taken.
I would like to keep those parts of my life separate, but I did figure after this Oreo versus Staten thing that might not be possible.
We'll see how much word is going around Harvard.
But yeah.
You're about to be a popular guy at Harvard if it's not already the case.
A lot of people know.
I was sitting down with a friend the other day and she's like, So, Nick, I heard about this thing.
And this was before it dropped.
See, I haven't been like.
In the hospital since it's dropped.
So, yeah, we'll see.
If Harvard actually covers it, then everybody, well, they'll basically get an email blast.
But anyway, we'll see.
That aside, I forgot what I was going on.
Oh, The Rock.
We were talking about you and The Rock.
Yeah.
Bottom line is like, if he was, well, first of all, if he were natty, but like he has so much more muscle and is just, you know, needs it for repair that his structural demands are going to be much, much higher than mine.
Even if we had the same body fat percentage.
So, what would that mean?
I mean, his LDL wouldn't go up as high.
Despite having similar body fat.
Because.
Because the LDL is needed to repair his muscles, and he's doing more muscle damage than I'm going to be doing because I don't have as much muscle as he does.
But he's not.
Does the fact that he's not naturally that muscular, the fact that he's taking all these fucking whatever it is, Tren or whatever it is?
I'm not an expert in exogenous compounds and how that would affect the system.
It's not something I've really studied.
There are some things I know very little about, and that's one of them that and alcohol.
Anytime you're in medicine, people ask you this, that, and the other about alcohol.
I'm like, dude, if you want to be a medical influence, you have to know about all this stuff.
You got to know about alcohol.
You got to know about cold plunges, saunas.
I will not do a cold plunge.
That's where I draw the line.
It could make me live to 200, and I'm like, No, it is so unpleasant.
I just find it so, so unpleasant.
I'm a giant baby around water.
I will, you know, I'd rather run a marathon every morning and get no benefit other than the benefit equal to a cold plunge than do a cold plunge.
I do not like that.
What about saunas?
Oh, I love saunas.
Do you?
I do.
I do.
I don't have a lot of time for it right now, but like, you know, when I'm a little older, I want a home gym, a nice studio like this.
Hopefully, I'll be doing some podcasts at some point, and then a sauna.
I really do enjoy that.
That's nice.
Yeah, saunas are great.
Actually, after a sauna, I could do like a three minute cold shower.
Yeah, I like the contrast.
Well, yeah, if you have the cold bath or whatever plunge right next to the sauna, you could be like sweating your balls off, hop in that cold water, and won't be as bad.
Right.
You'd think in Boston, I have the money for that right now.
You don't even need it, bro.
But you got the natural, you got the, you have Mother Nature.
Yeah, I was thinking about getting somebody who's trying to get me into rucking.
I might get into rucking because I have bad knees now.
That's a whole nother story, but I can't really run distance anymore.
What is rucking?
It's where you walk with like a heavy sack on your back, like a weighted vest or like a backpack with weights.
Oh.
So it's supposed to be good cardio.
Oh, I see.
A weighted.
Okay.
So I think I might give it a go.
I have a weird.
I used to run a lot, but I actually have a weird mutation and a gene called LRP5.
And it makes it so my bones don't respond well to heavy mechanical loads.
So running impact.
Marathon Running And Bone Health00:03:28
Actually, funny story there.
You're not going to believe me when I say this, but you can Google it.
I started running intensely when I was 17, 16, 17.
I was pretty good.
My marathon PR, even at that age, was like a 245.
So I was fast.
And I qualified for Boston for 2014.
But that's when my bone problems manifested because I was doing such high loads.
And so I ended up getting a tibial fracture.
Oh, no.
Six weeks out from the race.
So what do you think I did?
You're like David Goggins.
You just powered through it.
Google Norwich's crutches marathon.
Stop it.
You raced the marathon on crutches?
I did.
That was my senior year of high school.
Wow, look at you.
So, yeah.
Did you get last?
No.
Really?
Well, because here's the thing you go out in waves, right?
So, there are four waves, and because of my quality, they place you based on your qualifying time.
So, I was in the first wave, and they stagger the waves by 30 minutes.
So, I actually had a, let's say, a head start on the people that started last.
And it only took, even with that, just under seven hours.
Because you can kind of keep a clip.
So, yeah, it was a long day and it was a great day.
It was pretty cool at the beginning because I started in a mass of all the fastest runners.
Like a little bit ahead of me were the people who were going to win the race.
And obviously, wave one, they just take off.
I couldn't move as fast.
So then I'm kind of like just hobbling along there.
But because it's the beginning of the race, everybody's kind of like stacked up, like dozens of people deep and waiting for the waves to come.
So, wave one goes.
And then they're like waiting.
They're like, all right, wave T will be here in like 40 minutes.
And they're like, what's that in the distance?
Because I'm between the waves.
Because the first wave's gone off.
The second wave hasn't started.
And then I just had the solo moment when it was literally just me and the crowds at the beginning of the race.
And like, that was kind of cool.
So it was a good day.
And then I collapsed at the finish line, was brought to the tent, med tent.
They gave me some potato chips.
My sister and my dad carried me down in Chinatown to my favorite restaurant, Faux Pasteur.
And I got a big pho and some dumplings.
It was good.
Pre keto days.
Oh, pre keto days.
Yeah.
I.
Yeah, no.
Especially in college, my diet was a lot of carbs and sugar.
It was just that you know from like, yeah, it's the culture there, especially with you go to the dining hall, you're, you know, with your other like sporty male friends, and you're all just like, you make eating basically a game.
In fact, it was a thing.
We had at Dartmouth these amazing soft baked chocolate chip cookies under these heat lamps called focal cookies.
And it became a thing where my friend would try to eat as many as he could in a sitting.
In fact, he set the record at 24, which I think was 6,000 calories of cookies after being a little bit drunk and eating dinner.
Wow.
And then the funny part was, in my valedictory address, I called it out.
I called him out for setting the record, and they put it in the graduation statistics.
It was like this many students graduated with military commendations, and yeah, Brant ate 24 foot cookies in 30 minutes.
It was funny.
And then we used to steal ice cream tubs as well, like five gallon ice cream tubs.
Alzheimer's Trials And Metabolic Dominance00:07:50
Really?
Yeah.
There's pictures around there.
I think the statute of limitations on that has passed, so I can't get in trouble now for stealing ice cream.
But no, no, I was not Le Carb in college.
So, what you were saying about Dom weightlifting or people who are heavy weightlifters and the LDL consumption of the muscles, is that the same thing?
Is there anything similar with cardio?
Is there any sort of effect with lots of cardio?
Because, you know, like Atiyah, Peter Atiyah always talks about, or at least recently I've noticed, saying that doing the specific type of cardio, like Two hours of zone two cardio every single week or whatever reduces all cause mortality by like 70% or something.
I think cardio would increase LDL.
Cardio would increase LDL.
In people who are keto and lean.
Okay.
In lean mass hyperresponderance, right?
Yeah.
Yeah.
No, I think it would increase it.
Is there, I would be curious to see what sort of effects a ketogenic diet has on the brain.
I mean, like, cause there's plaque, you know, the plaque that builds up in the brain.
Alzheimer's disease.
Alzheimer's disease or anything, any sort of effects on the brain.
Yeah, there's pretty compelling data now that it could be beneficial in neurodegenerative conditions, Parkinson's, Alzheimer's.
There was a randomized controlled trial in 2021 by Matthew Phillips.
Google that just Phillips Alzheimer's disease, randomized controlled trial, showing a ketogenic diet can have benefits as compared to, like, I think it was New Zealand healthy eating pattern.
Maybe it was Australia healthy eating.
But there's been an RCT in Alzheimer's disease.
There's data in Huntington's disease, and well, a case study in Huntington's disease.
What is Huntington's disease?
It's a genetic disorder that's very, it presents with something called like chorea.
You can get like depression, dementia, and you die generally very young.
It's a genetic disorder.
There's only a case study at that level.
There's data in Parkinson's disease.
There's a case study that just came out on ALS, amyotropic lateral sclerosis, or Lou Gehrig's disease.
Again, that's case study level, but you also then hear, you know, there are animal models supporting the efficacy and also just the biological plausibility of.
These are molecules, ketones, which are energy efficient substrates, particularly for nervous system cells, neurons.
And they produce less oxidative stress, radical damage.
They can be used when there's glucose intolerance in these cells, whereas glucose isn't used as well.
And again, they have these really potent signaling mechanisms.
So we have a lot of animal model data, in vitro data, and now the clinical data are starting to come out.
So, like that Phillips Alzheimer's trial.
And, um, Other work along those lines.
I think one of the videos I'm going to be dropping, I've already recorded it, was going over to the case study of the ALS patient, had bulbar onset ALS.
Really?
Which is a severe form.
It affects the lower cranial nerves.
The average, I think the median life expectancy is 24 months.
And when they were reporting on this case, the patient had actually improved some of his scores, despite the fact that it's a generative disease and was 45 months after symptom onset.
A case study, but one, you know, in a disease that really has no good treatments.
Provides a lot of hope, and it's definitely something that needs to be explored in a rigorous fashion.
But to do that requires money.
Right.
And nobody's going to make money, or it's not clear how the business model would work treating patients with this.
So, you know, again, not the best research infrastructure for pursuing studies in metabolic health.
Dom's story is fascinating how he got funded.
You know how he got funded by the Department of Defense for his.
Is this DARPA?
Did they split the.
Was it DARPA?
Maybe.
Well, so my lab at Oxford first got their $10 million grant from DARPA.
It was like the, I forget what the project name was called.
But anyway, I don't know.
Really?
Yeah.
Kieran Clark's lab at Oxford, $10 million grant from DARPA.
Well, Dom's was for treating oxygen toxicity seizures for Navy SEALs who had to dive under the water without having the bubbles so they could do covert missions and not, they could use those oxygen rebreathers.
And I guess these guys were getting epileptic.
Oxygen toxicity seizures.
And Dom was putting these guys on ketogenic diets and using exogenous ketones and basically eliminating those oxygen toxicity seizures.
And he was defunded by the DOD, but I don't think it was DARPA.
Okay.
But what was the DARPA one?
I forget what the grant was called.
It was like something like Project Human Optimization or Human Optimization.
I don't forget.
Google this.
We got to find this.
Yeah.
Delta G ketones?
Yeah.
DARPA grant to develop it.
What?
Stop.
Yeah.
So this was what we were using at Oxford.
The Oxford ketone ester developed by T. T delta S. T delta S to achieve new height of human performance in extreme conditions.
Whoa.
So I got interested in this lab when I read a 2017 paper by Cox et al.
And I thought the metabolism was just beautiful.
So, yeah, that's her on the far left.
That was my PI at Oxford.
And yeah, I thought that the research is just beautiful.
I will say the ketone ester tastes absolutely horrid.
It tastes like jet fuel mixed with nail polish.
Really?
Yeah.
When I gave it to patients, because I was running like Parkinson's trials, I knew as soon as I gave it to them, they would hate me.
And they always did.
It tasted pretty bad.
Does it tell you what exactly DARPA was trying to do with these ketone esters?
It was like the program name was like something like Metabolic Dominance.
It had a really cool name.
It sounded like something that would be like out of Marvel.
I loved it.
I loved it.
Metabolic Dominance.
It was something cool like that.
I forget what it was called.
Zoom in.
Can you punch in on this at all?
Anyway.
Yeah.
The pioneering research that led the exogenous ketone drink Delta G began in 2003 when Joe, whatever, the program director at the Defense Advanced Research Projects Agency, DARPA, Elite Defense Science Office, DODSO, and blah, Okay.
Okay.
Here's what they were trying to do.
They were trying to have energetically efficient food that would allow soldiers to maintain their physical and mental performance over five days on the battlefield.
What is that?
Ten years later, they proposed to invent an exogenous ketone food group for DARPA.
Took many years.
This was way back in 2003, though.
Yeah.
No, the field has evolved quite a bit.
I think, you know, it was used for sports performance.
I think some of the Pelotonists and the Tour de France have used it.
And, um, And now it's transitioning to medical grade usage.
We're trying to give our soldiers ketones.
I mean, if the government is doing that, then we know it's good.
It's better than McDonald's.
Super soldiers fueled by ketones.
Yeah.
Call Steve Rogers.
I'm a big Marvel fan.
I don't know if you're a Marvel guy.
The Phase 4 was eh, although Loki 2 was excellent.
I'm not a big Marvel guy.
I could never really get into the Marvel stuff.
It's a big commitment at this point.
Yeah, it's a huge commitment.
There's too much, man.
There's so much.
I'm a big DARPA guy, though.
So, yo, so we were about to wrap up, but I forgot I wanted to ask you about these things.
So, Dom is the one who told me about these candy bars because I was asking him, I'm like, Dom, I'm working all day and I'm trying to, I got a snack on shit.
What are some good snacks?
And he told me to check out these RX sugar chocolate bars.
So, and it's something that I'm fascinated with, but I haven't done enough research on it.
Allulose Metabolic Benefits Revealed00:14:28
But I guess that they replace the sugar with allulose.
Mm hmm.
What is the story with this allulose stuff?
So, allulose actually is a sugar.
It's a rare natural sugar.
It's kind of a cousin of, or let's say a twin of fructose.
I think it's a C3 epimer of fructose.
So, I think the way to kind of like break it down and think about it is if fructose is like, let's say, the evil twin, allulose is the good twin.
But they're very similar molecules, but allulose isn't processed by your body like fructose.
So, to conceptualize what the benefits might be, One could say, okay, what are you gaining by just removing the fructose?
So that's one element of it.
Is fructose uniquely metabolically harmful?
And actually, I've done like a YouTube series on going organ system by organ system, showing how actually fructose can play a role in the process of dementia, including fructose that's made in situ in the brain.
So your body can actually make its own fructose via the polyol pathway, and you can ingest fructose.
But it has unique properties as well.
The metabolism of fructose is very fascinating.
So, there's this one process of energy production in the cell called glycolysis.
Maybe people remember that from eighth grade biology.
I'm sorry if I'm causing PTSD, but the first enzyme in that pathway, say you're breaking down glucose, what it does is it adds a phosphate group.
It's called hexokinase and it traps the glucose in the cell.
But normally in biology, what happens is with these enzymes, they'll have an off switch, which is part of a negative feedback system.
So, if you produce a lot more product, it will kind of Feedback to turn off the enzyme so things don't get out of control.
But fructose is unique in that the enzyme doesn't have that off switch.
It's called ketohexokinase.
And because it doesn't have an off switch, if you have a lot of fructose and it goes down that pathway, what ends up happening is you actually get intracellular, so within the cell, energy depletion.
The ketohexokinase phosphorylates the fructose a lot and ATP levels drop.
That's that kind of cell's energy currency.
And then what'll happen is the AMP, which is a breakdown product, builds up.
That can generate intracellular uric acid.
That can cause the translocation of something called NADP oxidase 4 to the mitochondria, damage your mitochondria, cause things like citrate to build up, causing de novo lipogenesis.
All these jargony terms aren't things you have to understand, or you can go to some of my videos where I break them down.
Yeah, I need English.
Bottom line fructose has a unique metabolism, and it isn't a matter of just calories, but it's a matter of it can cause things that are uniquely metabolically harmful if you have high enough doses.
I will caveat I'm not saying that.
Fruit is bad.
You shouldn't like not have blueberries or a banana.
Your body actually, in your small intestine, processes a lot of fructose to other sugars, and lower doses aren't necessarily harmful.
Although we eat now sucrose, which includes fructose, that's table sugar, and fructose itself at very high doses to the point where it is damaging.
And there are schools of thought that fructose is contributing, especially to the obesity epidemic.
I don't think that captures the whole picture.
Perfectly.
But point being, fructose is not just bad because of calories.
It has unique metabolic properties that can make it uniquely damaging to the body, in part by generation of new fat, also called lactopic fat, but also damage certain organ systems, including even the brain.
Now, allulose tastes similar.
It's again the cousin of fructose, but your body can't break it down.
Generally in biology, you can think about it like there's left and right handed molecules, and your body's enzymes can only work on one form.
So if you use the other hand, You might be able to taste something, but it's not necessarily uniquely damaging.
So, I think one aspect, let's call this the tip of the iceberg, is that you can get rid of the fructose if you use allulose.
You can therefore also reduce the caloric intake.
So, there's that, and you're not getting the damaging effects of fructose, which also means you have better blood sugar control.
So, your blood sugar is not spiking and falling.
In fact, if you have, you know, I know patients with type 1 diabetes that can use these quite fine.
And actually, it actually attenuates blood sugar spikes when there is sucrose.
So, what I mean by that is, It's not just neutral, but if you have this and you have sugar, your blood sugar response to the sugar is lower than if you just had the sugar.
This has been shown now in randomized controlled trials as well.
So we can link those below.
So if you mix this with a regular chocolate bar?
If you had this and you had a regular chocolate bar together, the blood sugar spike will be less than if you just had the chocolate bar.
Okay.
That's fucking insane.
And it actually, I mean, there are really.
It seems too good to be true.
So there are unique metabolic properties of natural compounds that we can exploit.
One really cool one that I think is this is actually an inducer of GLP 1.
So I think we even mentioned earlier the GLP 1 receptor agonist class of hormones are what, so sorry, are the like Ozempic and Wigovy, the weight loss drugs.
Those drugs are trying to mimic this hormone called GLP 1.
Allulose actually causes the release of GLP 1.
And that's been shown.
And it acts via the vagus nerve, the wandering nerve, the 10th cranial nerve to, Have effects on brain activity, hunger, and metabolic status.
So that's just kind of one example of weird things that allulose can do.
There are other things that we're studying or I'm peripherally associated with that I can't talk about.
But I've been fascinated by it too because I'm one of those people, first of all, I have no drive for sweet myself.
So I'm not looking for like an excuse to have something sweet.
And I'm typically of the opinion that, you know, if it sounds too good to be true, it probably is.
But then we also have to look at what the data say.
And broadly speaking, I'd say on non-nutritive sweeteners, so sweeteners without calories, they're the ones that I think definitely have negative metabolic impacts.
Things like aspartame and Diet Coke.
People try to defend it.
It's actually really funny watching social media spaces.
You see these people.
It's like, oh, Diet Coke isn't bad for you.
Yeah, Lane Norton.
Yeah.
I'd say, like, dude.
Didn't you have an exchange with him?
We've had a few.
Well, this was actually about fructose because he recently retweeted.
I just did that break.
You know how I did the intracellular breakdown?
That I just talked about.
Yeah.
So, like, all right, you know, ketohexokinase, you know, depletes ATP, AMP builds up, causes, you know, blah, Aconophase, a lot of enzyme names.
I caveated it as this is an interest piece explaining a biological mechanism.
He retweets it with something like, oh, but saturated fat increases liver fat by 70% more than fructose.
Ouch.
It was trying to, like, dunk on me.
The issue is he didn't look at table one of the paper he quoted, the paper he linked to try to dunk on me, where it actually showed that the fructose increased.
Ectopic fat in the form of circulating triglycerides by 70%.
So, yeah, there wasn't fat in the liver because it was being dumped into the freaking bloodstream, dude.
So, look at figure one before you try to dunk on me.
So, I did a response video.
And then, actually, he was very polite.
He replied to the email that he hadn't replied to for a month.
And we had a nice exchange.
I honestly, here's the thing.
I know I was just kind of poking Elaine.
The people I think are very, some people are deliberate about their social media style.
Yes.
He is clearly very, his persona on Twitter is very hot headed.
And it works for his brand.
I like the fact that he points out a lot of the charlatans.
Yeah, I do.
So I actually have no big issue with Lane.
I think we definitely come from things from different angles.
I've heard behind the scenes that he's a pretty thoughtful guy.
And I actually think he is pretty smart.
And I think we would actually, in real life, be pretty good friends.
We've had good email correspondences.
So you brought up, I wasn't going to bring up Lane.
You brought up Lane.
But that was just an example of look, there's more here to the story.
I'm not saying Fructose is, you know, in.
I'm not saying foods that contain fructose are terrible.
Don't not eat blueberries because I'm talking about this, but I am saying it has unique metabolic properties and it's something that all things being equal, I think most people should reduce.
And this allulose based product provides an option.
And on top of that, the science is really, really interesting around it.
Oh, yeah.
And then the Diet Coke thing.
Like things like aspartame and stuff, the type of.
So on population level data, it doesn't show that it promotes weight loss.
So, the benefit is questionable.
Yes, it doesn't have calories, and you could try to presume something from a short term study about chronic effects, but I don't think that's fair as well.
There are data in humans that it screws up the microbiome and causes glucose intolerance.
They've done studies.
This was out of the Weizmann Institute in Israel.
So, they've done these kind of studies.
They also do them in mice where they can do germ free mice and fecal transplants.
So, they can actually show it's screwing up the microbiome because you can feed one group of mice, or actually, what you can do is they did this.
Humans.
Who don't usually have things like, I think this was actually using sucralose at this point in the study.
It's been a while since I read it.
But you give humans who don't have these sweeteners, these sweeteners, then they become more glucose intolerant on glucose tolerance tests.
And then what you can do is you can transplant the feces from the humans before and after they were exposed to mice.
And what you can actually find is that after the exposure, the mice will pick up the glucose phenotype of the human.
So the mice would be, you know, they get the human's feces.
The humans haven't been exposed to the sucralose, or maybe it was saccharin.
It was one of the S ones.
And then the mice are okay with respect to glucose tolerance.
But if you gave those mice the feces of the humans after they were exposed, if the humans then became glucose intolerant because they had the saccharin or the sucralose, I forget which one it was.
I think it was actually saccharin.
Then the mice pick up the phenotype, which shows that it was mediated by changes in the microbiome because the mice never were exposed to the non nutritive sweetener.
And we see similar things with aspartame.
Again, biological plausibility breaks down to phenylalanine.
I mean, even if like, To show it has biological effects, there are disease conditions like phenylketonuria where you cannot have aspartame.
If you have a kid that's test positive for this and they're screened for it, the first thing the doctor will say is, Your kid cannot have Diet Coke because it's terrible for them.
Now, most people definitely do not have that condition.
Point being, it's not just a neutral substance.
And there are data that I think are just interesting.
So we actually mentioned earlier, I think at the beginning of the podcast, the whole Diet Coke and anxious sperm.
Think about that experiment for a minute.
In that study, what they did is they gave mice.
Doses of aspartame, the sweetener in Diet Coke, that were equivalent to 7 to 15% of FDA regulated safe levels.
So low doses, equivalent to two to four Diet Coke.
That was the dose equivalent.
We're not loading these mice up.
Two to four Diet Coke dose equivalents.
They tested them for anxiety phenotype.
You can do like an open field test.
And they were like anxious mice.
Not only that, then you cross the mice and look at their offspring.
And their offspring, despite not being exposed, were themselves anxious.
And even the grand offspring at the four Diet Coke dose.
We're more anxious.
So it could be inherited.
Now, pause.
What claim am I making?
I'm not claiming that you can't use Diet Coke for weight loss, and I'm not providing human data that it's affecting mental health that can be transgenerationally inherited, but you have to think about what data we can acquire.
So if somebody says on Twitter, yeah, but these aren't human data, so I don't care, I'm like, yeah, but we're never going to have these data in human.
You can't do this experiment in human.
So all I can provide you is these animal data and then ask you the question, based on this, are you worth, is it worth risking your kids' mental health and anxiety to have a Diet Coke?
Do you care about it that much?
For me, I'm like, dude, I'll just have a water.
I don't need it.
People really need it.
I mean, you're an adult, make your own decisions.
I'm not saying you can't have Diet Coke.
What I'm saying is this isn't the equivalent of water.
So are there negative health effects?
I definitely think so.
Is it going to cause cancer?
Like, no, you're not going to wake up the glioblastoma.
So maybe some of the fear mongering is overblown, but I also don't think people should just be defending it for the sake of defending it.
Like, encourage people to just have water.
We don't need this.
Why do you think you need it?
And also, you know, be clear about your comparator.
Like, is it worse than a Coke?
Probably not.
But why are you choosing that as a comparator?
Right.
So, anyway.
And then, yeah, with these, this allulose product or the allulose in general, I think it has fascinating biological.
Properties.
A lot of the experiments have been done in mice, but I think there are more and more data coming out showing that it has unique metabolic effects, like promoting this GLP1 release.
And yeah, I'm trying to tread around it a little bit because I'm not sure what I'm actually at liberty to talk about with unpublished data.
But we can link that GLP1 paper.
Actually, I think I have a YouTube video called Nature's Sweet Ozempic from a while back that we can link as well, where I break down a little bit of that effect.
I think it's fascinating.
They taste delicious.
It is delicious.
It really tastes like chocolate.
Yeah.
And also, I'll just put a plug in.
You know, I really, this is the first company that I've really been affiliated with.
And I, I, I'm not like.
Full disclosure.
Full disclosure.
Well, yeah, I think they're in the process of bringing me on.
But I like the team.
Dom's on the team.
Ben Bickman's on the team.
Richard Johnson's on the team.
And the CEO, this guy named Steve Hanley, is just the most enthusiastic, sweet guy with a heart of gold whose mission is, I think, really pure.
He's not in it to make money for himself.
He's incredibly generous.
And he really just wants to get sugar out of the food supply as much as possible and replace it with something that is a better alternative.
Is there any potential downside to allulose?
Leveraging Shares For Future Work00:02:52
That you found?
The only downside is at higher doses, some people have a GI intolerance.
I would say that happens with a lot of sweeteners.
Yeah.
But some people just might have like loose stools or something.
But beyond that, I've only seen, honestly, benefits in the data.
So I think it's a very cool product.
I think the research on it is burgeoning.
And if I were to endorse one non nutritive sweetener, it would definitely be allulose.
Even head to head against other non nutritive sweeteners like Stevia, which is also natural.
There are some data, I'm not going to define them because, again, I don't know if I'm supposed to be talking about them, but they'll be coming out shortly that allulose has metabolic benefits.
And yeah, again, it sounds too good to be true.
And that would be my impulse to believe, but the data are what the data are.
So I'm just giving my breakdown of them.
I think it's a good company with a good mission.
And so I'm very happy to support it.
Well, Nick, thanks.
Is there anything we missed that we should talk about?
Nothing on top of my mind.
Okay.
Tell people listening and watching where they can find your videos, where they can find you on social media.
So I'm probably the only Nick Norwitz in the world.
So if you Google me, I'm not hard to find.
At Nick Norwitz on Twitter, N I C K N O R W I T Z. Nick Norwitz is my YouTube where I'm starting to produce some stuff there.
We'll figure out how I can up the quality.
I need to get a better mic and et cetera, et cetera.
And then, you know, I do have a call to action, which I've been.
If people can, you know, there's an eight minute video abstract going over Oreo versus Staten.
Check it out, share it.
And also, there's a link on my Twitter and my pinned tweet currently, and then the notes below the video.
Share that around.
Again, this is an interesting research ecosystem right now, and attention does matter.
And you can show that, and it gets genuinely reflected in scoring systems the more you share this kind of stuff.
So, I'd love to see our score go through the roof.
People take attention.
We get more resources for this funding.
And that happens when attention can be demonstrated through including social media metrics.
So if you think this is cool, I really do appreciate the shares.
It's not just a vanity metric for me, it's actually something we can leverage for future work.
Because, yeah, no, I'm not getting millions of dollar grants from DARPA anytime soon.
So I'm depending on listeners.
Well, we need to make that happen, Nick.
All right.
Thanks again.
I'm obsessed with this kind of stuff.
So I appreciate you giving us the time here today.
Thank you so much.
And I'll link all of your videos, your social media channels below.