Ep. 525 We’ve Been Misled About Metabolic Health – The Shocking Truth About Cholesterol, GLP-1 & Aging with Dr. Nick Norwitz
- Cynthia Thurlow
- 23 hours ago
- 40 min read
I am thrilled to reconnect with Nick Norwitz today. Nick is a researcher and educator with a mission to make metabolic health a mainstream concern. He graduated valedictorian from Dartmouth College, completed his PhD in metabolism at the University of Oxford, and earned his MD at Harvard Medical School. He has become known as a clinical researcher and metabolic health educator, speaking and writing on various topics, including brain health, microbiome, mitochondrial function, cholesterol, and more.
In our conversation, we discuss the challenges of providing evidence-based medicine, and Nick shares his personal story of overcoming inflammatory bowel disease with a ketogenic diet. We explore the research on statins reducing endogenous GLP-1 production, highlighting the importance of staying curious. We also clarify the different types of type 2 diabetes, the effects of biomolecular aging, and different perspectives on Lp(a).
Nick always provides thoughtful and valuable insights on a range of topics. His Substack is one of my favorites, sharing several ways to enhance your learning process, as a clinician or a layperson.
IN THIS EPISODE, YOU WILL LEARN:
How his struggle with inflammatory bowel disease led Nick to realize that the evidence-based care of western medicine is not always the best type of care, and how a ketogenic diet saved his life
How a recent study highlighted several major physical issues statins cause, yet it went largely unnoticed in medicine and the media
The need for clinicians to inform their patients about the potential side effects of their medications
How physicians tend to ignore evidence in favor of one-sided messaging that erodes trust and undermines informed care
The importance of remaining curious and acknowledging that what you learned initially might be incorrect
How technological advances will make personalized medicine the future of healthcare
The limitations of traditional one-size-fits-all randomized controlled trials
The sub-phenotypes of type 2 diabetes
How enzyme inhibitors (like statins) disrupt the gut microbiome
How metabolic health and oxidative stress affect Lp(a), and how vitamin C can potentially reduce its impact
Bio: Nick Norwitz
Nick Norwitz, MD, PhD, is a researcher-educator whose mission is to “Make Metabolic Health Mainstream.” He graduated Valedictorian from Dartmouth College, majoring in Cell Biology and Biochemistry, before completing his PhD in Metabolism at the University of Oxford and his MD at Harvard Medical School.
Nick has made a name for himself as a clinical research and metabolic health educator, speaking and writing on topics ranging from brain health, the microbiome, and mental health to muscle physiology, mitochondrial function, and cholesterol and lipids. His mantra is “Stay Curious.”
“Medicine is a noble profession, but the system’s setup and incentive structures built around it direct the focus in particular directions.”
– Nick Norwitz
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Transcript:
Cynthia Thurlow: [0:00:02] Welcome to Everyday Wellness Podcast. I'm your host, Nurse Practitioner Cynthia Thurlow. This podcast is designed to educate, empower and inspire you to achieve your health and wellness goals. My goal and intent is to provide you with the best content and conversations from leaders in the health and wellness industry each week and impact over a million lives.
[0:00:29] Today, I had the honor of reconnecting with friend and colleague Nick Norwitz. He's a researcher, educator whose mission is to make metabolic health mainstream. He graduated Valedictorian from Dartmouth College before completing his PhD in metabolism at the University of Oxford and is MD at Harvard Medical School. He's made a name for himself as a clinical research and metabolic health educator, speaking and writing on topics ranging from brain health, microbiome, mitochondrial function, cholesterol, and more.
[0:00:57] Today, I was joined to discuss the challenges of evidence-based medicine, his personal story with inflammatory bowel disease and a ketogenic diet, specific research around statins reducing endogenous GLP-1 production, why staying curious is so important, different types of type 2 diabetes, the impact of biomolecular aging and different perspectives on Lp(a). As always, Nick delivers such thoughtful, insightful commentary about a variety of topics. I always share with Nick that his Substack is one of my favorites to read and definitely one of many ways to help enhance your own learning process, either as a clinician or layperson.
[0:01:51] Well Nick, such a pleasure to have you back on the podcast. Thank you again for your time today.
Nick Norwitz: [0:01:56] Absolutely lovely to be here. Thanks for having me.
Cynthia Thurlow: [0:01:59] Yeah, we were talking before we started recording. You just finished med school at Harvard and you've been talking about some of the challenges that you see within the current medical paradigm, medical model, and a degree of cognitive dissonance. And so, I thought it might be interesting to start the conversation today around some of the things that you were noticing as you were finishing up your education that I'm sure would probably align with some of the things I was seeing as I was exiting the traditional model about nine years ago, because I think the average person probably doesn't realize what's going on beneath the surface in terms of our current medical system.
Nick Norwitz: [0:02:38] Yeah, that is a great topic to probe, a great question and one that I really want to deal with delicately. And the way I want to frame it up is I'm going to go on a little monologue now. We're going to have a discussion, but by the end of this, my goal is to get people to understand this that “evidence-based care does not equal the best care.”
[0:03:01] Now, going back to the beginning. I grew up in a medical household. I'm an MD, PhD, my mom's an MD, PhD, my dad's an MD, PhD. Both my siblings are in medicine. Like I grew up in Western medicine, “evidence-based care.” And I have the highest respect for the profession, for people who practice medicine, it really is a noble profession.
[0:03:23] But the way the system is set up, the incentive structures built around it, direct the spotlight of focus in particular directions. I came to notice this when I went through my own struggles. So, I struggled with inflammatory bowel disease “evidence-based medicine.” The standard of care that was available because of what randomized control trials have been done was insufficient to help me. So, I like many other people, did something that was out of the mainstream. And in my case, a ketogenic diet did save my life. And so that was something that happened as I was finishing up my PhD and starting medical school. And it left me scratching my chin and really framed how I went through medical school because I had to reconcile my personal journey where an intervention that wasn't, “evidence based.” I have no RCT to point you to say that a ketogenic diet is best for ulcerative colitis was the only thing that helped me.
[0:04:16] And so, I think what I came to realize, and I think you will definitely appreciate this given your background in medicine, is that the system is set up to provide standard of care based on studies that have been done, that have met certain checkboxes, and whether or not those studies get executed is not driven by what's best for patients, but by an economic incentive. And I want to be really clear, that is not me pointing the finger and blaming any individual, not blaming physicians or nurses, any healthcare workers, or even for that matter, Big Pharma. It's just doing what we built it to do. It is an institution. It's not evil. It's just built with certain economic incentive structures. And that really governs what research is done, what standard of care, but also what we talk about.
[0:05:05] And of all the things that we can explore and unpack, I think what we choose to talk about is the most in our control, especially now. And this is why I'm so excited to be coming out of the closet, so to speak, as a public figure, because we live in an unprecedented time with access to information, with social media, this tool that allows for a bridge between academia and the general public. So, while I can't determine what Pfizer is going to study. I can determine what my audience and you can determine what your audience is aware of. And in that way, we can start to change the tide of things.
[0:05:42] And I want to get a little bit more specific. But all that's to say, rather than generating conspiracy theories about evil Big Pharma or like doctors doing bad things, I think the most productive way to look at it is what are the incentive structures that have gotten us to where we are and recognizing what are the limitations of what we call evidence-based care? Because it sounds great, but part of it just might be a virtue signal because it doesn't actually mean the best care for your condition. Hopefully some of that landed. I know that was a lot.
Cynthia Thurlow: [0:06:12] No, no, I mean, I think it's important because I too, as a licensed medical provider, I always say, “Listen, the system is in many ways set up to fail us.” If we are looking at it as this narrow-minded perspective of unless there's been a randomized control trial, the power of your experiment with yourself, with diet, healing your IBS is significant. Yeah, inflammatory bowels disease is significant and yet I think one of the things that pulled me out of that traditional allopathic environment was that I saw in so many instances that when my patients changed their diet, when they managed their stress better, when they changed a lot of their lifestyle measures, it impacted outcome so significantly that we were able to get them off of medications and yet weren't incentivized to do that.
[0:07:01] And I appreciate, and I value how conscientious you are being about the language you are choosing to utilize and where we're not pointing fingers and saying it's pharma, it's the medical providers, it is a system that is not per se designed to be a well-care system. In many instances, it's designed to keep people on medications and on this straight and narrow path.
Nick Norwitz: [0:07:23] Yeah. It's no secret to you and probably no secret to your audience. Like when you delve into the metabolic health space, there's a lot of medicine bashing that blends with Dr. Bashing. And what I want to point out to people, not that I'm saying this is per se engineered by evil Big Pharma, but if you wanted to help out, those interests, keep doing that. Because the fact of the matter is, at least from my experience, doctors are just as frustrated with the system as anybody else.
[0:07:55] I have family, my girlfriend is in medicine like that she comes home every day talking about how she spent six hours on the phone when she also needed to be in the OR, she's a surgeon, just trying to deal with like bureaucracy and administration. Trying to advocate for her patients in a system that is shackling her. And so, the doctors I have, the doctors I know they're working so hard and they're as irritated with the system as anybody else. But if we fight amongst each other, the general public and physicians, and I know there is a gap of trust that's only going to perpetuate this, I think, sick care system. So, I'm all for outing incentive structures. I'm all for interrogating what's wrong with the system and trying to fix it, but I think the best way to do that is through a unity of the insiders and the outsiders. So little bit of a sore point for me, but hopefully that makes sense to people.
Cynthia Thurlow: [0:08:50] No, and I think it's important. Ultimately, we have to work together to actually change the system. It is not going to be on the backs of just one group or one individual, really. It has to be shared decision making, clinicians and lay public coming together and formulating some changes that will allow us ultimately to be able to focus more. Well, I don't want to say-- I feel like in many ways, we have allopathic medicine, which is necessary. There's a lot of emergencies. You mentioned your girlfriend is a surgeon.
[0:09:21] Emergencies, urgencies, we do a better job than just about anywhere else in the world. It's kind of the preventative and chronic disease management, where I see that there are some gaps in access to care, which is another significant piece in there as well.
Nick Norwitz: [0:09:35] Yeah, 100%.
Cynthia Thurlow: [0:09:36] Well, most recently you have been talking about a cell metabolism paper and one that, given our current climate, talking about GLP-1 drugs, which I think are certainly during my lifetime, I can't think of another drug that's probably had a larger imprint or footprint on not only the way that clinicians are treating patients, but also the way that patients are receiving care. And so, I thought we could talk maybe about statins first, just from a big picture perspective. It is a big business. Then talk about this paper and then loop in some of the work that's been done in the past. I'm thinking about AKA the Jupiter Trial from 2016, which is still-- when I was still in clinical cardiology, where we're dancing around this topic of medications and their net impact on insulin sensitivity, which is a topic that I know is near and dear to both of our hearts.
Nick Norwitz: [0:10:29] Yeah, I definitely want to unpack this. And again, I want to frame it as-- Or let me put it this way, I want to challenge people to really listen to what I'm saying. Because as soon as you say anything negative about statins, generally there's a visceral reaction towards either, yes, this is my confirmation bias, or this person's out of the mainstream, let's attack them. And I can give examples of how that happened recently.
[0:10:52] But the study in question was published in Cell Metabolism, which is a pretty prestigious scientific journal. And, it's hitting to me the news now. Actually, there's a couple legacy media outlets that are going to hit it, but not because it's new news per se, it's because I'm talking about it now. And the reason I'm talking about it with a degree of frustration. It was a major trial that came out about a year and a half ago, so February of 2024. And the punchline is this was a human controlled trial where they showed very clearly that statins not only increase blood sugar, not only promote insulin resistance and increase insulin, but smash GLP-1 levels down.
[0:11:34] Now, GLP1, as you mentioned, it's related to this big wave of, in this era of weight loss drugs, Ozempic, Wegovy and this combination agonist like Tirzepatide, but it's all GLP-1 centric, another multibillion-dollar drug industry. And so, at the metabolic level, it's ironic that the most profitable drug class in history lowers levels of a hormone that the new, probably next most profitable drug class in history is trying to mimic. So, I'll let people draw their own conclusions about that one.
[0:12:04] Now, of course you super physiologically dose Ozempic, yada yada, but point being, to me, it was very strange that at the time this came out, I was in my third year at Harvard Medical School, like spending my days in hospitals, including on like cardiology floors, not only did this not make national headlines, which quite honestly, I have this little thought experiment in the video. If you replace the headline statins, cut GLP-1 levels in half in humans with the word steak, I bet you that headline would have run if you replaced statins with steak. So thought puzzle, you can agree or disagree, but I thought it was interesting this didn't hit headlines when it should have, but it also wasn't discussed in academic medicine.
[0:12:41] So, when I read this paper, I then went and polled 12 doctors. None of them heard about this. And remember, this is not some dinky nothing. This is a human controlled trial in a major scientific journal, so how is it that doctors don't know about it? And if doctors don't know about it, they're not telling their patients, which means patients can't have proper informed consent for starting this medication. I'm not saying they can't take it. I'm not saying don't take statins, I'm not saying don't take GLP-1s. I'm saying this is the basics of informed consent. And the really alarming thing to me is actually in this trial they figured out the mechanism. We can delve into that. But then they figured out a very easy solution, which I'm not going to make medical recommendations, but in theory, you could reverse this effect via something you can buy off Amazon pretty cheap.
[0:13:25] So, then the question becomes, this is a key example of where “evidence-based care,” because the large scale RCT hasn't been done, isn't necessarily the best care. And then the question I got from a reporter when we were talking about it is like, “Well, it was a small trial.” And I'm like, that's the point. These are robust findings. First of all, a study is not determined as rigorous or not rigorous based on its end value, the number of participants, it's how it's conducted and what the research question was. This is a rigorous randomized controlled trial with very clear outcomes that were consistent with other literature and provided a mechanism and a solution. The question becomes, okay, if this holds a lot of promise for patient care, why is there no follow up? Why? Because nobody wants to pay multi-million dollars to not make money.
[0:14:13] Not pointing fingers to say anybody's evil. It's just the incentive structure is very clear. So, this is a key example where a very commonly prescribed money-making medication, not saying it's a bad medication, just saying money making medication has a negative consequence. That negative consequence is very clear and actually can be addressed. But there's no follow up, no discussion about it in doctor's offices, least not to my awareness. So, this is a scenario where patients just aren't getting the information they need, I think to make a fully informed decision. Not because the doctors are hiding it, but because they don't know. So, what's up with that?
Cynthia Thurlow: [0:14:45] From your perspective, when you were asking, I'm assuming you were in cardiology service, were people surprised? Were they curious or was it more dismissive, like a degree of cognitive dissonance.
Nick Norwitz: [0:14:57] This is the interesting thing. So, when I put this out on social media behind my character avatar, people don't really interact with me as a person. There's kickback, and we can talk about that kickback, but it's very visceral and reflective, like people wanting to defend the mainstream. But when you're not in that ecosystem, when you're just an academic standing with another academic, there's no defensiveness. The walls come down. So, the answers I got when I polled positions were there were 12 people I asked. Seven of them just said they don't know. The other five said they didn't know, but they volunteered guesses just because they were curious. They're like, “Oh, I'll guess.” And four of those five guessed correctly.
[0:15:39] They guessed, now to think about it, we know statins can promote insulin resistance. So, it would actually make sense if that mechanism had something to do with the drop in GLP-1 levels. I'll guess GLP1 levels go down and it's like, oh, yeah, there's actually human trial data showing that. So, the weird thing is when you stop and think about it already makes sense based on the other data. It's not like a one off, it’s a unicorn that's contradicting everything else. It makes sense mechanistically to the point that if you just ask a physician to guess, sounds like 80% of them, when they guess, will guess correctly, which itself is interesting. And it wasn't like a guess correctly, oh, now I want to hide this information. It's just one of those things where it's like, you have a busy day, your mind goes different places. The mind just hasn't gone to this question before. And then when it's presented with this question, you open up a new discussion.
[0:16:27] So behind closed doors, when you're walking around the hospital or like talking to a resident or attending, I don't typically find they're defensive. I find they're curious, which is how things should be. Social media, though, is very different. I want to pause and then I want to at some point get to why I think it's different and why that's problematic.
Cynthia Thurlow: [0:16:46] So to give listeners context who may not be aware of statin drug therapy as an example, I pulled some information that I thought might be helpful. Here in the United States, and this is as of 2019, I was trying to find more current data. It was saying 35% of Americans were taking some kind of a statin to treat their cholesterol. That was a huge increase from 2009, when only 12% of Americans were taking a statin. And more concerning than that, it was saying across ethnicity, statin use varies wildly, even when people are at high risk for heart disease. For example, one 2023 study from JAMA showed that more than 37% of high-risk white participants took statins, compared to less than 24% of high risk black and Hispanic participants across the world. There are 200 million adults worldwide using statins. So, this is a significant piece of research that came out that no one was talking about. And as you astutely stated, this is like 18 months ago that this came out.
Nick Norwitz: [0:17:46] Yeah. And to round out the discussion around this and why it's so difficult to talk about, I then want to talk about how the media responds. So, I put this out. I describe what the controlled trial was, what the data showed, show all the graphs. Now, obviously my audience likes me, so 99% [Cynthia laughs] was positive. But of course, once things get traction, you start to get the quote, tweets and the rebuttals. So, there are physicians and laypeople chiming in that are more in line with convention trying to shut me down now. That's fine. I don't mind that.
[0:18:24] The interesting thing about literally every rebuttal statement, none of them have addressed the data. They've made general comments. They've thrown shade, been like, “Well, if someone talks about statins and they don't talk about all these outcome benefits, then, you know, 9/10 of them don't know what they're talking about.” I'm like, all right, you drop this after I drop a tweet with several hundred thousand views is obviously throwing shade at me. I won't even try to argue that I know what I'm talking about, I think I do, but isn't it a little bit conspicuous that you don't refute the argument I made? And the reason I bring this up is because it's so easy to speak past each other, to see the first part of a tweet or to see how other people are replying and assume you know the message that is being communicated, because at no point did I say people shouldn't stake statins. I don't make directives about individual care over social media, that's not appropriate. I didn't say they were bad. I didn't say they didn't have benefits. But if you want to have a balanced discussion, which we do not have, it's skewed against brushing these side effects under the rug, then you have to highlight these. And so, it's totally fair to say and here's a trial showing a negative effect.
[0:19:35] And here's the problem, I think broadly is that on social media we still have a tendency, or I think the physicians, I'd say the older generation of physicians mostly who choose to be active on social media are still caught in a paternalistic frame where they think they know better and maybe they do, but what that ends up leading to is very one-sided dogmatic statement. So, the one we hear again and again, I'm sure you've heard it is lower is better. When people talk about LDL and ApoB, and what people are really saying when they say lower cholesterol, lower LDL, lower ApoB is better is all things being equal, which they never are in an individual case.
[0:20:20] If you lower this one marker, then cardiovascular outcomes are more likely to be better than not. It doesn't say anything about what are the effects of the intervention because you're not just snapping your fingers and changing one marker and what are the broader impacts on the health of the individual. And the reason this is a problem, in my opinion, is because while the average person might not know all the RCTs or how to interpret histology, they can tell when they're being patronized to. So, when people try to vaguely shut things down, like even, “tweeting my thread,” about an RCT that shows negative effects of statins very clearly and they make some vague statements in line with the mainstream that only galvanizes the general public and excites their mistrust and makes them angrier at the establishment.
So, the irony is the people pushing publicly for the conventional point of view, or let's say the very conservative point of view by giving the non-nuanced hot takes like lower is better. They're the ones that are inspiring most. This is my opinion. They're the ones that are inspiring and perpetuating the counterculture. When honestly-- And I'm not even telling you this is a-- I'm not saying I'm an expert clinician, I'm saying I've been in the patient chair a lot. And when a doctor says, “Hey, this is what we know, this is what we don't know. Here are the side effects and here are the benefits. let's do an individualized risk-benefit analysis considering all the data we have and your preferences,” I trust them so much more. And yeah, I might start a medication that has side effects because the net benefits outweigh the side effects, that is informed care, and I don't know why that's so hard. But I can tell you from experience just trying to communicate about, “Hey, there's a human randomized controlled trial showing a negative effect of a statin. What the public kickback is. And I think that is interesting to dissect from a psychosocial perspective in addition to just the data.
Cynthia Thurlow: [0:22:18] Well, I also think that on social media people have-- They're easily triggered, that's number one. And I oftentimes will see, generally you have a very kind, thoughtful response to a point. And then you like anyone else can get frustrated and upset with people, but I think so many people, their knee jerk reaction is they don't read. They read like a sentence and come to a conclusion and fire off a response. And you'll actually encourage people, you'll say, “Did you read the article? Did you watch the video? Did you actually take the time to read my entire synopsis of this study?” And more often than not, it's lack of attention, they get triggered. What I find clinically that's interesting is 25 years ago when I started in medicine versus now, people are-- There's a visceral knee jerk reaction to draw conjectures immediately. And wherever someone's cognitive bias is, that they stay very rooted in that perspective and oftentimes are, as you say, stay curious. A lot of people are unwilling to entertain the possibility that what they originally learned might be incorrect. That's the point I'm trying to make.
Nick Norwitz: [0:23:27] No quick tangent because people don't believe it. My only tattoo is a stay curious tattoo. [Cynthia laughs] So, I went wholesome on that one. But that aside, I wrote like a-- I call them on my Substack nuanced nibbles where they're just like short thoughts, like 300 words or so. And I wrote one on the data don't challenge your N equals 1. And it was in response to an audience member's comment saying they're always surprised by my perspective that my opinions are like Russian nesting dolls. Of course, there's the thumbnail in the title and then there's like another level and another level and another level. And often if you dig down into it, my opinions don't match the character made of me, which is not just me, that is just general.
[0:24:10] But what I find so Interesting, which maybe isn't general, is people let other people's stories and just studies challenge their personal experience. So, I'll give an example or I'll make it a personal example. A ketogenic diet saved my life from inflammatory bowel disease. I wasting away with ulcerative colitis. I had no social life, my mind was shot. I went from being very physically fit to incredibly frail and it saved me. No doubt in my mind, but if someone adopts the opposite diet, so let's say I'm eating very high fat, low carb, mostly animal based. If somebody thrives on like a low-fat plant-based vegan diet, should I be threatened by that? No. Why would I be? My narrative is my narrative. What happened to me is what happened to me. I'm an individual.
[0:24:59] So, if somebody else thrives doing something else or a study comes out that says, “Hey, this new fiber is really good for you or really interesting.” I don't love fiber for my stomach. I don't feel threatened by it. It's still interesting. And I think it's bizarre, although very commonplace, when you step back to say it's really funny that people feel so threatened by other people's stories and by data that doesn't conform to their experience. And my thing is like, that's totally fine. In fact, that's beautiful when you think about it. So, I try to be driven by curiosity-- Like, of course I'm going to be driven by curiosity with respect to what happened to me, but sometimes interesting data come out and I'll talk about them in a positive light, even if they don't align with what I practice and do and that's not hypocritical. That is just being like interested in the complexity and beauty of human metabolism and physiology.
Cynthia Thurlow: [0:25:54] Well, the whole concept of bio individuality, what works for you may not work for me, may work for five other people. And the whole concept of-- I was trained even as a clinician and I trained at another big research hospital, I trained at Hopkins and we’re taught that what we believe now would be very different than what we believe 2, 3, 5, 10, 15 years from then. And I think some people just, they become more rigid there, whether it's rigid dogmatism or it's their just personal philosophy. A lot of people just really struggle with the fact that we can all respond very differently to the same strategies or metrics. And I think that's really what I hear you speaking to.
Nick Norwitz: [0:26:37] Yeah. And what I would say on an optimistic note, not to be doom and gloom is with the advances we have in technology, I think personalized medicine is going to be the future. I'll get more specific. So right now, we were talking about what is the hierarchy of evidence, what is “gold standard care?” And we talk about randomized control trials. Well, fun fact of the top 10 grossing drugs, they on average help between one in four and one in 25 people who take them. I can send you the Nature letter where that statistic was published. It was out in I think 2015. But the point is you can run a large scale, “rigorous randomized control trial,” get statistically significant results and sell the medication at a huge profit while it actually helps a minority of people, but you can still have that P value that you need to publish the paper and get the drug approved.
[0:27:25] That creates a problem because you could be throwing out the baby with the bath water and the majority might be the baby. But what I see happening in clinical translational medicine coming towards clinical opportunities is really remarkable. So just because it's on my mind-- two days ago I don't know if you know the work of Michael Snyder. He's a researcher at Stanford, just like the Thanos of PubMed. His h-index is 220. He's publishing in Cell, Science and Nature left and right. My understanding is he was just on Huberman Lab. So that podcast is probably going to drop in a moment. In fact, he's the only person I've ever recommended to Andrew, I'm like, “You have to have him on.”
[0:28:02] But what his lab is top class in the world in is something called multiomics. So multiple ome’s, genome, proteome, transcriptome, fecal microbiome, all of this. And what they're doing and other labs like them are doing is they're doing deep profiling of the individual. So not just like a CGM curve, but your whole genome, your proteome, your transcriptome, and then using machine learning to figure out really what's going on with you in your body. So, the analogy I use in our podcast and I'll share it here because I think it hammers on the point is like when you go to the doctor's office and you get a lab test that's like an eight-year-old doing a Doodle on a post-it note of [Cynthia laughs] what looks like you.
[0:28:38] Now imagine you get tens of thousands of biomarkers, right? That's like a 4k or 8k image. But then imagine you do it longitudinally over time, multiple measures that is the difference between a Doodle on a post-it note and like watching Avatar in 8K on an IMAX screen. And that's where we're going. And the reason that's so powerful is because that provides insights for personalized care. So, I'll give you an example from Professor Snyder himself. If you look at him, he's a lean guy, I would guess his BMI is 22. He has type 2 diabetes, very unusual.
[0:29:13] Now one of the research projects his lab did was to uncover sub phenotypes of type 2 diabetes. So actually, there are four types, about four types of type 2 diabetes. So, the insulin resistance, obesity associated, typically diabetes. Specifically, there are underlying pathologies. So, there's muscle insulin resistance, your muscles are resistant to insulin. And I'm going to-- This is going to come somewhere, I promise, not just a biochemistry lesson. There is liver glucose dysfunction, there's incretin dysfunction, so that's the GLP and then there's beta cell dysfunction. So, your pancreas is misfiring. And depending on what underlying dominant pathology you have, you're going to respond to different interventions.
[0:29:50] So, Professor Snyder found out that he has beta cell dysfunction. What that means is his muscles are fine. So, whereas most people would say, “Oh, to improve your glucose tolerance, build up muscle because that's a good glucose sink,” doesn't matter for him, he could weightlift all day, doesn't make a difference. And he's a metformin non-responder, which he knows, but unconventional, not first line treatments work very well for him. So, this is a case where if he just went with first line, he would not be treated well. But then, and this is where things get exciting. To uncover your sub phenotype, say you have type 2 diabetes or pre diabetes, you typically need to go through a bunch of advanced testing in a lab that you cannot get in your clinic. People are going to be like, “All right, bummer, like I'll never know this is important,” but what they did in this study, and I can share with you, the study was in Nature Biomedical Engineering, I'll do a newsletter on this too, was that they could take a CGM, pop it on people and then use machine learning to decode from the different curves. Things that no human eye, no physician eye could decode, but they could see the signature, the machine learning could find the signature in the CGM curve to tell the person based on an at-home CGM read what is their underlying pathology, which is crazy.
[0:31:03] It's like in The Matrix when they're looking at like all the zeros and ones and they see like what was the woman in the red dress? It's like that. But you could do this with at-home biomonitoring. And I bring this up because I truly believe three to five years, this will be clinically accessible. You can have an app on your phone that doesn't just say your blood sugar's high. Says your blood sugar's high because specifically it's your beta cells in your pancreas, not your muscles and that means you should eat this or do this. In fact, he hasn't shared with me the protocol I mentioned on the podcast. He's going to send me the protocol, but based on these different phenotypes, there's going to be different responses to food. So, you can actually do an at-home test with your CGM based on your relative responses to potatoes or grapes to figure out your underlying pathology, which to me is cuckoo bananas. It's just so cool.
Cynthia Thurlow: [0:31:50] Yeah, no, that's fascinating. Think about and having like a very personalized approach to your specific diabetes diagnosis.
Nick Norwitz: [0:31:58] Yeah, it's unreal.
Cynthia Thurlow: [0:31:59] That's fascinating. I'm so glad you shared that. I do want touch back on that cell metabolism research just because I find it really interesting because my next book is talking about the gut microbiome and what's changing in perimenopause and menopause. So, I think this is particularly impactful. We know that statins impact the gut microbiome and they then impact bile acids. And so, this is the pathophysiology of the process of how you get from taking a statin to losing insulin sensitivity.
Nick Norwitz: [0:32:30] Yeah, so it makes a lot of sense when you think about it. The microbiome is the interface between the outside world and our bodies. And so, when you throw something that is a potent enzyme inhibitor in there, worse things are going to get shaken up. And bile acids, you mentioned that term. People think of them as just helping to digest fat. They are so much cooler than that. So, your body makes bile acids, puts them into the intestine, then your microbiome, the bugs there metabolize them into what are called secondary bile acids. You can think of these as basically your microbiome's hormones or types of hormones, because they do then go into the blood and they circulate around, they affect your endothelium, your cardiovascular risk. They cross the blood-brain barrier and bind receptors there. They can even affect depression. And there are papers on this.
[0:33:14] [unintelligible 0:33:14] papers, but still, this is pretty conserved physiology. So, in this case, what they found was that the statin changed levels of certain bacteria and changed levels of a secondary bile acid called UDCA. What they did in mice and then in humans was they're like, all right, if it's the depletion of UDCA by the statin that's causing the GLP-1 to drop and insulin resistance, what if we just gave back the secondary bile acid, shouldn't that recover the problem? It did.
[0:33:43] By the way, this UDCA is an available medication. It's used for liver disease. So, I bring this up again because it's like, okay, I never said don't take a statin, but if you're going to prescribe a statin, it's like giving Coenzyme-Q with the statin. It's like, okay, there's going to be these side effects, but we want you to get the benefits in your particular case, let's maybe supplement you with something else that might be negatively affected. It's not even really polypharmacy. I know people might know that term where you give lots of drugs and they complicate each other. This is more like, “No, no, no.” We know this is having this effect on this endogenous, normally produced compound. So, if it's going down, let's just give it back. It's like if you have hypothyroidism, just give back thyroid hormone. It's not even that complicated.
[0:34:27] And so what's cool about this study is it actually doesn't just say, it's not scaremongering about statins. It says, “Oh, here's the mechanism, here's the solution,” and that's why this is shocking to me, because it's like-- And this wasn't talked about, you could see how this could actually translate into just better patient care. Pro or anti-statin, doesn't matter, this translates into better patient care. Didn't get talked about, why not? Economic incentives or let's just say incentives. Not to point fingers, it's just an observation of clearly what's going on here. So, then it becomes interesting. There's this layer of when you reveal this to the masses, don't actually say anything negative per se, other than to just claim, “Hey, there's a human RCT saying there's negative side effects,” People get automatically defensive. And I'm just going to observe that.
Cynthia Thurlow: [0:35:12] Well, and I think you bring up a good point. This is not judgment. This is just talking about this is what the data shows and here's a way to address it. And just like when I was prescribing statins like daily, almost everyone we talked about CoQ10 because we know statins can deplete that. And in many instances, it either alleviated or improved some of the side effects that we saw, which for most of my patients were things like myalgias or muscle achiness, which is problematic and bothersome.
Nick Norwitz: [0:35:39] Yeah, yeah, I had myalgia. I was on 20mg Crestor for an experiment for six weeks and they were uncomfortable. They weren't like debilitating, you to go to the gym, you're like, this isn't a good way to live life. [Cynthia laughs] So, I know. And then there's data on like even in people that are asymptomatic causing mitochondrial dysfunction, I think particularly in Complex 4. And now I know what the conventionalists will say. Well, they'll say something to the effect of, “Well, is that really clinically relevant? And you have to consider the benefits.” My bigger thing is there are the known side effects and there are all the unknown side effects because you don't do a 50-year follow-up phase IV trial or whatever before you approve a drug. And so, it really is individual dependent.
[0:36:24] Let's talk about dementia, for example. I would say the trials on balance say that at a population level statins don't promote dementia. Maybe they can even protect against it. Maybe in particular like vascular dementia. But that is in a broad population with metabolic dysfunction. It doesn't mean that if someone has Alzheimer's vulnerability and is metabolically healthy, the net effect in them might not be a negative consequence. So, we can't discard just our basic understanding of the physiology and say, “Because there's no proven-- without a shadow of a doubt negative consequences in this domain, that we don't want to consider the unknown negative consequences.” It's just not, I don't think, responsible. And this becomes incredibly difficult.
[0:37:03] I'm in this position. I have astronomically high LDL. I'm actually going to do a letter specifically on my case. And I agonize over the decision, I truly do because I just don't have good information to inform my choice. And there are all the platitudes that people throw out there, “Well, the preponderance of evidence shows this, that and the other.” I'm like, but the preponderance of evidence was collecting people that are not like me. The entire body of evidence is collecting people who are not like me. So don't throw these platitudes at me because they're not actually that relevant. Let's think about what's going on physiologically here, what data we have, what data we don't, how they contradict and then make a decision. And the art of medicine is making hard decisions with incomplete or imperfect information. So, I'm not being prescriptive and I'm not saying do as I do. I'm trying to bring some authenticity here to the complexity of these decisions.
Cynthia Thurlow: [0:37:53] Well, and I think one of the reasons why I appreciate and value your work so much is that you are constantly encouraging people to think. Ultimately, it's like, let's talk about a paper. Let's look at the information. Will this cause us to look at this disease process differently or this medication differently or should we be anticipatory? And as you astutely stated earlier having true informed consent with our patients before we're utilizing or selecting an intervention.
Nick Norwitz: [0:38:21] Yeah, 100%.
Cynthia Thurlow: [0:38:24] All right. There's another really interesting paper that you talked about recently, both on Substack and social media in Nature Aging, the biomolecular aging of two key spikes, which I thought was really interesting and how there are things that we might be able to do to, I don't know if I don't want to use the word lessen the impact-
Nick Norwitz: [0:38:44] Yeah.
Cynthia Thurlow: [0:38:44] -or just proactively [crosstalk] yeah. Proactively look at these spikes in the aging process which ironically enough, when I think about females, I'm going to be slanted, gender slanted here, 40 and 60, you're talking about perimenopause and so many years into menopause.
Nick Norwitz: [0:39:02] Yeah, I can give you a little insight on this paper because actually this was, I mentioned Michael Snyder earlier, the sub phenotypes of diabetes, also his lab. Not only that, but this was the most viral paper ever published in Nature Aging. It’s out metric score, which is a media attention score, is 5571, which is like grotesquely high. It's absurd, but it really hit the media huge last year. And basically, what they showed was they did what we described earlier, this deep multi-element profiling of people over time and found, whereas you might think aging is linear. I age as much between 20 and 25 as I do between 40 and 45 that’s not the case. There are spikes in aging. So, one around 44 and one around 60 where you age faster during those windows, which is fascinating.
[0:39:51] Like you look at the graph, it's very stunning. So basically, what they did is they took like multiomic profiles and just saw like how things change. Did they change linearly? I think it was 6.6% of biomolecules tracked and they tracked tens if not hundreds of thousands across the multiome were linear. So, the other 90 plus percent were not linear patterns, which is fascinating. And then there were particular things that popped out. So, for example, I think both at the 44 and 60 peak, like caffeine and alcohol sensitivity changed. What does this mean? Well, maybe at 65, a cup of coffee hits much harder than it does at 35. I don't know if that lines up with people's experiences. I'm neither 35 or 65, I'm 29. [Cynthia laughs]
[0:40:32] So having experience and the life experience of these things. A quick aside, I was just on a-- It's funny, I talk about health span and longevity. So, I was on a pod and people were like, “So what are your tips for people over 30 to like stop aging?” And I gave two tips and the third tip was like, “And then don't listen to anything a 29-year-old says.” [Cynthia laughs] So, I appreciate the life wisdom of everybody listening. I can talk about the data, but yeah, their life experience, they don't have. That aside, very fascinating work by the Snyder Lab. We can get into the some of the most actionable specifics. But one thing I want to highlight and I put Michael Snyder on the spot about this is, I said, “Do you think you can flat out these aging peaks? Like why do they occur? Are they genetically primed? Are they like lifestyle?” And he's like, he doesn't know for sure, but he thinks the next step now that we've discovered the pattern, is to figure out how do you intervene to flatten out the pattern? I definitely think we can, maybe you can't flatten it to zero, but if you know what's causing the spike and also your own aging profile. So, other work they did basically shows people have different age omes. So, like you might have a 20-year-old liver and a 6-year-old heart. Like your organ systems age differently. So, as you start to develop that picture, you can develop very precise interventions to curtail your aging and at least extend your health span. So that was the high level of the paper.
Cynthia Thurlow: [0:41:52] Well, it's interesting because you started to say you could have this discrepancy between the age of your liver versus your heart. And then I start thinking about, at least in younger women, the most mitochondria in our body are in our ovaries and for men in their testes. And so, it's like I just start to think about, I'm sure there are life choices that we make that will accelerate the aging of specific organ systems.
Nick Norwitz: [0:42:13] Yeah. If we get a chance. Some of the most exciting work going on. I talked to him briefly about mitochondrial transplants are something that is actually being explored very seriously. There's some very cool work there. But quickly, also, just for actionable takeaways on this Nature Aging paper, things that I was reading, I think maybe the most interesting to me, well, two. One was in fatty acid metabolism and the other was in antioxidants. So, on fatty acid metabolism, they noted changes I think it was at the 60 peak in particular in like omega 6 and omega 3 fatty acid metabolism.
[0:42:44] The reason I think this is so interesting is it relates to this whole seed oil controversy and omega 6s. My high-level point and I'll focus on omega 6s because they're the one that get the bad rap. These are precursors to a ton of different things in your body. And so, it's not that they're good or bad. It is, what does your body do if you give it omega 6? If you give it in particular linoleic acid, what happens to that? It can be turned into-- It can be oxidized. In fact, if you have more body fat, it's more likely to be oxidized. There's an enzyme body fat mix called myeloperoxidase. If you're younger, it turns out that you have a better capacity to turn the omega 6, linoleic acid into something called 12,13-DiHOME. And what this does is it actually slows heart aging.
[0:43:26] So, I can go through other examples, but the point is this is a precursor biomolecule that can go down many different paths depending on your metabolic status and where you are in your life frame. So, I can't give a definitive protocol, but I can say it's interesting to consider you might have different fatty acid sensitivities. So, I could speculate that maybe above age 60, you're more omega 6 sensitive than someone who's younger.
[0:43:51] Food for thought. And as just a quick aside, there's actually a way, irrespective of your age, to boost the generation of this 12,13-DiHOME. It's cold exposure. There’s human trial showing about a 40%, 39%, I think, increase in this molecule when you engage in cold exposure. So, if you like cold showers, want to add a benefit.
[0:44:10] And the other thing was on antioxidant status. So, antioxidants decline around age 60. Antioxidant defenses. The reason I bring this up is because evolution wasn't optimizing for us to live to a 100. So, kind of makes sense. If we know as you age your antioxidant defenses decline, then maybe that's the appropriate timeframe in which you start supplementing. It makes sense. People are like-- ancestral principles. Well, our ancestors didn't plan to live to 100. So, if you know this is changing your body at age 60 and you want to give some-- We were talking about Coenzyme Q, vitamin C, whatever, as additional defenses, why not?
Cynthia Thurlow: [0:44:43] It certainly makes sense. And to of round out the conversation, I think you and I both share a high Lp(a).
Nick Norwitz: [0:44:50] Yeah.
Cynthia Thurlow: [0:44:51] And so I know that you did an amazing Substack around this. I'd love to round out the conversation because I think you and I both share this desire to address it, but be conservative and navigate what does this actually represent? We know on paper and in the research, it can be a causal risk factor for heart disease. It's more atherogenic. You probably inherited it from your parents like I inherited it from mine.
Nick Norwitz: [0:45:17] Thanks for that, yeah.
Cynthia Thurlow: [0:45:17] How do we navigate conversations around Lp(a)?
Nick Norwitz: [0:45:21] Yeah. So first, on what it is you think of LDL particles. It's like an LDL particle, but it has a little tail. Makes it a little more-- So to speak, the tail is made up of something called Kringle repeats. The longer the tail, the less Lp(a), the shorter the tail, more like the corgis-- [Cynthia laughs] Yeah, I use analogies. I like little analogies in the video I animate in. It's like if you had dangerous little corgis because they have short tails that are going to get-- This isn't even landing. This is going to be on audio. Nobody's going to get it. It's not going to be funny.
[0:45:48] I like to pull in jokes and I like to show corgi butts and among other things. So, this was just an excuse to me to show little corgis because now they're just like all my Instagram feed. By the way, you'd think my Instagram feed was nutritional stuff. No, it's girlfriend, boyfriend memes, dog butts and Harry Potter and puns. Dad jokes. That's like my entire Instagram feed. So, you can use that for whatever. I don't even know I'm bringing this up, sometimes I just go off.
[0:46:11] But anyway, so Lp(a) is thought of as a causal risk factor. I want to caveat that word though. Causal doesn't mean most important, all ApoB lipoproteins are probably causal. LDL particles are probably causal. It doesn't mean it's going to cause-- oxygen is causal to have a fire. But just because you have oxygen around you doesn't mean you're going to combust into flames. So just a point on that word causal because I sometimes think people over interpret it.
[0:46:37] But yeah, Lp(a) is more resistant than say LDL to changes with lifestyle. I can bounce my LDL around. Lp(a) is pretty genetically set. Ask for the risk, the absolute risk set. I do think the data suggests a large influence of your metabolic state. So, for example, one thing Lp(a) does is it's the janitor for oxidized and damaged fats, oxidized phospholipids. And so most people have a very pro-oxidative environment. They're metabolically unhealthy, they have a lot of inflammation and so they're going to have more oxidized phospholipids that Lp(a) can serve as a reservoir for. But interestingly, some of the data show that if you control for oxidized phospholipids on Lp(a), the negative effects are reduced. They're not eliminated, but they're reduced quite a bit.
[0:47:25] So, I think on basic principles and what I understand of the physiology, step one is just the basic. Are you metabolically healthy? Do you eat well, do you sleep well, do you exercise? Low inflammation, low insulin, low hs-CRP, yada yada. And if you're in that category, I will be more reassured all else being equal. In addition to that I still do have some concern, but the question is, what is the action item? What can you actually do about it if it's genetically set? One thing I will say is there are drugs in development which again, we're talking about incentive structures. It's probably why it's the hot kid on the block. It was one of the most popular newsletters ever put out. Kind of esoteric, right? Lp(a), you wouldn't think it's that popular, but now everybody's talking about it because there's five drugs published in some of the major journals like the New England Journal, including, I think most of them are SIRNA therapy, small interfering RNA to lower Lp(a). They haven't translated to improve cardiovascular outcomes. But they are incredibly effective at lowering Lp(a) by up to 99%, so like basementing it.
[0:48:24] And then the only lifestyle hack that I would mention, actually I'd mentioned two. One is Niacin, but that's controversial. It will lower Lp(a), but it's not been shown to improve outcomes. The other one, which I just find very scientifically curious is vitamin C. So, the origin of the vitamin C idea for Lp(a), actually we derive from a guy named Linus Pauling. Maybe that name rings a bell for people. He's smartish dude, he won two Nobel prizes, which, yeah, smart to win two Nobel prizes. Him and his colleague, Dr. Rath. This was around 1990. And one of the things they observed is, okay, what does Lp(a) do? It clots stuff up. It helps with wound healing. But here's an interesting thing. There's this pattern where organisms that make vitamin C don't have Lp(a), mammals in particular, and mammals that don't make vitamin C do make Lp(a). So, humans lost the ability to generate our own vitamin C about 40 to 60 million years ago. I think it was the GULO gene they lost or we lost. And then subsequently we developed ability to generate Lp(a). And it helps with wound healing, broadly speaking. But there's a pattern whereby this happened independently in other organisms. So I think the European hedgehog is one, also doesn't make vitamin C, also makes Lp[(a). I think some rabbits, for example, mice, don't make Lp(a) naturally. They do make vitamin C. I'm pretty sure they make vitamin C.
[0:49:46] So, in general, there's this interesting pattern where, oh, it suggests Lp(a) might be a surrogate for vitamin C. And so, this has led to this idea that maybe if you supplement vitamin C and also potentially combine with an amino acid, L-lysine has to do with how the Lp(a) binds with something called lysine binding sites. In theory, it could make one, for a less oxidized environment because vitamin C is antioxidant. And two, it potentially could make your Lp(a) less sticky, so less likely to actually adhere to the endothelium and generate plaque.
[0:50:19] This has been shown in guinea pigs that have been deprived of vitamin C or given vitamin C. So, less Lp(a) accumulates in their plaque and say, like the aorta. You can't really do this in humans without a post mortem. Some people have anecdotally reported vitamin C lowers their Lp(a). Although I wouldn't say you need to see a drop in the Lp(a) numbers to have any benefits. So, this is an area of speculation. Sorry if it's a little bit waffly. I would say on Lp(a), jury's still out, medications in development, of interest haven't shown benefits in clinical outcomes. If you're more metabolically healthy, have a lower oxidation environment, better antioxidant status, lower inflammation, you're going to better off.
[0:50:59] And then if you're interested in reading the newsletter and I did a whole separate one on vitamin C around the science around that, I don't think vitamin C supplementation is going to be harmful. Although a caveat, if you do very high-dose vitamin C, don't take your ketones or glucose afterwards, because a little postprandial spike can actually lead to oxidation of a lot of the strips and can give you these crazy numbers that make you look like you're in diabetic ketoacidosis. I played this prank on people for kicks and giggles when I discovered it. I did this experiment. I'm like, “Why is my blood sugar reading at 400 and my ketones are like 9? I don't think I have type 1.” So, it turns out you can oxidize the strip. So that's more of an aside. Don't play a prank on your doctor.
Cynthia Thurlow: [0:51:39] Yeah. No, so two things. Number one, one time I was getting high-dose vitamin C and I was wearing a CGM.
Nick Norwitz: [0:51:44] Yeah.
Cynthia Thurlow: [0:51:45] And it whacked out the CGM, like the data went nuts and I didn't feel symptomatic so I figured it was probably some vitamin C. Other thing about vitamin C that's interesting, you high dose it enough, you will get diarrhea. Like sometimes we'll actually say vitamin C to bowel tolerance because if you take too much.
Nick Norwitz: [0:52:04] It's an osmotic.
Cynthia Thurlow: [0:52:05] Yep. It'll give you some diarrhea. That's pretty hideous.
Nick Norwitz: [0:52:08] Yeah. Yeah, I know. So that's what-- Some people are like, “Oh, it works if you dose like 18 g.” I'm like-
Cynthia Thurlow: [0:52:14] No.
Nick Norwitz: [0:52:14] -Mm. I know people that have done like 18 g. I at about even 1 g, a 1000 mg get like bloating.
Cynthia Thurlow: [0:52:22] Yeah. Yeah. I would say 1 to 2 g usually that's the metric that people will get--
Nick Norwitz: [0:52:29] People have like-- yeah, two 500 mg doses will probably be fine. Especially like consumed with food should probably be fine. It's pretty cheap supplement to get, but yeah, 18 g oral would send me.
Cynthia Thurlow: [0:52:41] You would be in the bathroom all day for sure.
Nick Norwitz: [0:52:42] Yeah.
Cynthia Thurlow: [0:52:44] Well Nick Norwitz, I always love these conversations. I so value the work that you're doing and the voice that you bring to the space. And as you state astutely, keeping everyone curious, stay curious, why it's so important. Please let listeners know how to connect with you, how to get on your Substack email list or if they've been underneath a box and weren't aware of what you're doing, how to connect with you across social media.
Nick Norwitz: [0:53:08] Yeah, nice thing about being named Nick Norwitz, nobody else is named Nick Norwitz to my awareness--
Cynthia Thurlow: [0:53:12] [laughs] Little bit of alliteration.
Nick Norwitz: [0:53:13] N-O-R-W-I-T-Z is my last name. My biggest socials are YouTube and I'm on X, Instagram. And then my Substack is where I'm having the most fun. So that can be found if you just type in staycuriousmetabolism.com, all one word. It'll bring you there. I put out newsletters at least three times per week, typically on deep dives of what—I literally get up at 04:00 AM with insomnia. I'm like, “What's new in nature? Let me read.” [Cynthia laughs] So that's how I spend my time and I just absolutely love it. And it has been the pleasure of my life to have people in the community feedback my enthusiasm and curiosity. This is something I do anyway, the fact that I can make a career of it and I'm a very transparent person, my Substack makes money. It gives me incentive to like build this up as a business, provide education and engage with people. I think it's a powerful thing and I just want to thank everybody in the community for engaging and helping to make with me and you, Cynthia, metabolic health mainstream. Because I truly believe that we have the power in a bottom-up manner to change the medical system based on what we discuss, so everybody has that power.
[0:54:18] And honestly, the last thing I'll say is there's a lot of statistics that are negative about metabolic health in this country. Nothing preventing you from being the outlier. You don't need to be within the statistics. If you understand the physiology, if you're willing to learn and engage in your own N equals 1 experience, I guarantee you can be the outlier.
Cynthia Thurlow: [0:54:35] Amazing. Thank you again.
Nick Norwitz: [0:54:36] Thank you so much.
Cynthia Thurlow: [0:54:39] If you love this podcast episode, please leave a rating and review. Subscribe and tell a friend.
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