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Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade | #200
https://mindandmatter.substack.com/p/dietary-fats-and-seed-oils-in-inflammation?utm_source=publication-searchÂ
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Title: Dietary Fats & Seed Oils – Podcast Transcript (Host: Nick Jacobas; Guests: Tim Yateman, Ganesh Halade)
Key Takeaway Points:
Omega-6 to Omega-3 Ratio Impacts Inflammation
A high omega-6 to omega-3 ratio in modern diets promotes chronic inflammation.
Seed oils (e.g., soybean, sunflower) and grain-fed animal products skew this ratio to 20:1 or higher, overwhelming enzymes that process both fatty acids.
Chronic Inflammation Drives Cancer Risk
Persistent inflammation creates an immunosuppressive tumor microenvironment.
Conditions like ulcerative colitis and Barrett’s esophagitis demonstrate how unresolved inflammation increases cancer risk over time.
Lipid Mediators Determine Immune Response
Omega-6 derivatives (e.g., arachidonic acid) produce pro-inflammatory mediators like leukotrienes.
Omega-3 fatty acids generate resolvins and protectins that resolve inflammation.
Virchow’s Historical Link Between Inflammation and Cancer
Rudolf Virchow observed immune cells in tumors, proposing cancer as a "wound that won’t heal."
Chronic inflammation disrupts tissue repair, fostering mutations and tumor growth.
Immune Surveillance Prevents Cancer
Healthy immune systems detect and destroy precancerous cells daily.
Chronic inflammation suppresses immunosurveillance, allowing mutated cells to proliferate.
Seed Oils Are Major Omega-6 Sources
Industrial seed oils (e.g., canola, cottonseed) are cheap and ubiquitous in processed foods.
Their high linoleic acid content converts to arachidonic acid, fueling inflammatory pathways.
Grass-Fed Animal Products Offer Balanced Fats
Grass-fed beef and dairy have a 1:1 omega-6 to omega-3 ratio.
Grain-fed animals, by contrast, have ratios as high as 30:1 due to corn/soy diets.
Enzyme Competition Exacerbates Imbalance
Enzymes like ALOX5 process both omega-3 and omega-6, favoring the more abundant substrate.
High omega-6 intake "hijacks" these enzymes, increasing pro-inflammatory mediators.
Modern Diets Disrupt Evolutionary Fat Ratios
Pre-industrial diets likely had a 1:1 omega-6 to omega-3 ratio.
Industrial agriculture and processed foods have shifted this balance to 20:1 or higher.
Sedentary Lifestyle Worsens Inflammation
Physical inactivity reduces metabolic efficiency, impairing fat processing.
Poor sleep and stress further disrupt immune coordination, amplifying inflammatory responses.
Phospholipase A2 Links Diet to Inflammation
This enzyme releases arachidonic acid from cell membranes, a precursor to inflammatory mediators.
Elevated phospholipase A2 levels correlate with chronic inflammation and cardiovascular risk.
CRP vs. Phospholipase A2 as Inflammation Markers
CRP is a general marker, while phospholipase A2 specifically reflects lipid-driven inflammation.
Tissue-specific inflammation (e.g., gut, tumor) may not always show in plasma markers.
Cancer Is Both Genetic and Metabolic
Mutations (e.g., APC, KRAS) initiate cancer, but metabolism determines progression.
Obesogenic diets in APCmin mice increase polyp formation, linking metabolism to tumorigenesis.
Leaky Gut Fuels Systemic Inflammation
Ulcerative colitis involves neutrophil infiltration (calprotectin in stool) and bacterial translocation.
Chronic gut inflammation raises colon cancer risk, necessitating regular surveillance.
Essential Fatty Acids Are Necessary but Toxic in Excess
Omega-6s are vital for acute inflammation (1-3% of diet).
Overconsumption overwhelms resolution pathways, perpetuating inflammation.
UK Biobank Study on Omega Ratios and Mortality
Higher omega-6 to omega-3 ratios correlate with 26% higher all-cause mortality.
Cancer mortality rises 14% with imbalanced ratios, underscoring dietary importance.
Inuit Diet Example Highlights Balance Risks
Extreme omega-3 intake (e.g., Inuit diets) may increase heart disease risk.
Balance, not elimination, of fatty acids is critical for health.
Tumor Microenvironment Is Lipid-Rich
Immune cells in tumors (e.g., macrophages) rely on lipid mediators for signaling.
Pro-inflammatory lipids suppress antitumor immunity, aiding cancer progression.
Circadian Rhythm Affects Fat Metabolism
Sleep regulates immune patrols that clear cellular debris and resolve inflammation.
Disrupted sleep impairs enzyme activity, worsening lipid mediator imbalances.
Economic Factors Drive Unhealthy Food Choices
Seed oils are cost-effective for mass-produced foods but nutritionally harmful.
Grass-fed meat production is slower and costlier, limiting accessibility.
Systems Biology Approach to Inflammation
Inflammation involves diet, enzymes, lipid mediators, and receptors as interconnected systems.
Perturbing one component (e.g., diet) cascades through the entire system.
Genetic Engineering’s Unintended Consequences
Modifying crops (e.g., wheat) may introduce proteins triggering autoimmune reactions.
Single-gene edits can unpredictably affect broader metabolic networks.
Immunosuppressive Macrophages in Cancer
Tumor-associated macrophages secrete lipid mediators that inhibit T-cell activity.
Targeting these cells or their lipid pathways could improve cancer therapies.
Resolution Mediators Counteract Inflammation
Omega-3-derived resolvins promote macrophage efferocytosis (dead cell clearance).
Enhancing resolution pathways could treat chronic inflammatory diseases.
APCmin Mouse Model Demonstrates Diet-Cancer Link
High omega-6 diets in APCmin mice increase polyps by 60%.
This highlights how diet amplifies genetic cancer risks.
Microbiome’s Role in Inflammation
Dysbiosis (e.g., leaky gut) allows bacterial toxins to enter circulation, triggering inflammation.
Future research may link microbiome composition to lipid mediator profiles.
Modern Food Processing Degrades Nutrient Quality
Refining seed oils (e.g., canola) involves high heat and chemicals, oxidizing fats.
Oxidized lipids are more inflammatory than their natural counterparts.
Athletic Greens as a Nutritional Supplement
AG1 provides vitamins, minerals, and adaptogens to support metabolic health.
Free vitamin D with purchase addresses widespread deficiency linked to immune dysfunction.
Consensus AI Tool for Scientific Research
Consensus synthesizes studies, ranks evidence quality, and summarizes findings.
Premium features (e.g., unlimited queries) aid researchers in navigating dense literature.
Public Health Implications of Dietary Fat Policies
Current guidelines prioritize reducing saturated fats but overlook omega-6 excess.
Revising recommendations to emphasize omega-6/3 balance could mitigate chronic disease.
transcript of podcast
Whether food, drugs, or ideas, what you consume influences who you become. On the mind and matter podcast. We learn together from the best scientists and thinkers alive today about how your mind body reacts to what you feed it. Before starting mind and matter, I spent ten years in academia doing scientific research. I got a PhD in neuroscience where I focused on neuro endocrinology and the neurobiology of behavior.
And before that I specialized in molecular developmental and evolutionary genetics. I use my scientific background to help parse and translate the information that guests share on the podcast. In addition to the podcast, I write long form written content inspired by the show where I integrate what I've learned across episodes. I also have a free weekly newsletter where I provide you with upcoming guests, share links, and provide commentary on scientific studies and research that I'm reading and more. Visit mindandmatter.substack.com to find all of my content.
The full version of this episode is available to paid subscribers at the mind and matter substack at mindandmatter.substack.com. The full version is also freely available on my YouTube page. Just look up mind and matter or my name, Nick Jacobas on YouTube, and you'll find the episode there. This is a partial version of the episode and so it'll cut off partway through, but you'll still get a significant portion. So sign up to become a paid subscriber at Substack or visit my YouTube page to get the full episode.
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I highly recommend this if you are using outdated tools like Pubbed or Google Scholar or you just do your own research. For a limited time, you can use the code mind matter special, all one word, to get a free premium subscription for one year that is a $150 value for free if you use the code mind matter special today. So click the link in the episode description or check my support page and give consensus a try. Use the code mind matters special to unlock your free premium subscription today. Introduce yourselves and talk about what you guys study.
Sure. I'm I'm Tim Yateman. I'm a surgical oncologist by training. I'm currently a professor of surgery at the University of South Florida, and I'm an associate center director for translational research and clinical innovation at, the Tampa General Cancer Institute, Tampa General Hospital Cancer Institute. Ganesh Halaade.
I'm associate professor in the department of internal medicine, a division of cardiovascular disease, and I'm kind of my research is more focused on inflammation and resolution signaling that focuses on the chronic inflammation, that intersects, not only cardiovascular disease, but also the cancer and other lifestyle related disease. Mhmm. And and you guys have a really interesting new paper out. I I I read it just because it's the type of thing, that that comes into my, my alert box. I'm I've been, you know, talking to a lot of people on the podcast and reading on my own about topics that connect things like inflammation and diet to various chronic disease states, including cancer.
And we're gonna talk about lipids and and diet stuff. We're gonna talk about inflammation, and and we're gonna dive into your new paper. But there's also some background I wanna I wanna get into at different levels. I wanna give people a sense of how you guys think about chronic inflammation and factors that feed into it and cause it, including diet, including dietary lipids in particular. I wanna talk about cancer and how you guys think about it and and how the field has thought about it historically.
And one place I thought was interesting to start because I am you know, I'm not certainly not a historian, but I do love the history of science. You mentioned at the beginning of the new paper a man named Virchow. So who was this, and what were his ideas about what cancer actually is? So maybe I can address that. I mean, Rudolf Virchow was a, I think he was born in 1821 and lived in nineteen o two.
He's a pioneering German physician and pathologist, and he's often regarded as the father of modern pathology. And, basically, he he introduced the concept of cellular pathology where he looked under the microscope at at various, tissues and tumors. And and it's been attributed to him that he saw first, inflammation in cancer. And inflammation was the influx of of white cells basically into a tumor, immune white cells. And, it I think it's been also attributed to him and others that the concept of cancer is like a a wound that won't heal.
And I always, remember you've you've had animals like a dog where they have sunspots and and, that wound just won't heal. They keep licking, won't heal. It's sort of a ulcerated wound that won't heal. In a human, it might be a diabetic ulcer that won't heal or an infected wound. And so he saw that.
And remarkably, you know, in the in the eighteen hundreds, identified the inflammatory process as being a component of cancer. Yes. So the cancerous, the the VirTra actually started the concept, like, how the inflammation is a fundamental there in context of developing towards kind of continuous process and uncontrolled. In reality, if we see the inflammation is designed helpful, but mainly it is in the acute process, and that is coordinated by the 1% of the immune cells that we are kind of having, since, kind of long time of history of the human beings, and that's kind of real historical perspective that how our immune system is built. And in that one, the added the kind of real, key that how this chronic inflammation is involved, not only the acute inflammation and not only the kind of, various type of metabolic diseases, but also in the cancer and many other diseases.
Mhmm. Mhmm. So so is is an idea here that, you know, inflammation so on the one hand, we we want inflammation. We want our bodies to be capable of this. It's it's a part of clearing out infections.
It's a part of clearing out debris and tissue debris when when we get, you know, physical damage. But I think, you know, a key thing, at least for me and my understanding of information is you want it to be very spatially regulated. You want the information to turn on at the appropriate time and then turn off at the appropriate time. You want it to be at the site of an infection or at the site of damage, but not anywhere else. You don't want it to to bleed out to other tissues because there's always this chance of, collateral damage.
And I don't know much about cancer biology in particular or or the history here, but it sounds like this this idea that maybe goes back to Virchow is that if the inflammatory process itself becomes dysregulated, that can actually be a a a factor in causing cancer? Yeah. So, let's just, go back a step. So evolutionarily, you might say that inflammation evolved as an important component of of human existence and mammalian existence. Mhmm.
Because the greatest threat to to life early on was probably infection. Mhmm. Cuts and and and viral infections and bacterial infections. So we evolved to, you know, try to fight those things also. Inflammation, the whole body is geared towards turning on inflammation for that reason, I think.
Evolution just kinda makes sense. Right? That Yeah. You'd really wanna be ready to attack anything that that comes at you. But you're right.
If if that inflammation, persists, inadvertently, can it cause problems? And I'll give you, some great examples in cancer. So it's well known that inflammatory bowel disease, and that's, ulcerative colitis and possibly Crohn's. But ulcerative colitis is a great example. In that disease, you see what's called leaky gut.
And I always thought leaky gut was kind of a funky term that no one really understood. But the truth be told, it refers to the epithelial cells that have normally have tight junctions like your fingers sticking together, and they open up. And when they open up, they can release basically blood cells, lymphocytes, blood cells, neutrophils into the bowel lumen, which is the a stool. So it's interesting that the the most, effective, diagnostic test for active UC is something called calprotectin, stool calprotectin. Calprotectin is a neutrophil specific marker.
So if you see that in the stool, that means you've got neutrophils leaking from your capillaries into the stool. And that's why people with ulcerative colitis have bloody diarrhea. So they they they now now you understand that's what true leaky gut is. Right? Mhmm.
And and when you leak that gut, then you can have bacteria going both ways, and we should get a discussion of microbiome in the future. But let's hold that, put it on pause for right now. Mhmm. So so you get this leaky gut and these these inflammation, and it doesn't seem to to go away much. Although in ulcerative colitis, it's called relapsing and remitting.
Yeah. It's sort of you get inflammation, then it sort of heals. You get inflammation, it sort of heals. So there may actually be an attempt at resolution of inflammation in that disease. But if it goes on for long enough inflammation, then you can get cancer.
So it's well known that in ulcerative colitis let go for, you know, ten years, you increase your risk for cancer. That's why people with ulcerative colitis have to go undergo, surveillance colonoscopy, and they get biopsies every ten centimeters throughout their colon when they have this long lasting inflammation because there is a risk. The other disease would be Barrett's esophagitis, a risk for esophageal cancer, some, skin ulcers, cancer. So it's this sort of this chronic ulcerative condition that can lead to cancer. And and ulceration, by the way, is a bad sign for all cancers.
If you take melanoma, an ulcerated melanoma has a worse prognosis than a non ulcerated one. And and, you know, why? Well, one theory I've got, and and and it's it's interesting. We've always thought of cancer as a a true genetic disease, and it is. Right?
Right. And from Bert Vogelstein and his group identifying APC, you know, as the sort of the initial seminal mutation in most in many of these cancers and subsequently getting KRAS and p fifty three mutations and other things like that, we we now know that, that maybe, metabolism is part of this too. So could cancer be a metabolic disorder as well as a genetic disorder? That's that's my question. And I think the answer is yes.
So so we now know that, that, you know, inflammation appears to be present in a tumor microenvironment, and that inflammation likely causes immunosuppression and reduced immunosurveillance. So one one possibility would be that when you develop these common mutations in your billions of cells lining the colon wall, and that happens every day. And they're normally they're normally destroyed, by your immune system. They become apoptotic, and they go away. But what if you have an immunosuppression locally, a chronic immunosuppression?
Would more of those take hold or take foot? And one example of that is, is the, is a mouse study, and there's been a number of them, but there's a mouse model called the APC min mouse. And in that mouse model, they basically, have a single hit in APC, kind of two hits, but one hit in the APC allele, and the mouse is born with that in every cell of its body. And if you, give that mouse a highly obesogenic diet, rich in arachidonic acid, rich in omega six effectively, they produce many more polyps, 60% more polyps than a normal mouse. So you're putting that inflammatory milieu in the presence of a mutation Yeah.
That could cause cancer. And all of a sudden, you're getting more of them, more deaths. Double whammy, kinda. To me, that's kind of de facto evidence that that an inflamed environment could lead to increase, increased I don't know what it's increased mutability, but increased, chance of mutations taking foot. Yeah.
So if I'm tracking here, because I was I was actually about to ask you, you know, as someone who's never been a cancer biologist, I never studied cancer biology per se, but as someone who's always in biology, you know, I remember as a student sort of just having the notion in my mind, oh, cancer is from mutation. You get x number of mutations in tumor suppressor genes or whatever, and then the normal cell becomes a cancer cell and off you go. If I'm following you, Tim, what you're basically saying is, yes. There are these mutations involved in in creating cancer cells. But, normally, I mean, there's so many cells in the body getting so many mutations every single day that all of us at some rate is generating, you know, cancer cells.
And oftentime more often than not, when things are working appropriately, our body takes care of that. Those those cells are detected and they are destroyed, and and the immune system is involved in that. It sounds like what you're saying, Tim, is that if you're in a certain inflammatory state, if you have chronic inflammation or or what have you, then immune surveillance can actually be sort of turned down such that the probability that any one of those cancer cells that would have very likely been destroyed before it became full blown cancer and problematic actually doesn't get destroyed. And so, even though mutations are necessary to generate a cancer cell, the the inflammatory state of the tissue can also dictate sort of the probability of of whether or not that cancer cell will actually be handled when it when it should be. Right.
And we call that tumor genesis, by the way. So our carcinogenesis or tumor genesis, basically, the increased ability of of the metabolic state to enhance tumor genesis is what we think could be happening. Mhmm. It's also possible that once you have a tumor, that the inflammation could make things worse. And and and we don't know whether there's a threshold of inflammation or whether in other words, you you just exceed this threshold of inflammation, it's all bad, or whether there's a, a sort of a linear or logarithmic relationship between inflammation and immunosuppression.
Yeah. We we do know that many of the cells in a tumor environment are micro macrophages. I think about 50. And many of those are immunosuppressive macrophages. And we know that the card carrying currency of the TME is lipid mediators.
And, so having a lot of these inflammatory lipid mediators in the tumor microenvironment, likely contributes to this immunosuppression and and decreased immunosurveillance. Mhmm. And when you say lipid mediators, is the basic idea here that you've got all of these different immune cells. Some of them can stimulate information. Some of them can suppress the immune system.
When you say lipid mediators, you mean that these are molecules that immune cells have or they release that are sort of the the information signals that are saying turn information up or down and things like that? I'm gonna let doctor Hallad, the expert on, take you maybe through the Yeah. The pathway from maybe a a seed oil that has linoleic acid, you know, to arachidonic acid to you know, how you get to this Yeah. Yeah. Lipid meters and what they actually are.
Yeah. Sure. Yeah. I like to. Kinda glad.
Before that, I just wanna use the analogy for the chronic inflammation, like, you know, what happened when, you have acute inflammation. It just like, you know, when there is a fire, firefighters come Mhmm. Very precisely on time, control the fire, and they leave. But in the chronic inflammation, the first thing is these firefighters don't come on time. Mhmm.
And even if they come on, they just hang on where there is a fire, and they forget to leave. So the immune cells get in signal, their transit signal, and get out signal is totally discoordinated, and that's where the Tim Edmonds really nicely, kind of explain how the immune suppression is developing. So that's the discoordination of that leukocytes that's developing the chronic inflammation. That is kind of where many metabolic diseases are kind of, developing the whole process. I see.
So so so you have signals calling in the firefighters, separate signals telling them when to leave. And if these things aren't properly coordinated, you the firefighters go to the wrong place at the wrong time. Wrong time. Exactly. And, plus, especially, if they are coming late at the tumor site, plus just they are hanging, doing the party with the facts that every day we are taking in the body, and then just there is a continuous progression of the tumor, and that's whole tumor environment we have described in the paper.
That's now here is the question of the how this, molecules are formed. And, we know that historically that these fatty acids, they are not synthesized in our body. That's why they call as essential fatty acids. And then those are necessary one to three to 5% depending on where we are on the growth curve, in our life. Like, if we are, like, early in the adult phase, we need slightly kind of more quantity.
And then down the line, it has some old or, you know, in the kind of late phase life, we may need relatively lower. But what happened to these, fats or essential fatty acids, they get used by the immune cells more rapidly in response to acute inflammation and make number of lipid mediators. Same process happen in the chronic inflammation where these, fatty acids used by those discoordinated firefighters or the immune cells where these fatty acids from the diet get converted into the second generation of those molecules. And those second generation molecules we call as lipid mediators or the bioactive lipids. And here, we need to note this point that these second generation molecules are more potent than the actual original fatty acids present in the diet.
And as you know and that the standard American diet is enriched with the linoleic acid, that linoleic acid, get converted into arachidonic acid, and that further forms the many second generation molecules. And those are the inviting the immune cells. That is the first step of the initiation of the chronic inflammation. So that's how these lipid mediators forms a continuous process that invites more any more immune cells that leads to the tumor progression and, kind of continuous, growth of the tumor in various regions of body depending on where it is initiating. That is one step.
Now in contrast to that, if you think about, imagine instead of this, unhealthy fat, you have the healthy fat, which is coming from omega three and other, kind of similar, related sources, fish or other related sources. And then the same enzymatic system and the immune cell converts those to the healthy molecules. Those are called as a resolution mediators, and that helps to control the immune cells or give the immune cells to get out signals, and there is a clearance of the system and limit the inflammation. So there are totally two arms of, the process in the body. Imagine if we have unhealthy fat, then our enzyme system with the help of immune cells, then that unhealthy continuously, kind of feeds the chronic inflammation.
In contrast, if we have a healthy fat, then our immune system with the health help of this immune response to metabolic enzymes make the molecules, helps to clear the system. So that's how this process if it is really balanced, then we stay healthy. But if it is imbalanced, then leads to continuous chronic inflammation. But there is a very tight ordination of the fat, what we take every day, and the enzymes present in the immune cells, especially the leukocytes that determines the biosynthesis of those lipid mediators. And down the line, those lipid mediators, those are very important than the fatty acids actual fat in the diet and use the clear signal to our immune cells.
Mhmm. So we've got these lipid mediators that are super important for the inflammatory response, you know, how it's gonna initiate, how it's going to resolve. And in essence, it seems like there needs to be a balance of sort of two classes here, the the pro inflammation mediators and then the resolving mediators. And these have to do with things like dietary fatty acids. So we eat fat.
Certain certain fatty acids serve as precursors to these different lipid mediators. One one thing I wanna talk about here is this concept of balance versus imbalance that's gonna become important, I think. So is it is it true that if I have if I just if I just eat a bunch of fat, let's just say I'm not tracking it too closely. That's probably true for a lot of people. I'm not paying too much attention to the specific fatty acids I'm eating.
Seed oils, saturated fat, omega threes, you name it. I'm just sort of eating what I eat. Can't my body just make doesn't it just know how to make the perfect needed balance of these things, or does the balance of what's coming on coming into me from my diet really dictate whether or not there's going to be an imbalance? So have you ever heard that phrase? You are what you eat?
Yeah. I think there's some truth to that. So, we have to, again, get into the biology of this a bit, but the the enzymes that process omega six derived fatty acids or omega three, they're actually the same. The ones that that process omega three and six are the same enzymes. So it's it's called Alox five and five AP.
And those enzymes, can handle either one, the pro inflammatory, the proresolving, lipid precursor, you know, omega six or omega three. So as as with any enzyme, if you give it a substrate in excess, it's going to favor that, that substrate if it's got equal propensity to treat to to affect both. I see. So if you load your body up with omega sixes at a ratio of 30 to one or 25 to one, you know, your enzyme is gonna be more likely to convert that to a pro inflammatory lipid mediator than a proresolving lipid mediator. And that's kinda we think what happens where we have, you know, our diet is so over whelmed with, omega sixes.
You can't eat enough omega threes to balance it. The the the lipid mediators are evanescent, by the way. They they they get turned on off like you said. It's a temporal thing. It's very it's timed with inflammation.
And there's a certain time when these things come on. There's a certain time when they should go off. But the substrates are always floating around. Right? And and so there is a, there's a there's a nuance to the science here, understanding what the substrates are and then what the lipid mediators are and measuring both.
So if if if you look at and I looked at myself, I have a 13 to one ratio, for example. Ideally, it'd be one to one or two to one, favoring, you know, more towards the omega three. You'd like two two, omega six to one omega three. Yeah. But, like, I'm 13 to one, but the average American may be 25 to one or 20 to one.
Now if you look at the foods we eat, let's take beef, for example. Beef or or pork or anything of that nature, it's about 25 to 30 to one because the beef is grain fed. And you've heard of fattening the calf with grain using grain to fat. Well, that's why. It's basically, you know, this sort of carbohydrate rich diet that that, and and there may be, by by the way, maybe soybean oil in in, things like cattle feed.
I don't know for a fact. But if if they're if you're if you're getting a a grain fed animal, that's where the meat is now 25 to one, and you're you're getting every bread, that you eat or every, cookie or or piece of pie or whatever you're eating is loaded with, you know, basically, omega sixes, then your body's gonna see much more of that. So you are what you eat. I think you're gonna be flooding your your receptors and your enzymes with these, this this, inappropriate ratio. Yeah.
Now what can you do to correct that? You can, well, like, if you go to grass fed beef, the ratio is one to one. Yeah. Amazingly. And grass fed milk, one to one.
And grass fed butter, one to one. So just switching to grass fed, you know, animals and and milk can really help, because, you know, we many people do a lot of meat and butter and and, and milk. And, so that's that's one thing you can do. The other thing you can do is try to be, vigilant looking at labels and seeing what you're actually eating. Yeah.
Yeah. But you have to have a micro microscope to get the labels that when when you see so many ingredients, it's hard to actually find where the soybean oil is, but you can see it if you look very carefully. Yeah. Well, I mean, yeah, I think one of the places you know, one of the things implied here is, you know, it's it's not sufficient just to look at the total fat content. You've gotta actually go down at least one more level and say, how much is polyunsaturated, how much is saturated, and so forth.
There's a lot of literature. You know? We grew up, I would say, in the early days where it was butter and Crisco. My my grandmother was known to have made a, a, a jingle for Crisco. North, south, east, west, creamy Crisco is the best.
And, of course, we got away from all that because we realized that saturated fats were bad too in excess. Right? And they can cause heart disease. And then, then I think when when people moved over to margarine and things like that, maybe that helped heart disease to some degree. But, you know, when you go full spectrum and and put every food you have loaded with, these, these types of oils, Then you've changed the balance.
So you may have reduced the saturated fats, which is good, but you've you've increased the polyunsaturated to the inflammatory side, which can be bad. So, again, life is a balance, and eat eat in moderation is is the right approach. Do everything in moderation. Yeah. And so I I wanna get into the idea of balance more and really dig into some of the biochemistry before getting to the paper.
But just to tie off on some terminology because we're gonna have people listening with variable levels of of knowledge coming into this. So when you talk about so I wanna I wanna sort of make it clear for people. What are omega threes? What are omega sixes? When you guys talk about omega sixes, you're talking about certain polyunsaturated fatty acids that, come to us from our diet.
And, Tim, you know, a number of the things that you said, and I'll let you guys expand on this, but a number of the things that you said are the average American, the average westerner, probably the average person on planet Earth at this point, is getting an imbalance of omega sixes and omega threes. So we're getting way more omega sixes, most of us, compared to omega threes. Historically, in evolutionary terms, if we go back before industrialization back in time, most people are consuming a pretty balanced ratio of these omega threes and omega sixes. And these omega sixes are what people refer to as either vegetable oils or seed oils. Is that correct?
Yes. That's correct. That's correct. So what happened is kind of now our source of the kind of food intake is slightly changed. We moved from home cooked food to the processed and packaged food.
So that's the source. Then, from there, why the processed food industry will healthy use the healthy oil for your health. So the majority they use, the seed oils, which are much more, cheaper so that, they can mix more revenue, but that is costing to our health because of the presence. Now for that one, we will use the easiest way, the car analogy. So what happen if our car oil goes bad?
We go and take out the old oil and put the new oil. But here, in the human, we don't have that knob to take out the old oil. And even if we go switch to another healthy, but there at old oil, it's still there long time in the body. This is very simplified version of this. And, you know, for the to work the car perfect manner, you know, need a kind of sort of four wheels.
Same way happens into the fat. So the fat is the number one component that we take from the environment from different products. Then that get used by the enzymes which is present our in body. And then the third product is the lipid mediators. And once these lipid mediators are formed, then the last wheel is the receptor.
So the diet enzymes, lipid mediator, and receptors, those all are the four wheels, that makes or decides whether the fat is going to either helpful or harmful side. Now the first step itself, our body is fully loaded with the omega six continuously from the environment, then, obviously, it's driving towards the proinflammatory side. Obviously, it has no choice that the enzymes using that because of the abundance making more proinflammatory molecules and the receptor related to to the proinflammatory molecules, those are constantly activated. So the body is kind of going towards the proinflammatory. This is kind of super simplified version of very complex pathway because one single fatty acids, like omega three linoleic acids, gets to the arachidonic acid.
The arachidonic acid makes more than 20 to 25 molecules at the site of tumor or at the site of injury depending on the progression. So that's how the fat biology even it's very complex, but this is kind of very simplified version that how the imbalance of the omega six to omega three is kind of leads to that point of the chronic inflammation because of these key four components driving or feeding the chronic inflammation. Yeah. So I wanted Go oh, go ahead, Tim. I was gonna add to that that, you know, you can look at, omega six to omega three ratios and body fat.
And over the years from 1950 to more recently, there's been a tremendous rise in the omega six to omega three ratio in the in the Western population. And so that's, you know, prima facie evidence that you're taking more in and the diets have changed. Yeah. And so that that's a fact. And the other thing that's interesting is, fat when you eat fat, it can go everywhere in your body, basically.
So, there's a guy named Garth Nicholson who identified the, lipid bilayer, of the the cell membrane is, you know, two, two lipid, bilayers. Right? So, or two layers, a lipid bilayer. And phospholipids, right, compose this, the cell wall of all our cells. So those fats that you're eating get inserted into every cell in your body.
Yeah. And so of course of over course of decades of eating, you know, the wrong diet, you can imagine that all your cell walls have that makeup. Right? That constituency. The other thing that's interesting is, there is a enzyme called phospholipase a two, and that's an enzyme that releases, arachidonic acid from, the lipid cell wall.
And phospholipase a two is actually a a cardiac test for inflammation that you can actually get with Labcorp and Quest. You can measure your level of inflammation. And and I think it's it's different than measuring, c reactive protein that a lot of people use. Mhmm. So it's interesting.
How do you determine inflammation in the body? You know? One one one is to look at phospholipase a two levels. And if they're they're active in releasing arachidonic acid. And and, Tim, I want I'm gonna I'm gonna say here that I wanna come back to that maybe because one of the things that often gets brought up in this realm among aficionados or people who claim to be is there's some maybe gaps in the clinical literature where people will look for things like CRP or certain inflammatory markers, and they'll say, well, we don't really see a correlation between intake of these things and inflammation.
Inflammation meaning, like, the one marker they look for. I think what you're saying is you have to look for the right markers in the right places, in order to pick things up properly. Absolutely. And I think that, you know, plasma levels of things are different than tissue levels of things. Mhmm.
So people will look at plasma levels and say, well, I didn't see anything there. And but but if you look at the tissue, it's a different story. So I think the science is still in its infancy in in understanding lipidomics and and lipid speed. And it's a very con remember, people are complex and Right. Also remember there's heterogeneity.
So if you look at, you know, one person, another person, even our own data, we saw some people with sort of very high LTB four levels and some people with less high and some with lower levels. And you say, well, on on par, they were all elevated. But, why why is the heterogeneity there? What does that mean? Yeah.
Again, I don't I don't know yet. We're we're gonna look into it with more samples. It's certainly possible there's a threshold that you exceed. Like I said before, where you exceed a certain threshold of, like, LTP four, you're inflamed. Mhmm.
Or it may be that a really high level is is is worse than a really low level. Yeah. You know? We don't know yet. But but, clearly, there's an on par average median elevation of these things.
But okay. So let me see if I can tie some things together and maybe simplify a little bit and then dig into to what what if I'm hearing you guys correctly, so the key biochemistry for why certain things are true. So you've got omega sixes, you've got omega threes, you've got other types of fatty acids. But if we're just talking about the PUFAs, the polyunsaturated fatty acids, two big classes, omega sixes, those are what we mean refer to when we're talking about seed oils. Then you've got omega threes that's typically referred to, in as fish oil.
Omega sixes are gonna serve as the precursors to the pro inflammatory lipid mediators most of the time. The omega threes are basically gonna serve as the precursors to the resolving lipid mediators. And so you want these things in balance. And the and it it sounds like it really does matter what your balance is on the intake side, your fatty acid intake, the food you're eating, and its fat content. Because when these things are the reason these things go out of balance, I think, ties to what you said, Tim, which is they have the same the same enzyme is responsible for processing both of them.
And so they're sort of like this this rate limiting thing or this funnel where if you've got an imbalance on the intake side, then you're gonna produce more of the one class of lipid mediators on the output side of that enzyme because it's the same enzyme processing both the omega sixes and the omega threes. And so you're unfortunately, your you know, it it would be great if your body could just take an arbitrary set of fatty acids and then make exactly everything in perfect balance. But based on this biochemical, limit here on how these enzymes work, that's not the case. And so your your intake really needs to be balanced, if I'm hearing you correctly. In supporting that, there are some studies that are very interesting.
You know, we, insurance companies have used, you know, LDL levels and say, we get your LDL level below a hundred, and that's healthy. Yeah. Get your HDL level up a little bit. That's healthy. But I don't know whether everybody's ever used omega six to omega three ratios.
Mhmm. And and it might be a better index of health, because there are studies that, show that a higher omega six to omega three ratio in plasma is linked to increased mortality risk from all causes. Cancer, cardiovascular disease, individuals have the highest ratios and have had a twenty six percent higher risk of mortality and a fourteen percent higher cancer mortality. So there you know? And there's some confusion on this.
Some recent studies where some some cancers show a lower, incidence with higher ratios, like like breast cancer, but it's a small. It's like a decreased eight percent. So I, a lot more a lot more works needs to be done here, but the concept that omega six to omega three ratio might, be important, indicator of health, I think, is something needs to be explored. Mhmm. Mhmm.
And go ahead, Ganesh. Were you gonna say something? Yeah. I I just wanna point out that, as already Kim mentioned, like, you know, you are what you eat. But, again, there is slightly more than that there.
So when you eat, what you eat and how much you eat. So those are getting granular because, down the line, your you know, everyday biology in context of circadian rhythm contributing to that component. And that's where it is coming to the point that when these lipid mediators form using the processed fat And, sometimes people think that, hey. Those are absolutely kind of these seed oils are bad, but one point we just need to understand their name. They call as essential fatty acids.
Means they are absolutely essential into one to 3% for the initiation of inflammation when there is injury or infection because those molecules are the one gives a signal to our immune cells. Hey. There is a problem. Come over there. So those in wide the immune cells, that is there.
Yeah. Here is the what happening is that they are continuously giving that signal. Hey. Come here at the site of the tumor. Here party is going on.
Ganesh, you said I think you said that the the omega sixes are necessary at one to three percent. What did you mean by that one to 3% of calories? One to 3% in terms of, their, depending on the growth curve. If you are in the adult phase, then probably in the, one to 3% in terms of the, kind of how much, you are taking as the in the in the form of the grams, how much you are taking in the diet. I see.
Yeah. So grams. So so a tiny percentage should be Yeah. Tiny percentage. Tiny percentage.
And and that also needs to kind of, club with how much you are active, versus what's your sleeping pattern. So Yes. Those all three components necessary for the activity of the enzymes. Missionary, what the team was mentioning, that because this missionary process both the omega three and omega six in response to injury Mhmm. Or or the kind of tumor where there is a continuous chronic inflammation where the lipid mediators are formed that we have quantitated by using very state of the art, mass spectrometry.
Yeah. But, you know, it's oh, go ahead, Tim. I wanna get back to, you know, what's what's healthy and what's not healthy. So, you know, we think a balanced ratio of omega six to omega three in your plasma, a balanced ratio in your food, therefore, makes the most sense. Close to one to one is possible.
And, again, the UK Biobank study of 86,000 patients found increases in all cause mortality and cancer mortality and heart cardiovascular disease increased with the increased omega six to three ratio. So that's really good evidence. But if you go the opposite direction, let's say you really remember, omega sixes are essential fatty acids. You have to have them to live. Yeah.
But it's the question of how much. Right? But if you go the opposite direction and try to reduce your ratio from one to one to one to four, in other words, four on the omega, three side and one on the omega six side. That's very hard to do. But, apparently, the Inuits of Alaska, have set sort of ratio, and they have a high risk of heart disease.
So if you imbalance it the other way, you may actually increase problems too. So it's this balance, this life balance that doctor Hialati often talks about Yeah. Is is important. Yeah. And so getting to the question so we talked about sort of the biochemical reason why balance makes sense and one to one makes sense because the omega sixes, omega threes kinda get processed by the same enzyme.
And in some sense, you might say that the body is expecting balanced input. And so I I wanna ask if that's true. And so if we think about this from an evolutionary perspective here, is is it would you say it's accurate or reasonable to say that for most of human history before we started industrialization when we were, you know, out out in the wild, so to speak, except in extreme environments, perhaps, like where the Inuit lived, Tim, that in most natural environments, humans were just we were intaking a one to one ratio of mega sixes to mega threes because that was what was more or less naturally present in the environment. It was only after we started creating synthetic environments, industrial environments, or, you know, and maybe extreme cases where some people moved up to the Arctic where you got this imbalance of omega six and omega three inputs. Yeah.
Abs you're absolutely right. So modern agriculture, big agriculture has tried to mass produce foods at a lower cost. And, so you're right. In in in those days, I'm sure that all, beef was grown on grass and and had this one to one ratio. And I hear that, it takes about three years to bring a steer to to market on grass fed versus maybe one year on grain fed.
So there's an economic advantage to go with the grain feeding. And and that and that's where we've gone. But the same things too with these other oils. It's a lot cheaper to put in, canola oil, which has horrendous processing to get there from seed. If you actually read and and look how it's actually processed, or soybean oil or cottonseed oil or sunflower oil versus an olive oil or avocado oil.
Those are more expensive. So, you know, we've we've put these cheaper oils into things and tried to promote the idea that omega sixes are healthy. But in fact, just this imbalance has has it did everything now. So you can't go overboard, and we have, in all our foodstuffs. Yeah.
Yeah. Yeah. One thing happened is that our kind of food source is changed, and that is shifting the omega six to omega three. But at the same time, what happened, we have really kind of our whole lifestyle becomes more sedentary. So it so we increase our pro inflammatory input in the body, but same time we become sedentary.
Another one confounding factor is added that we are less sleeping. So that kind of what we may ask, like, okay. What is the connection of these two components? One, that is kind of because of the proinflammatory input, the body is kind of moving towards the obesity, and that kind of correlate to the kind of number of high cases of the cancer. And the component, the lesser, these both the components actually impacting the your the enzymes which processes the fat, whether it is omega three or omega six.
Then if your enzymes become weak because either overabundance or your sedentary lifestyle or you are not sleeping on time, that leads to obviously what happened, that whatever intake you are taking, your machinery to process the fat is already cramped, weak. So the quality of mediators will be a very, fragile or totally collapse or distrope. And that's why whatever you are eating, it's not getting cleared or whatever the debris is from different sites in the body, that is not clear. That is the kind of primary function of the immune cells when you are sleeping as a patrolling different immune cells, going at different sites, find out the wear and tear and clear it. So that's how kind of hold the immune system and the fat.
They have very tight coordination every single day and find out where is the debris, how it can be cleared with the help of those four components, the fat, enzymes, lipid mediators, and the receptors. And they work as a very precise type fashion so that they can clean the body and maintain the health. Yeah. And then so so, you know, one of the themes here, I think, is that, there are multiple points of variability here or where the the potential for inflammation can be altered. So one is just what's the total amount of fatty acid substrate you have to work with to begin with?
And that gets into the this idea of the omega six, omega three balance in terms of our fat the fat component of our diet. But also, Ganesh, as you're saying, you know, there are other factors that determine the extent to which true inflammation will come from that, potential. And that, you know, that ties into things like lifestyle, how much are you moving, how sedentary are you, how much stress is there, what are your sleep patterns like. All of that will tune, the extent to which that inflammatory potential from the omega sixes actually then gets turned into bona fide inflammation in the body. Nick, you're you're describing systems biology.
So systems biology is the the concept that, we're not you just can't look at one molecule, one cell in isolation. You have to understand how everything is orchestrated as a system. And that when you perturb the system, it's like the butterfly effect sometimes. You can perturb many different things. And I've always thought that, you know, genetic engineering was interesting.
Right? I actually wrote a paper years ago, Egypt in the year February, and and this was a paper written in '76 predicting the use of genetic engineering in agriculture. But, the reality is that when we put a single gene into a cell, do we really know what effect that one protein produced by that gene or knocking out a gene is doing on the other 20,000 genes and a 50,000 proteins. Are there subtle changes in patterns we don't know that can relate that can stimulate autoimmunity in the body, for example. And all of a sudden your your body's recognizing, you know, a form of wheat that, is not natural in a sense that it there's a genetic.
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