Nick speaks with Dr. Isaac Harris about the biology of antioxidants and oxidative stress. Harris shares his lab’s recent work showing that breast cancer tumors catabolize extracellular glutathione to acquire cysteine and support growth. The conversation explores how reactive oxygen species (ROS) arise in metabolism, the central role of glutathione as a natural antioxidant, why high-dose antioxidant supplements can backfire, and emerging strategies that target cancer’s reliance on antioxidant systems.

TOPICS DISCUSSED:

• Oxidative Stress: Reactive oxygen species (ROS) generated by mitochondrial metabolism cause damage; context determines whether they promote or suppress cancer.

• Glutathione Biology: Primary cellular antioxidant made from cysteine, glycine, and glutamate; works with peroxidase enzymes to protect against ROS.

• Antioxidant Paradox: Clinical trials (SELECT vitamin E, beta-carotene) showed supplements increased cancer rather than preventing it.

• Cancer Antioxidant Hijacking: Tumors ramp up antioxidant systems to handle high metabolic rates and survive stress including metastasis.

• Extracellular Glutathione Catabolism: Cancer cells break down external glutathione into amino acids, particularly cysteine, to fuel growth (new findings).

• Therapeutic Window: Blocking glutathione breakdown slows tumors in models while sparing normal cells.

• Diet vs Supplements: Balanced diets support glutathione needs; excess isolated antioxidants may enrich the tumor microenvironment.

ABOUT THE GUEST: Isaac Harris, PhD is a biologist working on the role of antioxidants in health, disease, and cancer metabolism.

RELATED CONTENT:

• M&M 229: Linoleic Acid, Seed Oils, mTOR & Breast Cancer | Nikos Koundouros & John Blenis

KNOW YOURSELF:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners, including products to help you measure and manage your health.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

PRACTICAL TAKEAWAYS:

• Obtain amino acids like cysteine through whole-food protein sources rather than isolated antioxidant supplements.

• Exercise caution with high-dose vitamin E, NAC, or glutathione supplements, especially with a cancer history.

• Prioritize evidence-based metabolic approaches over blind antioxidant megadosing.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Summary of main points:

• Frying in beef tallow vs. seed oils will expose you to a very different cocktail of potentially hazardous substances.

• French fries cooked in seed oils strongly predict weight gain in large human data, more-so than all other other foods, yet this was downplayed in publication.

• Polyunsaturated fats are inherently unstable: heat + oxygen generates toxic byproducts (4-HNE, acrolein, trans fats) that soak into food; saturated fats resist oxidation.

• Animal studies: Ω-6 PUFA-rich soybean oil diet causes more weight gain, adiposity, and fatty liver than beef tallow, plus unique liver B1 depletion and oxylipin-driven effects.

• Human trials are too short and poorly controlled to fully settle the question.

• Choosing beef tallow fries over traditional fries isn’t going to transform your health as much as making more consistent changes: eating out less and avoiding industrial foods generally, which are high in macros like Ω-6 PUFAs and fructose.

Does it matter if potatoes are fried in beef tallow or seed oils?

Questions like this have entered popular culture, prompted by the political ascension of Robert F. Kennedy Jr. and a renewed interest into questions of healthy fats. Fast food chains line Steak ‘n Shake have made headlines by announcing transition to beef tallow for frying.

Since the mid-20th century the “mainstream” view in the US—the view held by most large health institutions, physicians, and many other “health experts”—is that saturated fats are basically bad and should be moderated or minimized; polyunsaturated fatty acids (PUFAs) are “heart healthy” and should be encouraged, as they decrease cholesterol.

As detailed here, the mainstream “consensus” view is neither organic nor a true scientific consensus—it arose from a confluence of political, social, and economic interests aligning between entities in the academic, private, and non-profit sectors. The “marketplace of ideas” was artificially tilted in favor of Dr. Ancel Keys’ diet-heart hypothesis and away from contradictory evidence from people like Dr. George Mann. That “tilt” corresponded to biases in who got NIH grants (Keys and “heart mafia,” including this guy), and who was not funded.

What did those people do with that funding? More studies, sometimes often minimizing the prominence of any results that highlight a possible connection between Ω-6 PUFAs and bad health outcomes. As thoroughly documented here, some of these researchers blatantly misrepresent clinical trial results in the papers they write today. In their own studies, they appear to go out of their way to downplay anything that might make PUFAs look bad.

This classic Mozzafarian paper was published in the prestigious New England Journal of Medicine back in 2011. It’s been cited over 3,500 times—very high for an academic paper. It has all the features that would make an LLM select it as a high-quality piece of scientific evidence.

The paper looked at a large dataset of >100,000 US adults. They basically analyzed how a bunch of lifestyle factors correlated with weight change over time, including different foods.

The whole point of that study was to identify which foods best predict weight gain. Suspiciously, they neglected to mention the single food that had, by far, the strongest association: French fries. The association was stronger for French fries than any other food, including potato chips and mashed potatoes. Fries are boiled in seed oils and showed the strongest association. Chips often contain added seed oils and showed a smaller, but still strong, association. Boiled, baked, and mashed potatoes do not typically contain added high-PUFA oils, and showed a much smaller association than even chips.

How are French fries made? By boiling potatoes in seed oils! Chips often contain added seed oils and showed a smaller, but still strong, association. Boiled, baked, and mashed potatoes do not typically contain added high-PUFA oils, and showed a much smaller association than even chips. But the abstract states that, “4-year weight change was most strongly associated with the intake of potato chips, potatoes, [and other foods.” It doesn’t call out French fries at all, even though they had by far the strongest association.

That’s odd, isn’t it? This article unpacks the data in more detail.

Learn more about suspicious behavior in nutrition science:

• Article | How to Lie With The Science: AI, Academic Expertise & Nutritional Narratives

• Podcast | How to Lie With Science: Seed Oils & Inflammation

Why are French fries today, and virtually everywhere at the time of the above study, deep-fried in seed oils rather than beef tallow, as they originally were?

Two synergistic reasons for this: soybeans and other crops have been heavily subsidized, making them cheaper to produce; that surplus generates the impetus for companies to market soybean and related products as “healthy.” Soybean oil is big a business today. Ω-6 PUFAs are in most processed foods. The single most abundant Ω-6 PUFA in the industrial food supply, linoleic acid, represents around 6-10% or more of caloric intake for the average person today (US estimate).

Think about that: roughly one in ten of the calories consumed today come from a molecule that represented a <1-2% of calories for most of evolutionary history.

One of the “current things” is fast food chains like Steak n’ Shake starting to use beef tallow to fry their french fries, instead of seed oils. Will deep frying potatoes in beef tallow instead of seed oil make a difference for your metabolic health?

Before moving on, let’s briefly review and settle on some basic terminology around dietary fats. Commonly used terms like “seed oils,” “vegetable oils, and “animal fats” are often thrown around with imprecision, sometimes intentionally abused in academic papers to obscure the results that show differences in outcomes based on fatty acid profiles.

After that, we will consider what happens to different dietary fats when exposed to what and oxygen (as in a deep fryer), comparing the toxins that may be produced to what we see in cigarette smoke. We will then go through preclinical and clinical literature looking at the effects of “fresh” dietary oils on obesity, adiposity, and liver health.

(Note: many fast food chains use oil blends in their fryers. These often include seed oils such as soybean, but in some cases including things like high-oleic oils, with much more MUFA content than most seed oils. The specific blends vary by restaurant chain.)

Avoiding Confusion on Dietary Oils: Think in terms of dominant fat profile

If you can teach yourself to think primarily in terms of fatty acid profiles, you can avoid confusion from inconsistent use of terms like “seed oils,” sometimes intentionally deployed by academics to misrepresent study results.

The key difference between oils is in their fatty acid profile. Instead of trying to memorize chemistry nomenclature or the names of dozens of fatty acids, simply think in terms of which general class of fatty acids is the most abundant in any given oil: PUFAs (polyunsaturated fatty acids), MUFAs (monounsaturated fatty acids), or SFAs (saturated fatty acids).

How basic fatty acid profiles relate to common cooking oil terms:

• PUFA-dominant oils include most “seed oils,” such as soybean oil. The most abundant fats in them are Ω-6 polyunsaturated fatty acids (PUFAs), like linoleic acid.

  • By default, “seed oils” are PUFA-dominant, rich in linoleic acid (Ω-6). There are exceptions. Canola oil is a seed oil, but is MUFA-dominant like olive oil, not PUFA-dominant like most seed oils. “High-oleic” seed oils have also been engineered—MUFA-dominant, not PUFA-dominant.

  • The term “seed oils” should really refer to PUFA-dominant oils, regardless of whether or not they are literally derived from plant seeds.

• MUFA-dominant oils predominate in monounsaturated fatty acids (MUFAs). Like PUFA-dominant oils, they are a mixture of different fatty acids.

  • This profile tends to be seen in “fruit oils” and is characteristic of genuine olive and avocado oil.

  • Many commercial fruit oils may not be MUFA-dominant, as many companies use adulterated oils in their products. Similar to drug dealers diluting pure product with cutting agents, “olive oil” at the store may be cut with cheaper, PUFA-dominant seed oils (see M&M 116).

• SFA-dominant oils have higher saturated fatty acid (SFA) content than unsaturated fats (MUFAs or PUFAs).

  • This profile is commonly associated with “animal fats,” including beef tallow. It’s perhaps better to think of SFA-dominant fats as “red meat fats” (see below).

  • Coconut oil is a major exception to the rule, as it’s a plant fat high in SFA. Likewise, many non-ruminant animal fats today, such as pig and chicken fat, predominate in unsaturated fats because of the grain-based diets they are fed.

In the studies below, we will see data comparing dietary oils of each type. The specific oils used in the studies below often include:

• Corn oil or soybean oil, which are PUFA-dominant oils displaying the classic “seed oil” profile (rich in Ω-6 PUFA), even if not literally derived from seeds.

• Olive oil will be the MUFA-dominant oil.

• Beef tallow will be the major SFA-dominant animal fat, rich in saturated fat.

Before reviewing studies on how different oils affect animals and humans, let’s consider how heat + oxygen exposure affects saturated versus unsaturated fats.

Learn more about lipid peroxidation and cellular health:

• Article | Burning Down the House: Lipid Peroxidation, Oxidative Stress & Cell Death

• Podcast | Cell Death, Oxidative Stress, PUFAs & Antioxidants | Pamela Maher

Polyunsaturated fatty acids (PUFAs) are inherently unstable chemical compounds, much more prone to non-enzymatic oxidation than monounsaturated or saturated fats. “Non-enzymatic oxidation” basically means heat + oxygen results in burning of a PUFA molecule, yielding reactive and often toxic byproducts, not unlike the fumes emitted by a burning campfire or combustion engine.

PUFAs can be oxidized “on purpose” by enzymes in the body to generate ATP. At some rate, the PUFA in your cell and mitochondrial membranes will be non-enzymatically oxidized (burned “on accident”) by reactive oxygen species. The extent to which this happens depends on your antioxidant capacity, oxidative stress burden, and PUFA tissue density. If those things are off-balance, PUFAs will undergo lipid peroxidation more often, creating cell toxins that drive cellular dysfunction and even cell death.

In the context of French fries, PUFAs are oxidized before entering the body, producing nasty byproducts. This includes trans fats, which everyone agrees are terrible, as well as reactive chemicals you will also find in cigarette smoke: acrolein, 4-HNE, and so on. Evidence shows that, “these toxins penetrate into and hence are ‘carried’ by fried foods available for human consumption.” In other words, those toxic chemicals will soak into potatoes that have been placed into a vat of boiling oil.

Don’t get lost in the details. Oxidation of PUFAs in a deep fryer will produce all kinds of nasty, toxic chemicals. Saturated fatty acids do not produce the same oxidation byproducts as PUFAs. Even if those PUFAs are not pre-oxidized in a kitchen prior to consumption, they can oxidize within your cells later on. To some extent, this can and will change the potential oxidative stress burden of your tissues, as described in much more detail here.

For most of the animal research out there, the effects of various diets, such as those using soybean oil (PUFA-dominant) or beef tallow (SFA-dominant), are done using “fresh” oils that haven’t been deep fried. We will examine studies where subjects were fed two or more diets, each with one the fat profiles above, where weight gain, liver fat, or similar aspects of metabolic health were measured.

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Pros & Cons of Animal Studies vs. Human Clinical Trials

Animal studies have the advantage of better experimental control, including the use of isocaloric diets and precise measurement of body composition and organ-specific nutrient status. A major disadvantage with animal studies is that we can never be sure that the results, on their own, will generalize to humans.

Human studies have the obvious advantage that humans subjects are used rather than animals, but often suffer from their own issues, such as:

• Short duration, lasting just a few weeks, rather than many months or years that would make for better comparison to studies in shorter-lived species.

  • Many diet-induced effects in animals take several weeks or more to play out, corresponding to many months or years in “human time” due to the non-linear scaling laws the define the relationship between body mass and metabolic rate across species.

  • Similarly, effects in animal studies can move in different directions over the course of weeks, before stabilizing. This would again correspond to a much longer time period in humans, beyond the length of most clinical trials.

• Less strict diet control.

  • Many human trials do not strictly control food intake, but instead rely on indirect and less rigorous estimation of food intake. Multiple dietary variables often differ between groups. For example, PUFA and saturated fat content might differ between groups, but carbohydrate levels or other factors also differ, preventing clear interpretation of what drives outcomes.

The animal and human studies below usually compare the effects of different fats without frying them first. We’re not looking at situations directly comparable to what we encounter with French fries from fast food joints. Instead, we’re comparing the effects of “fresh” oils which, in the case of PUFAs, have not been thoroughly oxidized prior to consumption.

With that in mind, past and upcoming animal research as shown clear and significant differences in the metabolic effects of isocaloric diets with distinct fatty acid profiles, such as beef tallow versus soybean oil-based diets. We will focus on studies that looked at overall body fat composition and weight gain, as well as liver health.

After reviewing animal studies, we will look at human trials, asking whether or not the results are in agreement and why.

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Animal Studies: High Ω-6 PUFA + Low Ω-3 + High Fructose Promotes Fatty Liver Disease

“Fatty liver disease” used to be called “alcoholic fatty liver disease” because it was seen almost exclusively in adults after many years of alcohol abuse. Today, fatty liver disease is common in young children.

My general take is that high fructose load in the liver, promoted by a combination of high fructose intake and low fiber ingestion, elevates oxidative stress in the liver. If that liver contains lots of fat with high PUFA content, you get more lipid peroxidation, producing toxins that damage cells. (Lipid peroxidation results from peroxidation of polyunsaturated fatty acids, not other fatty acids).

From a macronutrient standpoint, the modern “industrial diet” is characterized by exactly that combination: High Ω-6 PUFA, high fructose, low fiber. Thus, we are seeing more oxidative stress in the livers of children even they haven’t been slamming vodka for years. To the extent that fatty liver disease is promoted by lipid peroxidation in the liver, we would expect to see less fatty liver disease with lower Ω-6 PUFA density in the liver, even after exposure to substances that elevate oxidative stress.

In animals, that’s generally what is seen.

A diet with very high linoleic acid (Ω-6 PUFA) produces more body weight gain and just as much fatty liver as one that is higher in both saturated fat and fructose. This effect takes >9 weeks to emerge in mice, which roughly corresponds to over 1-2 years in “human time.”

In the preclinical literature, a great macronutritional recipe for generating fatty liver disease is “high-fat + high-fructose.” Although fatty liver can be promoted with sufficiently high levels of other fats, the most effective fatty acid profile for promoting fatty liver in animals is a Ω-6 PUFA-dominant profile, with very little or no Ω-3. Introducing Ω-3s at even a 5:1 or 2:1 ratio favoring Ω-6s can reduce or prevent fatty liver.

Note: Most people today have Ω-6:Ω-3 ratios well above 5:1; you can test your levels with the fatty acid test listed here.

High Ω-6 PUFA + high fructose + low Ω-3 PUFA produces more lipid peroxidation and fatty liver disease when animals are exposed to elevated oxidative stress from substances like alcohol or acetaminophen.

Examples:

• In rats, a high Ω-6 PUFA + high fructose diet (with very low Ω-3) readily induces fatty liver disease. Substituting some Ω-3 PUFAs for linoleic acid (Ω-6) results in much lower fatty liver.

• In rats given high-dose acetaminophen (Tylenol) to induce oxidative stress, PUFA-dominant corn oil drives more liver injury than SFA-dominant (beef tallow) or MUFA-dominant (olive oil) diets.

• Compared to a diet high in saturated fat + ethanol, a diet with PUFA-dominant fat from corn oil + ethanol drives more liver injury.

• In rats fed intragastrically for precise diet control, saturated fat from beef tallow and MCT oil protected against alcoholic liver disease. The worst alcohol-induced liver pathology was seen with an Ω-6 PUFA-dominant fat profile from corn oil.

• In rats, replacing Ω-6 PUFA fat from corn oil with saturated fats from coca butter or MCT oil protected against alcohol-induced liver injury over 8 weeks. A corn oil (Ω-6 PUFA)-based diet produced the most ethanol-induced liver fat accumulation and inflammation.

• In mice, soybean oil drives more obesity and diabetes than coconut oil (saturated fat) and fructose, under isocaloric conditions. Fructose did not drive as much obesity and diabetes, but did drive a very fatty liver.

The studies above lasted anywhere from 6-32 weeks. Roughly speaking, this works out to between five months and ~2-3 years in human terms. Most human trials do not last that long, will less strict dietary control.

Upcoming research discussed on the podcast has replicated the basic effect of Ω-6 PUFA diets on weight gain and fatty liver, adding an additional wrinkle: Ω-6 PUFA-dominant diets can also lead to malnutrition in the liver.

Learn more about how Ω-6 PUFAs can impair liver function:

• Article | Fructose, Fiber & Lipid Peroxidation: How to Protect Your Liver & Metabolic Health

• Article | Seed Oils & Body Fat: ω-6 PUFAs Cause Obesity & Fatty Liver

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Animal Studies: Seed Oils & Liver Malnutrition

M&M 269 with Dr. Frances Sladek is excellent, covering her research on how soybean oil (PUFA-dominant) affects liver and gut health in animals. A very brief summary of what she shared:

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Nick Jikomes speaks with Richard Johnson about the distinct metabolic pathways of glucose and fructose and the central role of fructose in driving metabolic disease. Johnson presents his fructose survival hypothesis, arguing that fructose metabolism evolved to help animals prepare for periods of food scarcity by promoting fat storage, foraging behavior, and insulin resistance. Key concepts include the liver’s first-pass metabolism of fructose leading to ATP depletion and uric acid-driven mitochondrial oxidative stress, the separation of sugar craving from metabolic effects, and how chronic activation of this pathway in modern environments contributes to obesity, fatty liver, and Alzheimer’s-like brain changes.

TOPICS DISCUSSED:

• Glucose vs Fructose Metabolism: Fructose is rapidly metabolized in the liver by fructokinase without feedback, causing ATP depletion and uric acid production, unlike glucose metabolism.

• Liver Effects: Fructose induces uric acid production, NADPH oxidase activation, mitochondrial oxidative stress, and de novo lipogenesis even under caloric restriction.

• Fructose Survival Hypothesis: Fructose signaling promotes fat storage, leptin resistance, foraging behavior, and metabolic syndrome as adaptations for hibernation or starvation, including metabolic water production.

• Brain Impacts: Endogenous fructose production from glucose (polyol pathway) triggered by high glucose, salt, or stress leads to insulin resistance, mitochondrial damage, and neuroinflammation in Alzheimer’s-vulnerable regions.

• Evolutionary Context: Human uricase mutation ~12 million years ago enhanced fructose effects for fat storage during seasonal starvation but increases vulnerability today.

• Modern Triggers: Added sugars, high fructose corn syrup, salt-sugar combinations, and omega-6 fats synergize with fructose to amplify inflammation, appetite, and disease risk.

• Alzheimer’s Link: Fructose-driven brain changes mirror Alzheimer’s pathology, with high brain fructose in patients and potential for fructokinase inhibitors as therapy.

ABOUT THE GUEST: Richard Johnson MD, is a professor of medicine who has conducted clinical practice and NIH-funded research on sugar metabolism since the late 1990s. His work focuses on the role of fructose in metabolic syndrome, obesity, and related diseases.

RELATED CONTENT:

• Article | Dietary Fructose & Metabolic Health: An Evolutionary Perspective

• M&M 249: Fructose, Microglia, Anxiety & Brain Development | Justin Perry | 249

KNOW YOURSELF:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners, including products to help you measure and manage your health.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

PRACTICAL TAKEAWAYS:

• Prioritize cutting liquid sugars and high fructose corn syrup, as they deliver rapid liver loads causing ATP depletion and uric acid spikes.

• Reduce high glycemic carbs, especially when salted, and limit alcohol to minimize endogenous fructose production via the polyol pathway.

• Favor whole fruits in season over processed foods, recognizing natural fiber and seasonal limits help buffer fructose effects.

• A ketogenic approach can block both glucose and fructose survival pathways, reducing metabolic drive toward fat storage and insulin resistance.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick speaks with Dr. Floyd Chilton about dietary polyunsaturated fats and human genetic variation. Chilton presents evidence that ancestry-linked differences in fatty acid desaturase enzymes create “big pipe” versus “small pipe” metabolic pathways, leading to profound variation in oxylipin production and disease susceptibility. Key concepts include the massive rise in linoleic acid consumption since the 1960s, competition between omega-6 and omega-3 pathways, and why one-size-fits-all recommendations on seed oils may harm certain populations more than others.

TOPICS DISCUSSED:

• Linoleic Acid Rise: Linoleic acid now comprises 6-8% or more of energy in Western diets.

• Metabolic Pathways: Omega-6 linoleic acid converts to arachidonic acid and pro-inflammatory oxylipins; omega-3 ALA converts via shared enzymes to EPA/DHA with anti-inflammatory effects.

• FADS Genetic Variants: Ancestry-linked haplotypes in the FADS cluster create large “pipe” size differences, altering fatty acid by up to 40% between ancestral and derived versions.

• Population Differences: African ancestry populations often have high-conversion “big pipe” genotypes; Indigenous American ancestry populations have low-conversion “small pipe” genotypes; European ancestry comes with a mix of both.

• Omega-3 Deficiency: High linoleic intake suppresses EPA production, especially in small-pipe populations, contributing to hypertriglyceridemia and fatty liver in Mexican cohorts.

• Clinical Evidence: Reanalysis of VITAL trial showed 83% reduction in myocardial infarction with omega-3 supplementation in African Americans; Mexican data link low EPA to unique diabetes forms.

• Methodological Issues: Compositional data (from GC-FID measurements) versus absolute concentration measurements can flip relationships between linoleic acid and key biomarkers.

ABOUT THE GUEST: Floyd Chilton PhD is Professor and Director of the Center for Precision Nutrition and Wellness at the University of Arizona. His research focuses on functional genomics, fatty acid metabolism, and precision nutrition, particularly how genetic ancestry influences responses to dietary fats.

RELATED EPISODE:

• M&M 291: Omega Polyunsaturated Fats & Inflammation | Philip Calder

KNOW YOURSELF:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners, including products to help you measure and manage your health.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

PRACTICAL TAKEAWAYS:

• Reduce linoleic acid intake where possible by minimizing seed oils and ultra-processed foods to help balance omega-6 vs. omega-3 pathways.

• Prioritize direct EPA/DHA sources like fatty fish or high-EPA supplements, especially if you have Indigenous American or mixed ancestry.

• Consider genetic testing for FADS variants to better understand your metabolic tendencies.

• Focus on whole-food eating with oils low in omega-6 fats and fish rather than relying solely on seed oil-based polyunsaturated fat guidelines.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick speaks with Dr. Sherwood Brown on the steroid hormone pathway and neurosteroids. Brown details the biosynthesis of steroids from cholesterol to pregnenolone, pregnenolone’s direct actions as a positive NMDA modulator and negative CB1 allosteric modulator, and his placebo-controlled trials showing antidepressant effects in bipolar disorder. They also examine corticosteroids’ impact on hippocampal volume and memory, hormone fluctuations across the female lifespan, and emerging research on neurosteroids for mood and substance use disorders.

TOPICS DISCUSSED:

• Steroid Biosynthesis: Cholesterol converted to pregnenolone, the precursor for all steroid hormones including cortisol, aldosterone, and sex hormones.

• Corticosteroids: Synthetic versions like prednisone primarily target glucocorticoid receptors for anti-inflammatory uses but can impact mood and cognition.

• Pregnenolone Mechanisms: Positive allosteric modulator of NMDA receptors for cognition and negative allosteric modulator of CB1 cannabinoid receptors.

• Allopregnanolone: GABAergic derivative of pregnenolone; its IV form Brexanolone is FDA-approved for postpartum depression.

• Clinical Trials: Pregnenolone at 100-500 mg improved depressive symptoms in placebo-controlled studies of bipolar disorder patients.

• Cannabis Interaction: THC robustly induces brain pregnenolone production; supplementation may reduce cannabis and alcohol use.

• Corticosteroid Brain Impact: Prednisone use associated with smaller hippocampal volumes and memory deficits.

ABOUT THE GUEST: Sherwood Brown, MD, PhD is Vice Chair for Clinical Research in the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas. With a background in chemistry, his research focuses on steroids and comorbidities in people with mood disorders.

RELATED EPISODE:

• M&M 124: Hormonal Contraception, Sex Hormones, Menstruation, Pregnancy, Puberty, Estrogens, Androgens, Effects of Birth Control on Cognition | Adriene Beltz

KNOW YOURSELF:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners, including products to help you measure and manage your health.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

PRACTICAL TAKEAWAYS:

• Pregnenolone is sold as an OTC supplement and has been studied at doses of 100-500 mg with good tolerability in mood disorder trials.

• Corticosteroids for conditions like asthma can cause measurable, often reversible changes in hippocampal volume and memory.

• Cholesterol is essential for producing all steroid hormones including those supporting brain function and mood.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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M&M written content is human-created, independently researched, and filled with resources to deepen your learning. Click here to see all the ways you can support this work.

Summary of main points:

• Fructose is non-essential: the body produces it endogenously via the polyol pathway

• The question of whether some dietary fructose is beneficial requires asking what zero consumption looks like.

• The essential/non-essential distinction doesn’t settle the question: taurine, CoQ10, and glutathione are all non-essential yet supplementation provides clear benefit, particularly against oxidative stress and lipid peroxidation.

• Too much fructose is well-established as harmful: liver ATP depletion, de novo lipogenesis, uric acid formation, oxidative stress, impaired brain development, and enhanced tumor growth—all dose and context-dependent.

• Hereditary Fructose Intolerance (HFI) is a rare autosomal recessive disorder in which Aldolase B deficiency causes F-1-P to accumulate, leading to ATP depletion, hypoglycemia, lactic acidosis, liver damage, and potentially death.

• HFI as a natural experiment: children maintained on strict zero-fructose diets from birth offer a rare window into whether any dietary fructose is actually necessary for normal development and health.

From minerals like copper and zinc to essential macronutrients like dietary ω-6 and ω-3 fats, the relative balance of nutrients if often a key factor in how our biology is impacted by what we consume.

Not too much, not too little.

But exactly how much is too much, and how little is too little? For any given nutrient, the answer depends on whether it’s essential or non-essential, the balance of other things it’s consumed with, and your overall state of health (age, disease status, etc.).

Essential nutrients are those our body cannot synthesize itself and must be obtained from diet. ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) are examples. For essential nutrients, we know how much is too little: zero. Unlike non-essential nutrients, we must consume some amount of essential nutrients to ensure adequate intake for the body’s needs.

Determining how much is adequate and how much is too much can be a bit trickier. For ω-6 and ω-3 PUFAs, here’s my answer: a few grams of each per day is more than enough, ideally in a balanced ratio. As I’ve covered extensively, there are benefits to getting ω-6 intake down to ~3% of calories or less. (Normal intake for modern people is 10% or more).

What about non-essential nutrients?

By definition, the body can make its own. Does that mean there is no additional benefit to consuming these things, so long as the body is equipped to produce what it needs? Nope. There are plenty of examples where supplementation of non-essential or “semi-essential” nutrients provides benefit. Even when endogenous production exists, it is often constrained by other factors or diminishes with age.

Examples of nutrients that are not strictly essential, for which intake or supplementation can provide benefit:

• Taurine can be synthesized from cysteine but declines with age. Supplemental taurine has shown benefits, such as lifespan extension, in a wide range of species.

• Coenzyme Q10 is endogenously synthesized within mitochondria, but declines is age, statin use, and certain diseases. Supplementation can provide benefit. Most people do not consume natural food sources, like organ meat.

• Glutathione is powerful endogenous antioxidant made from glutamate, cysteine, and glycine. Levels decline with age and oxidative stress, but there is benefit to supplementing it or precursors such as glycine and NAC.

Those are not the only examples and were partly chosen because each also helps protect the body from the toxic effects of oxidative stress and lipid peroxidation. Protecting the mitochondria of neurons from oxidative stress and lipid peroxidation may even be the core metabolic function of sleep.

In fact, everywhere you look, protecting tissues from lipid peroxidation seems to be one of best ways to protect health. For example, the dietary fiber inulin protects the liver from lipid peroxidation, in part by boosting antioxidant systems like glutathione, and by limiting fructose load in the liver, which increases oxidative stress.

As covered in the following content, too much fructose can drive a variety of problems:

• High-fructose during early life impairs brain development in mice, leading to anxiety-like behaviors in adolescence. [M&M 249]

• High-fructose diets enhance cancer tumor growth in adult mice. [M&M 215]

• Fructose can enhance the palatability of foods, favoring more consumption. Excess fructose intake favors fat synthesis and storage. [M&M 185]

In animals, we know clearly that diets high in either ω-6 fats (“seed oil fat”) or fructose can drive obesity and fatty liver.

Too much is clearly a problem, especially in the concentrated forms common in processed foods devoid of fiber. Sugar-sweetened beverages are a major source, and clearly involved in this unfortunate, human-created trend:

Fructose is a non-essential nutrient. The body can produce fructose endogenously, as a side effect of glucose metabolism. But is there any clear benefit to consuming some dietary fructose?

One way to come at a question like this is to ask what the effects of zero consumption are. Are there any clear downsides from zero consumption, as there are for essential nutrients?

As it turns out, there’s a rare congenital disease of metabolism in which children cannot tolerate fructose. Those children need to be put on zero fructose diets in order to avoid serious adverse reactions and death. What is this disease and how do children placed on zero fructose diets look health-wise? Do they have any obvious health problems?

Learn more about fructose metabolism:

• Podcast | Metabolic Effects of Oxidative Stress in Development & Neurodegeneration Disease | Robert Lustig

• Article | Fructose, Fiber & Lipid Peroxidation: How to Protect Your Liver & Metabolic Health

Hereditary Fructose Intolerance

Hereditary Fructose Intolerance (HFI) is a rare disorder of metabolism. Symptoms usually start in infancy when fruits, juices, or sweetened foods are first introduced. It’s autosomal recessive: two faulty copies need to be inherited, one from each parent.

In HFI patients, typical reactions after fructose intake include:

• Nausea, vomiting, abdominal pain, bloating, diarrhea.

• Hypoglycemia (low blood sugar), sometimes with lethargy or faintness.

• Over time: poor growth, enlarged fatty liver, liver and kidney dysfunction, and, if untreated, possible liver failure or death.

A more detailed version of the simple diagram above, is below.

Don’t get lost in all the details. Just notice that excess glucose can be turned into fructose. From there, fructose turns into F-1-P, a substance the Aldolase B enzyme can act on. The ALDOB gene is mutated in HFI, leading to enzyme deficiency in the liver and other organs. Fructose from any source, endogenous or dietary, will lead to accumulation of F-1-P in tissues due to Aldolase B enzyme deficiency.

F-1-P accumulation leads to:

• Depletion of ATP and inorganic phosphate

• Inhibition of gluconeogenesis and glycogenolysis, leading to hypoglycemia (low blood sugar)

• Disturbances such as lactic acidosis, hypophosphatemia, hyperuricemia, and liver cell damage

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On M&M 272, Dr. Robert Lustig talked about how this condition often presents early in life, when parents don’t know about it ahead of time:

When you are missing this enzyme [Aldolase B], you can’t convert the fructose all the way to pyruvate. And what happens is you end up hypoglycemic. So these are babies who are born normal—look fine, everything’s good. They’re eating breast milk or formula (doesn’t matter). And then they get their first taste of juice at four months to six months, somewhere in there.

All of a sudden, they have a seizure at home and the parents go ballistic and they go crazy and they called 911 and the paramedics come and they check a glucose, you know, by glucometer and the kid’s got a blood glucose of five, when it should be seventy.

And so they give the kid glucose by IV and they show up in the emergency room. And then the doctor is trying to figure out what the hell happened to this baby that the blood glucose was five and that the seizure occurred. And depending on how long the seizure occurred depends on how many neurons the kid lost. Because these kids invariably end up severely retarded because of the insult that they took, just a disaster. And some of them die because of it.

F-1-P accumulation from the genetic inability to metabolize fructose is obviously bad. Even in normal people, without Hereditary Fructose Intolerance, excess fructose can cause problems, including acute ATP depletion in the liver, as well as uric acid formation and oxidative stress. In the context of a high-PUFA diet, this can be recipe for lipid peroxidation and cell death, which is what advanced fatty liver disease looks like.

Anyways, we already know that excess fructose is problematic. Fructose intake is deadly serious for those with Hereditary Fructose Intolerance (HFI). Nowadays, the parents of those born with this metabolic dysfunction often know about it early. The solution is a fructose-free diet.

The question for us here: when kids are born with HFI but parents know about it ahead of time, keeping them on a strict no-fructose diet, what happens? Beyond saving them from the problems of congenital fructose intolerance, are there any issues which might be attributed to lack of dietary fructose?

Do kids who grow up on zero fructose diets have problems? Learning disabilities? Metabolic dysfunction?

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M&M written content is human-created, independently researched, and filled with resources to deepen your learning. Click here to see all the ways you can support this work.

Summary of main points:

• Glucose and fructose are chemically similar but metabolically distinct. Fructose metabolism has different consequences, with fewer regulatory checkpoints.

• High hepatic (liver) fructose load → ATP depletion, uric acid production, de novo lipogenesis, and oxidative stress.

• New research: dietary inulin (an indigestible fiber) stimulates gut microbes to catabolize fructose before host absorption, reducing hepatic fructose load and reversing insulin resistance and fatty liver in mice.

• Inulin also boosts glutathione, protecting the liver from lipid peroxidation—connecting fiber intake directly to antioxidant defense.

• High fructose + high ω-6 PUFAs (seed oils) + low fiber is the Western diet in a nutshell— a recipe for fatty liver and metabolic disease.

• To minimize fatty liver: minimize fructose from non-fibrous sources, minimize dietary ω-6 PUFAs, ensure adequate fiber (inulin) intake, and support antioxidant and lipid peroxidation detox systems (e.g. taurine, NAC, glutathione, CoQ10, etc).

Fructose is a sugar named for being abundant in fruit. Fruit is widely considered a quintessential healthy food, but we also constantly hear about the dangers of added sugars, including fructose. In just the past couple of years on this podcast, we have heard about new research showing negative health effects of fructose, including:

• High-fructose during early life impairs brain development in mice, leading to anxiety-like behaviors in adolescence. [M&M 249]

• High-fructose diets enhance cancer tumor growth in adult mice. [M&M 215]

• Fructose can enhance the palatability of foods, favoring more consumption. Excess fructose intake favors fat synthesis and storage. [M&M 185]

So… is fructose bad? But fruit is good for you? What’s going on?

Learn more about the biology of fructose metabolism:

• Article | Dietary Fructose & Metabolic Health: An Evolutionary Perspective

• Article | Fructose, Corn Syrup & Cancer

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Biological Context & Metabolic Diversity

To understand biology in general and your own health specifically, you have to internalize that it’s about balance, tradeoffs, and context. The essence of biological systems is homeostasis, the maintenance of conditions—temperature, salinity, and so forth—within the narrow ranges conducive to life. To maintain homeostasis, living organisms are composed of tissues, cells, and sub-cellular systems integrated together in complex, nested feedback loops that sense and respond to changes in the environment. This of course includes sensing and responding to whatever is ingested.

The effects of what we ingest depend of context. You and I might consume the exact same things, but experience different outcomes. There might be intrinsic metabolic differences between us. Perhaps we differ in fatty acid metabolism, so our cells process dietary fats in different ways; or perhaps we belong to distinct mitochondrial haplogroups, so our tissues exhibit distinct patterns of energy flow, even in response to identical inputs.

There will also be extrinsic differences between us, based on our life history. Even if we were identical twins separated at birth, different life circumstances may have led one of us to stay lean and metabolically healthy, while the other became obese and insulin resistant, despite identical genetics.

Another way that context matters when it comes to what we consume: the exact same substance can have distinct effects, within the same individual, depending on whatever else was co-ingested with it.

Three types of context to keep in mind for this post.

• Environmental context is the physical environment you’re in, what we normally mean when we talk about “context.” All of the factors in your environment generally.

• Diet or consumption context includes all of the things you consume, such as food and pharmaceutical drugs. Two people might occupy the same physical environment but consume different sets of substances.

• Tissue context is the the general state of your tissues. Two people can occupy the same physical environment and consume the same substances, but if their tissues have a distinct compositions, outcomes may differ. Tissue context can dynamically change within an individual, on shorter timescales, based on current physiological state (e.g. stress level, hormones, etc.)

These contexts are not mutually exclusive. They partially overlap and are nested within one another. Environmental context sets limits on what the diet/consumption context and therefore tissue context can potentially be. It’s useful to distinguish between these things, however, as different people can differ from one another at each level.

Within a single individual, the composition of your tissues can change slowly over time, in response to other contextual factors, such as what you eat. The physiological state of your tissues, and how they react to inputs from the consumption or general physical environment, can also change more quickly, on the timescale of of hours, minutes, or even seconds. The specific biological context that a stimulus enters with regard to your body will have a big impact on the response to evokes.

This post will unpack how one dietary substance, the sugar fructose, can have distinct effects depending on its dose and what else it’s consumed with. In particular, fructose consumed in the presence of absence of dietary fibers like inulin can change what happens to that fructose in the gut, how much of it gets absorbed, and what happens within key metabolic organs such as the liver.

Two important distinctions to always keep in mind:

• What goes into your mouth is not necessarily what goes into your cells.

• When absorbed, glucose and fructose have different metabolic consequences.

Recall that “sugar” often refers to sucrose, common table sugar. Each molecule of sucrose is one molecule of glucose attached to one molecule of fructose. Every time you consume sucrose, you will digest it into equal parts glucose and fructose, which are chemically very similar. Despite that similarity, the metabolic consequences of glucose and fructose are very different.

Before the metabolic differences can be realized, those glucose and fructose molecules have to be absorbed into the body. How does dietary context influence how much of those sugars get absorbed? We will focus on fructose, considering low versus high doses, with and without dietary fiber present.

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Fructose Absorption & Metabolism Basics

Unlike glucose, which can be metabolized for ATP production by virtually any cell in the body, fructose is metabolized by few cell types. The two major “fructolytic” cell types that are:

• Enterocytes of the small intestine

• Hepatocytes of the liver.

(Note: There are other cells that can metabolize fructose. Fructose can also be produced endogenously, as a consequence of metabolizing other things. However, most exogenous, dietary fructose will be metabolized by small intestine enterocytes or the liver hepatocytes.)

With smaller doses, fructose will be metabolized largely in the small intestine by enterocyte cells. Microbes in the gut can also catabolize (breakdown) fructose. So, if you eat a small amount of fructose, much of it will be metabolized within the gut and won’t enter general circulation or make it to he liver.

With larger doses, intestinal capacity eventually saturates. Most remaining fructose will be metabolized by the liver. With sufficiently high fructose intake, the majority of dietary fructose is metabolized in the liver. A diagram to give a sense for fructose metabolism within intestinal enterocytes and liver hepatocytes, and roughly how much dietary fructose is metabolized in each:

Don’t get too hung up on exactly what a “low” or “high” dose of fructose is. Instead, think of different foods relative to one another, in terms of their total fructose content and physical structure. Imagine consuming one of three things:

• One whole orange

• One glass of orange juice (no pulp)

• Multiple cans of soda

The single orange will likely have the lowest overall sugar content, perhaps 12 or so grams of sugar, fructose being about half of that. Much of it will get metabolized in your gut, with a fraction making it to the liver. With a whole orange, the fibrous food matrix will slow absorption compared to juice or sugar-sweetened beverages, lessening the “metabolic load” placed on liver hepatocytes (more on that below).

Now consider a glass of orange juice. Even if it had the exact same sugar content as the whole orange, the lack of fiber or a solid food matrix means that the liver will end up having to metabolize more fructose, faster. For a metabolically healthy person, this may be nothing to worry about. For someone with metabolic syndrome, this isn’t so great, even if it doesn’t feel bad in the moment. Fatty liver disease plays out over years and decades.

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Last, consider multiple cans of Dr. Pepper. Each contains around 40 grams of high-fructose corn syrup (HFCS), which means ~55% is fructose. That’s over 20 grams of fructose, or well over 40 grams for two cans. There’s no fiber or anything else to slow down absorption. Your small intestine enterocytes may be able to handle much of the fructose in the first can, but probably not all of it. After a couple of cans, you’re looking at a much larger dose of fructose, without anything to slow absorption. The liver will therefore have to metabolize more fructose, faster, relative to the other diet contexts.

If you think about how patterns of intake differ between people and add up over time, it will be no surprise that more and more young children are being diagnosed with fatty liver disease over time. Understanding why fructose can contribute to fatty liver disease requires understanding the consequences of fructose metabolism in the liver.

Learn more about the latest research on the effects of high fructose diets:

• Podcast | Fructose, Microglia, Anxiety & Brain Development | Justin Perry

• Podcast | Cancer Metabolism: Sugar, Fructose, Lipids & Fasting | Gary Patti

Liver Fructose Metabolism & Its Consequences

A recent review paper contains a wealth of information on what is known about fructose metabolism. The paper puts fructose metabolism in evolutionary context, similar to this article.

The “fructose survival hypothesis,” in a nutshell:

Fructose probably provided an evolutionary advantage by activating a ‘survival pathway’ that increased hunger, stimulated foraging and promoted efficient fat storage—traits that helped early hominids endure periods of famine. In modern environments with constant food availability, this once-beneficial mechanism can contribute to metabolic disease. Six boxes show fructose effects that were probably evolutionarily beneficial but are now problematic (for example, increased caloric intake, elevated systemic pressure). The final two boxes show overtly pathological modern consequences.

Understanding biology in evolutionary context can help explain why things are set up the way that they are, beyond the mechanics of how things work. Understanding the evolutionary history of genes related to fructose metabolism will help you make sense of the ways that fructose and glucose metabolism differ, such as why fructose metabolism drives ATP depletion, de novo lipogenesis, and uric acid formation.

A compact list of the major ways that liver metabolism of glucose and fructose differ:

A series of short excerpts from that review paper, to give a sense for how fructose and glucose metabolism differ, with some concrete observations about timing and dose:

In contrast with glucose, fructose metabolism is not tightly regulated by insulin or feedback signals…

Although seemingly paradoxical—an energy substrate depleting ATP—this reflects initial ATP-consuming steps outpacing downstream ATP generation. This occurs because of the rapidity of the reaction and because there is no regulatory feedback to slow the reaction to preserve ATP levels…

Fructose-induced ATP depletion has been demonstrated in the livers of individuals taking fructose orally (75 g) as measured by magnetic resonance spectroscopy, as well as intravenously using lower doses. ATP typically recovers within 1 h. This effect is most severe in pericentral hepatocytes and is not observed in mammals similarly administered glucose…

Both intracellular and serum uric acid levels rise rapidly—within 15 min to 60 min—following fructose ingestion, coinciding with a drop in intracellular ATP levels…

Isotope studies document that as much as 25% of fructose is converted to lactate; other major fructose fates are resynthesis into glucose and glycogen, glycerate generation and oxidation in the liver.

Glucose metabolism is more tightly regulated than fructose metabolism. There are more “checkpoints” for the body to “decide” what to do with the glucose it encounters, and far fewer for fructose.

Why would each type of simple sugar be subject to vastly different levels of regulatory control? For most of evolutionary history, dietary fructose came only from whole fruits, which needed to be actively foraged. Outside of the tropics, fruit availability is seasonal and often highly sparse. This stands in stark contrast to the present-day ubiquity of concentrated liquid fructose.

Our lineage never had extended periods of survival and reproduction in the presence of the fructose levels found in the modern food environment. Our livers were never under pressure to evolve mechanisms to cope the high doses that people are exposed to today. The human body is therefore not “expecting” more than a relatively modest intake of fructose, due to the mismatch between what our bodies evolved to deal with and what is now readily available.

The concentration and dose of fructose one consumes determines the pattern of fructose absorption and metabolism your body experiences—including your liver, the body’s main detox organ.

As we mentioned, the physical food matrix that fructose is ingested with, including its fiber content, has a big impact on fructose absorption. How exactly does fiber have this impact?

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Dietary Fiber: Major Factor in Sugar Absorption

The food matrix that a substance is consumed with or embedded in determines how the body processes it. A clear example is how dietary sugar is absorbed when consumed in the presence versus absence of indigestible fiber. In short, the presence of fiber tends to prevent or at least slow the absorption of simple sugars like fructose.

(Note: “fiber” is a generic term, covering multiple, distinct fiber types. Here, the term “fiber” should be taken as a general term for all indigestible fibers. Where applicable, I will refer to specific fibers, such as inulin, below. The term “fiber,” like many other dietary terms, gets thrown around liberally, as if all fibers are the same. Different fibers are different, just like different fats and carbohydrates. Always keep this in mind.)

If you eat a meal with lots of physical stuff, including fiber, it’s no surprise that it will take more time to absorb specific substances, including fructose. There’s just a larger mass of matter for the body to digest. This was something Dr. Robert Lustig discussed on M&M 272:

Our livers have an innate capacity to be able to metabolize some [alcohol], but when you overdo it, you get into problems. Same thing with fructose…

Fruit has fiber and the fiber actually limits the fructose absorption from the gut into the bloodstream in the first place. So really when you’re consuming fructose from fruit, you’re really basically providing that fructose to your bacteria, not to your liver.

But how, exactly, do specific types of dietary fiber affect fructose metabolism? Do they physically bind to fructose, preventing its absorption? Do they block fructose from going through the portal vein to the liver?

The latest animal research shows that the fiber inulin promotes the gut microbiome to break down incoming fructose, before it has a chance to be absorbed and metabolized by host (animal) cells.

Inulin Promotes Microbiome Catabolism of Fructose Prior to Absorption

Inulin is a plant fiber found is certain vegetables, such as chicory root, artichokes, onion, garlic, asparagus, and some potatoes. Bananas are the most notable fruit source, although they contain lower levels than high-inulin roots and tubers.

Like all dietary fibers, inulin is a complex carbohydrate that our own cells cannot digest into simpler sugars. Inulin is a “fructan-type polysaccharide,” a carbohydrate made mainly of repeating fructose units, usually ending in a single glucose.

A simple graphic to illustrate inulin’s structure compared to glucose (G) and fructose (F), from this paper:

Basic findings of the study:

• “In male mice, the gut microbiome, when adapted to dietary fibre inulin, catabolizes dietary fructose and mitigates or reverses insulin resistance, hepatic steatosis and fibrosis.”

• “Inulin s­up­pl­emen­ta­tion, without affecting the host’s small intestinal fructose catabolism, promotes the small intestinal microbiome to break down incoming fructose, thereby decreasing hepatic lipogenesis and fructose spillover to the colonic microbiome.”

• Inulin also activates hepatic de novo serine synthesis and cystine uptake, augmenting glutathione production and protecting the liver from fructose-induced lipid peroxidation.

In other words, when inulin is present in the diet, it stimulates fructose metabolism by specific microbes in the gut. This means less fructose goes to the liver, with less lipogenesis (fat production) and fructose “spillover” to the colon, all without preventing catabolism of fructose by small intestine enterocytes. The presence of inulin could mitigate and even reverse insulin resistance and liver disease.

Two important things of note:

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Nick speaks with Dr. Bill Harris, a researcher on omega-3 fatty acids and the scientist who developed the Omega-3 Index — a red blood cell biomarker that expresses EPA and DHA as a percentage of total membrane fatty acids. Dr. Harris explains why most people in the West have low omega-3 status, why the conversion of plant-based ALA to EPA and DHA is too inefficient to rely on, and what the epidemiological evidence suggests about optimal intake for heart and brain health. The conversation also covers how omega-6 fatty acids, fatty acid ratios, and omega-3 intake from whole food sources versus supplements.

TOPICS DISCUSSED:

• ω-3 chemistry: EPA and DHA differ from plant ALA in chain length and double-bond count, making them structurally and biologically distinct — and largely irreplaceable by ALA conversion.

• ALA-to-EPA/DHA conversion: A small percentage of dietary ALA converts to EPA, and conversion to DHA is even lower; vegans rely on this inefficient pathway for all long-chain omega-3s.

• Cardiovascular mechanisms: ω-3s lower triglycerides, reduce platelet stickiness, improve endothelial function, and slow resting heart rate, reducing cardiovascular risk.

• ω-3 Index: Defined as red blood cell EPA+DHA as a percent of total fatty acids; 8–12% is the target range, while most Americans sit around 4–5%.

• Brain & dementia risk: Higher DHA blood levels are associated with significantly lower risk of dementia and Alzheimer’s in large cohorts including the UK Biobank and Framingham.

• Linoleic acid nuance: Higher blood levels of dietary linoleic acid (omega-6) associate with lower dementia and cardiovascular risk; downstream omega-6 metabolites — not linoleic acid itself — associate with adverse outcomes.

• Supplementation practicalities: Most people need 1–2 g/day of EPA+DHA to reach an Omega-3 Index >8%; oxidation concerns with fish oil supplements may be overstated.

ABOUT THE GUEST: Bill Harris, PhD is founder of both OmegaQuant Laboratory and the Fatty Acid Research Institute (Sioux Falls, SD), where his work centers on blood fatty acid biomarkers as predictors of disease risk in large population cohort studies.

RELATED EPISODE:

• M&M 134: Omega Fats, Vegetable & Seed Oils, Sugar, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Disease | Artemis Simopoulos

KNOW YOURSELF:

• OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners, including products to help you measure and manage your health.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

PRACTICAL TAKEAWAYS:

• Aim for 1–2 g/day of combined EPA+DHA from fatty fish or high-concentration fish oil supplements; most Americans consume less than 200 mg/day, far below what large trials show to be beneficial.

• Test your Omega-3 Index (OmegaQuant, ~$55 finger-stick kit) before assuming your intake is adequate — target 8% or above and retest as needed, waiting 3-4 months after making lifestyle changes.

• Plant foods like flaxseed, chia, or other plant ALA sources alone may not be sufficient to meet your EPA and DHA needs; the conversion rate is too low to achieve adequate levels of EPA+DHA.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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M&M written content is human-created, independently researched, and filled with resources to deepen your learning. Click here to see all the ways you can support this work.

Summary of main points:

• The modern industrial food environment has created an excess of ω-6 PUFAs (“seed oil fat”) relative to ω-3 PUFAs.

• ω-6 and ω-3 PUFAs compete for the same enzymes and cannot be interconverted, so dietary intake ratios determine tissue PUFA composition in cell and mitochondrial membranes.

• Inflammation occurs in three phases (initiation, propagation, resolution), each regulated by ω-6 and ω-3-derived lipid mediators; ω-6:ω-3 imbalance doesn’t trigger inflammation directly; it dysregulates the response, altering its magnitude and duration.

• The “ω-6 = pro-inflammatory, ω-3 = anti-inflammatory” framing is too simplistic; both classes can contribute to inflammatory and resolving phases, with the specific mixture at each phase determining outcome.

• Many clinical trials on dietary fats and inflammation are poorly designed: no standardized inflammatory stimulus, no baseline tissue PUFA measurements, and ω-6/ω-3 interventions routinely conflated in meta-analyses.

• Average American linoleic acid intake (10% or more of calories) has risen dramatically over the modern era, with adipose tissue linoleic acid content rising.

• High linoleic acid intake lowers plasma EPA without raising ARA — it skews the ARA:EPA ratio by suppressing the ω-3 arm of the shared enzymatic pathway, not by boosting the ω-6 arm.

• Multiple human trials confirm reducing linoleic acid intake (from ~7–10% to ~2–4% of energy) consistently raises EPA (ω-3), even when ω-3 intake is held constant.

• Linoleic acid is bioactive, not just caloric — it signals through the mTOR complex and alters gene expression in ways linked to breast cancer and dysregulated colon tissue inflammation.

• The industrial food ecosystem simultaneously promotes high ω-6 seed oil consumption and ω-3 supplement use, while the underlying biology shows the former suppresses the latter.

“Essential fats” are those we must eat to obtain, as our cells cannot synthesize them from scratch. Omega (ω) polyunsaturated fats are examples. Two major classes of omega fats, with major examples of each:

• ω-6 polyunsaturated fatty acids (PUFAs)

  • Linoleic acid, the plant ω-6 that predominates in most seed oils (“seed oil fat”).

  • Arachidonic acid (ARA), an animal ω-6 more common in animal fat.

• ω-3 polyunsaturated fatty acids (PUFAs).

  • α-linolenic acid, a plant ω-3.

  • EPA and DHA, animal ω-3s (“fish oil fat”).

Omega fats serve as structural components of the lipid membranes of our cells and mitochondria. They also have functional effects, as they can be converted into various signaling molecules that affect cell behavior, ranging from the regulation of appetite to inflammation.

ω-6 and ω-3 PUFAs are non-interconvertible and share many of the same metabolic enzymes. You can’t make ω-3 PUFAs from ω-6 PUFAs or vice versa, and they effectively “compete” with one another for processing. The same enzyme can convert a dietary ω-6 PUFA into a different ω-6 PUFA, and it can do the same for a dietary ω-3 PUFA, but it can’t do both at the same time. These are key aspects of PUFA biology that many fail to grasp. Unlike non-essential molecules, the human body cannot synthesize PUFAs to fit its needs.

All of these features of ω-6 and ω-3 fats play into why dietary balance has important health consequences. Intake patterns determine how much ω-6 and ω-3 PUFAs are available to our cells, and therefore the relative abundance in cell and mitochondrial membranes, which also determines the pattern of molecular signals produced from these fats and therefore how our cells response to stimuli.

The balance of all fatty acids, including non-essential fatty acids like saturated and monounsaturated fats, has important structural and functional consequences for cells. This post will focus specifically on ω-6 and ω-3 PUFAs in the context of inflammation, and how high intake of linoleic acid (ω-6, “seed oil fat”) affects the ω-3 PUFA conversion pathway, thereby increasing the need for ω-3 intake.

Imbalances in these fatty acids lead to dysregulation of inflammation, which is not the same thing as saying that simply consuming these fats triggers inflammation directly.

Learn more about the basics of dietary fatty acid biology & human consumption patterns over time:

• Article | Eating Fat Like Never Before

• Podcast | History of Diet Trends & Medical Advice in the US | Orrin Devinsky

Inflammation Regulation & Dysregulation by Dietary Fats

A major aspect of cell behavior affected by the relative balance of ω-6 and ω-3 fats is the regulation of inflammation, which was discussed in M&M 291 with nutritional immunologist Dr. Philip Calder.

Note: there is not a singular “inflammatory response.” Inflammation can be triggered in a variety of ways, involving various complex mechanisms that play out over time.

Inflammation can be thought of as generally occurring in three phases: initiation, propagation, and resolution. Each phase is actively regulated by complex signals, including dynamic lipid signals that evolve over time following an inflammatory stimulus, such as tissue damage or infection.

Some of the key regulators of the inflammatory response are ω-6 and ω-3-derived lipids (fats). Dietary intake of omega fats determines the size and composition of the pool of lipid starting materials from which these inflammation regulators are produced.

An imbalance in the dietary intake of ω-6 and ω-3 fats can lead to dysregulation of inflammation. Dysregulation is an important concept to understand.

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A biological process becomes dysregulated when its normal controls become impaired or abnormal in some way. When a complex, dynamic biological process has become dysregulated, the way it plays out changes. It’s normal constraints have shifted to some extent. In the case of inflammation, this means it’s spatial and temporal strength and duration will be altered, if an appropriate inflammatory insult triggers the process to start.

One way that a process can become dysregulated is when there is an imbalance of key molecular mediators of the process. ω-6 and ω-3 lipids function as mediators of inflammation, with their relative balance helping to control the magnitude and duration of the initiation, propagation, and resolution phases.

Here is a conceptual diagram which will help you think about these three phases of inflammation, and how ω-6:ω-3 imbalance can lead to dysregulation of the process.

Unfortunately, things aren’t as simple as “ω-6 = pro-inflammatory” and “ω-3 = anti-inflammatory.”

Complex mixtures of ω-6 and ω-3-derived lipids regulate how inflammation is turned on and turned off. The function and composition of the lipid pools changes dynamically over the course of the inflammatory response. The same lipids can be involved in both the pro-inflammatory and resolving side of the equation, with the specific mixture of different lipid mediators at each phase shaping the duration and magnitude of the inflammatory response.

Hundreds or even thousands of lipid signaling molecules can be found in mammalian cells. Those interested in learning more about the complexity, and the experimental science of lipidomics are referred to M&M 200 (an excellent episode).

The diagram above should help you to appreciate how homeostatic regulation (maintaining conditions within a certain range) depends on the proper balance of molecular signals—in this case, ω-6 and ω-3 fats. Remember: these fats are not synthesized endogenously (in animals), so their relative balance is determined by dietary intake.

When the mediators of the inflammatory process are reasonably balanced, the magnitude and duration of the inflammation is big enough to take care of the problem and then shuts down, restoring things to their normal physiological range in a timely manner, with minimal collateral damage. If the process becomes dysregulated, because there’s a strong imbalance between pro-inflammatory and pro-resolving (anti-inflammatory) mediators, hyperinflammation and/or immunosuppression can result.

The process can play out in a regulated or dysregulated fashion. In either case, a triggering stimulus, such as tissue damage or infection, must kick things off. Dysregulated inflammation can play out if there’s an imbalance in ω-6 and ω-3 mediators, but only if the process is triggered in the first place. Many people fail to grasp this, including those who design simplistic clinical trials (which are abundant).

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In order to properly study the effects of dietary fat imbalances on inflammation, one needs to carefully control a variety of factors, beyond just dietary fat ratios—proper measurement of tissue fat profiles before, during, and after dietary interventions, together with proper control of inflammatory stimuli to trigger an inflammatory response, are needed. For example, it is not sensible to simply measure serum markers of inflammation (e.g. CRP, NF-kB, etc.) across dietary conditions without also carefully introducing a well-controlled inflammatory stimulus, accounting for individual tissue lipid concentrations, and so forth.

Dr. Calder put it this way in M&M 291:

Nutrition science, in the last ~10-15 years, and increasingly so, is producing a lot of systematic reviews and meta-analyses. Those approaches are very valuable if you want to collate a whole lot of literature and try and come to the “real answer.” And part of the reason is many trials don’t have the statistical power to find the effect that you imagine might be there. But by collating them, you get a much bigger sample size. So that’s an advantage.

But unfortunately, in our discipline, people mix up not just the apples and pears, but they mix up the apples, pears, and oranges. So this is super frustrating. I think you should only meta-analyse [trials] with the same study design. You should only meta-analyze the same intervention.

So I think there are things where people, for example, might meta-analyze the effect of polyunsaturated fatty acids [in general, including ω-6s and ω-3s separately]. That doesn’t make any sense to me, because we’ve got omega-6, we’ve got omega-3, we’ve got plant omega-3, we’ve got fish omega-3. We don’t think they all work the same. So why would you put them all together?

… this is a great cause of frustration for me, that people are not being sensible about the study selection.

Listen to M&M 291 if you want to learn more about the regulation of inflammation by omega fats. For now, let’s turn to how dietary linoleic acid (ω-6) affects conversion of ALA into EPA (ω-3), and how the modern ω-6-rich industrial ecosystem is set up to promote ω-6 intake in the form of seed oils and processed foods, while simultaneously driving demand for ω-3 supplements, all under veneer that dietary PUFAs are always healthy, more is better, and the shortest path to health is to recurrently purchase and consume industrial products engineered by experts.

Learn more about lipid dysregulation in human health & disease:

• Article | Seed Oils, Early-Onset Cancer & Human Metabolic Variability

• Podcast | Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

High linoleic acid (ω-6) intake suppresses EPA (ω-3)

The modern industrial food environment is characterized by overabundance of ω-6 PUFAs (largely from seed oils) relative to ω-3 PUFAs. As discussed in M&M 291, the average American today gets perhaps ~10% of their calories (or more) from the ω-6 PUFA linoleic acid, which amounts to roughly 15-18 grams per day.

This intake pattern has come with an increase in the linoleic acid density of human fat tissue over time. In other words, people not only got much fatter over time, but that fat become more and more abundant in ω-6 PUFAs.

Something telling you see in the discourse of dietary fats is that “experts” will simultaneously tell you that ω-6 fats from seed oils are heart healthy and anti-inflammatory, and that ω-3 fats are also heart healthy and anti-inflammatory. To defend this, they cite reviews and meta-analyses of clinical trials that routinely fail to control for the factors mentioned above, often lumping ω-6 and ω-3 fats together as “polyunsaturated fats,” all while measuring serum markers of inflammation without including well-controlled inflammatory triggers, measuring baseline or tissue PUFA levels, etc. Some of the most highly cited scientific defenders of this worldview have long-standing financial ties to seed oil and processed food giants.

As mentioned above, the underlying biology here involves “competitive” and often functionally distinct effects from ω-6s and ω-3s, the balance of which determines how inflammatory responses play out. When clinical chauvinists cite the clinical literature without having a firm, mechanistic grounding of the underlying biology, they’re unable to properly evaluate whether the trials themselves were rigorously designed.

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The same people who will tell you that ω-6 seed oils have no ill health effects and can be consumed to your heart’s desire will simultaneously tell you that ω-3s are critical for health, that you’re probably not consuming enough, and you should supplement with something like fish oil to boost ω-3s.

But guess what? Linoleic acid intake affects ω-3 levels in humans and animals. The more linoleic acid (ω-6) consumed, the lower the tissue levels of ω-3s like EPA tend to be. A recent clinical trial in healthy adults compared a low linoleic acid diet (2.5% energy), to a high linoleic acid diet (10% of energy, similar to what many Americans consume).

The high linoleic acid (ω-6) diet led to a decrease in plasma EPA (ω-3) and a higher ratio of arachidonic acid (ω-6) compared to EPA (ω-3), even though arachidonic acid (ω-6) levels themselves were stable in both groups. This suggests that linoleic acid (ω-6) interferes with the production of EPA (ω-3) from other dietary ω-3s. The results make sense when you consider the enzymatic pathway that converts dietary PUFAs to longer-chain PUFAs, remembering that ω-6s and ω-3s compete for access to the same enzymes in this pathway.

Again, look at the enzymatic pathway above and think of this as a competitive interaction. Linoleic acid is a dietary ω-6, ultimately a precursor to ω-6 arachidonic acid (ARA), not to ω-3 EPA. Higher linoleic acid intake does not elevate ARA levels, but does lower levels of ω-3s like EPA. Thus, increasing intake of linoleic acid (ω-6) increases the ARA:EPA ratio and overall ω-6:ω-3 ratio, not be increasing downstream ω-6s, but by lower EPA (ω-3).

The ability of high linoleic acid intake to interfere with endogenous conversion of ω-3 fats was discussed in M&M 291. Other human trials have shown similar effects:

• In chronic headache patients, decreasing linoleic acid (ω-6) intake from 7.4% to 2.4% of energy intake decreased linoleic and arachidonic acid (ω-6) levels in red blood cells, while increasing EPA + DHA (ω-3). (Lowering the ω-6:ω-3 ratio also reduced headache pain).

• In healthy men, decreasing linoleic acid (ω-6) intake from 10.5% to 3.8% energy, with constant ALA (ω-3), increased EPA (ω-3) in plasma phospholipids.

• Since the early 1990s, the effects of dietary ALA (ω-3) and linoleic acid (ω-6) have been observed to influence tissue levels of longer-chain PUFAs in a similar fashion.

These human studies are consistent with work in experimental animals, providing mechanistic detail that helps us understand the biological basis for this pattern. In rats, a low linoleic acid (ω-6) diet increases serum and liver levels of ω-3s by upregulating the expression of elongase and desaturase enzymes that convert dietary PUFAs into longer-chain PUFAs.

(Side note: in rats, estrogen also affects the expression of these enzymes, suggesting that hormone levels and sex differences likely play a role in how dietary fats influence tissue PUFA biology. These are also variables that human clinical trials often fail to control for).

It’s important to remember that linoleic acid and its derivatives act as a signaling molecules. For example, linoleic acid can directly interact with the mTOR complex, leading to dysregulated mTOR signaling and breast cancer in rodents. Linoleic acid and its peroxidized forms can also affect gene expression across many genes, which may be related to the dysregulated tissue inflammation observed in human colon cancer.

Many of the calories we consume aren’t merely calories, burned for energy. Linoleic acid is just one clear example.

EPA+DHA (ω-3) Intake Suppresses Tissue ω-6 Levels

The same basic phenomenon occurs in the opposite direction: intake of ω-3 can suppress levels of ω-6 polyunsaturated fatty acids (PUFAs). This illustrates the “competitive” nature of the ω-6s and ω-3s along the PUFA metabolism pathway.

For example, in this analysis of human clinical trial data, EPA+DHA (ω-3) supplementation not only increased EPA and DHA levels, but also decreased linoleic acid and arachidonic acid (ω-6) levels. As the authors note:

A central mechanism by which long-chain ω-3 PUFAs lower inflammation is through the decrease in ω-6 PUFAs, especially arachidonic acid [source].

Our findings align with recent studies showing that ω-3 PUFA supplementation (2 g EPA and 1 g DHA daily for 12 weeks) can significantly increase EPA and DHA in mitochondrial membranes while directly displacing ω-6 PUFAs across several phospholipid populations, suggesting a competitive relationship for membrane incorporation [source].

How many of the positive health effects seen in RCTs from supplemental ω-3 PUFAs (fish oil) come not from the increase in ω-3s per se, but the change in tissue fatty acid ratios, such as the ω-6:ω-3 ratio?

It’s impossible to separate the health effects of increasing ω-3 PUFAs from lowering ω-6 PUFA levels, or vice versa, precisely because of the competitive relationship they have for membrane incorporation and metabolic processing. This is also why it’s so strange that so many people talk endlessly about the health benefits of great ω-3 intake, while simultaneously saying ω-6 intake is not problematic in any way.

Why are there so many voices, from “expert” individuals to health institutions, that say that more is better when it comes to both ω-3 and ω-6 PUFAs, and that over consumption of ω-6 is not a health concern?

Learn more about how scientific research on dietary fats is affected by social factors and industry influences:

• Article | The Purpose of (Public Health) Institutions

• Article | How to Lie With The Science: AI, Academic Expertise & Nutritional Narratives

Consumer Culture & Converging Economic Interests

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Nick speaks with Dr. Philip Calder, a nutritional immunologist at the University of Southampton who has spent over three decades studying how dietary fats shape immune function. Calder explains that inflammation is not simply "turned on" by omega-6s and "turned off" by omega-3s, but is a three-phase process — initiation, propagation, and resolution — each actively regulated by competing lipid mediators. The conversation covers the biochemistry of prostaglandins and resolvins, why cell membrane fatty acid composition is a key determinant of inflammatory capacity, and why the U.S. dietary pattern of high linoleic acid intake may blunt the body's ability to synthesize EPA and DHA endogenously.

TOPICS DISCUSSED:

• Parenteral nutrition history: IV nutrition evolved from soybean oil alone in the 1960s to complex blends including fish oil as the biology of ω-3s became understood.

• Three phases of inflammation: Initiation, propagation (driven by ω-6–derived prostaglandins and leukotrienes), and active resolution (driven by ω-3-derived resolvins and protectins).

• Pro-resolving mediators: Resolution is an active biological process, not passive; EPA and DHA generate resolvins and protectins that actively terminate inflammation.

• Aspirin’s ω-3 mechanism: Aspirin inhibits arachidonic acid metabolism but allows EPA/DHA to access COX-2, upregulating pro-resolution mediators — a likely underappreciated mechanism of action.

• Cell membrane competition: EPA and DHA physically displace arachidonic acid in membranes, shifting the balance of mediators produced and improving resolution capacity.

• Linoleic acid & EPA synthesis: High linoleic acid intake saturates shared desaturase enzymes, inhibiting the body’s conversion of ALA to EPA — meaning reducing ω-6 can raise ω-3 levels without supplementation.

• Dose & timing of ω-3 incorporation: ~2g/day of EPA+DHA shifts the arachidonic acid-to-EPA ratio enough to measurably reduce prostaglandin E2 production; white blood cells reflect changes within a month.

ABOUT THE GUEST: Philip Calder, PhD is Professor of Nutritional Immunology in the Faculty of Medicine at the University of Southampton. His research focuses on how dietary fatty acids — particularly omega-3s — modulate immune responses and inflammatory processes across clinical and healthy populations.

RELATED EPISODE:

• M&M 200: Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

KNOW YOURSELF:

• OmegaQuant: At-home blood testing to see fatty acid profiles, including omega-3 fatty acids. Use link to see options and support M&M.

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Aim for 1–2g/day of EPA+DHA combined (from fatty fish, fish oil, algal oil, or krill oil) to meaningfully shift cell membrane fatty acid composition and reduce inflammatory signaling capacity.

• Reducing very high linoleic acid intake — common in U.S. diets averaging 16–18g/day from seed oils — may raise your EPA levels even without adding ω-3 supplements, because both fatty acid families compete for the same conversion enzymes.

• Cell membrane fatty acid composition changes are dose-dependent and reversible. Consistency matters more than any single high dose.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick Jikomes talks to Dr. Andrew Pieper about how Alzheimer’s has long been viewed as irreversible but recent work shows that recovery is possible in mouse models when mitochondrial function is restored. They cover the limits of classic theories of Alzheimer’s Disease, the role of mitochondrial function and NAD balance, and a neuroprotective compound (P7C3) that enhances neuronal survival under stress.

TOPICS DISCUSSED:

• Classic Alzheimer’s pathology: amyloid plaques and tau tangles identified over 120 years ago, long assumed to drive irreversible neuron loss.

• Limitations of amyloid focus: plaques appear in some cognitively normal brains; antibody therapies have shown limited clinical benefit.

• Metabolic perspective: brain energy failure as a tipping point where repair mechanisms are overwhelmed, linking genetics, injury, and aging.

• Neuroprotection via P7C3 compounds: discovered through hippocampal neurogenesis screen; preserves mitochondrial function and normalizes NAD/NADH ratio without elevating NAD excessively.

• Recovery in models: treatment after symptom onset reversed cognitive deficits, blood-brain barrier damage, oxidative stress, and axon issues in amyloid and tau mouse models, despite persistent plaques.

• Broader implications: energy restoration enables surviving neurons to function; similar protective effects seen in TBI and other organs under stress.

ABOUT THE GUEST: Andrew Pieper, MD, PhD, is a board-certified psychiatrist and neuroscientist, professor at Case Western Reserve University, and director of the Brain Health Medicines Center at the Harrington Discovery Institute. He directs a research group focused on neuroprotection after brain injury and neurodegenerative disease.

RELATED EPISODE:

• M&M 208: Glyphosate, Choline & Alzheimer’s: Toxins & Nutrition to Prevent Neurodegeneration | Ramon Velazquez

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Control cardiovascular health, engage in regular physical & social activity, prioritize sleep to support brain metabolic health and lower dementia risk.

• Avoid excess alcohol, as even moderate intake harms brain function over time.

• Maintain overall metabolic health (e.g., via exercise and diet) to reduce risk factors like obesity or diabetes that compound brain vulnerability.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Summary of main points:

• Sleep is universal across animals and serves a core recuperative function at the cellular level. New evidence points to the clearing rancid polyunsaturated fats (PUFAs) generated by mitochondrial metabolism.

• Sleep deprivation forces compensatory changes—up-regulating mitochondrial energy genes while down-regulating synaptic plasticity genes—while causing mitochondrial dysfunction, revealing sleep’s essential role in restoring bioenergetic capacity.

• During waking, neurons produce cellular trash in the form of oxidized PUFAs and sequester it in organelles before off-loading to nearby glial cells (astrocytes), akin to emptying household garbage in a dumpster.

• During sleep, immune cells (macrophage-like cells in flies) migrate into the brain, dock onto glia, and preferentially engulf oxidized LDL particles containing rancid fats—removing the toxic waste that would otherwise impair mitochondria.

• The same cleanup process operates body-wide: in arteries, macrophages clear oxidized LDL to prevent atherosclerosis, but sleep deprivation overloads them, producing dysfunctional foam cells and driving plaque buildup, inflammation, and cardiovascular disease.

• Excess dietary ω-6 PUFAs (from seed oils) accelerate rancid-fat production; combined with poor sleep, this overwhelms mitochondrial maintenance and immune-mediated garbage disposal, linking sleep loss to both neurodegeneration and heart disease.

Sleep is universal across animals—from humans to mice, flies, and even jellyfish without centralized brains—suggesting a fundamental biological purpose common to all creatures with nervous systems.

From experience, we know that sleep serves a critical recuperative function. Sleep deprivation leads to clear mental deficits, from memory impairment to motor coordination. What, exactly, is this recuperative function at the cellular level? What is being cleaned up during sleep? Why does this state require animals to undergo daily periods of behavioral quiescence in which they’re immobilized and vulnerable?

New research in fruit flies has been narrowing in on an answer: sleep need is rooted in mitochondria, and a fundamental recuperative function of sleep may be to remove rancid fats from the brain in order to preserve healthy mitochondrial metabolism. Two complementary episodes of M&M speak to this.

Podcast episodes that inspired this article:

• M&M 257 | Sleep, Mitochondrial Metabolism & Oxidative Stress | Gero Miesenbock

• M&M 286 | Sleep, Brain Fat & Oxidative Stress | Amita Sehgal

Let’s briefly review those findings one at a time, and then step back to consider that a core aspect of sleep may be to orchestrate body-wide changes in immune cell function in order to “clean up” cellular debris body-wide, not just in the brain. This “garbage” needs to be cleared out in order to maintain mitochondrial function which, when compromised, results in bioenergetic problems in neurons and cells throughout the brain and body.

For the same reason that you take out the trash and the garbage comes in a periodic fashion, at certain times of day, the body must segregate various cellular processes in space and time. Some reactions and cellular processes naturally interfere with one another, just as city garbage trucks deployed during rush hour traffic would. The periodicity of sleep cycles and circadian rhythms probably exist as a way for the body to keep incompatible chemical reaction and cellular processes separated in time, thereby preventing functional interference.

How the Brain Measures Sleep Need & Triggers Sleep

Fruit flies like Drosophila melanogaster are used in research because they reproduce rapidly and are easy to care for. Decades of scientific innovation have gone into building a wide array of technologies that can be used to image, record, and manipulate fly cells with great precision. Every connection of the fly brain has been mapped. Individual neurons can be recorded or activated at will. Specific genes can be measured and manipulated. This level of experimental control enables scientists to figure out the mechanics of core biological processes at a level of detail impossible to achieve in humans, or even experimental animals like mice.

Applying evolutionary thinking, we can infer that, because all animals sleep, there must be a core function or set of functions that sleep serves, which was ancestrally present in the earliest animals. More complex animals like vertebrates have probably layered on additional functionality, but those things are stacked on top of the common core conserved across animal phylogeny.

Sleep deprivation disrupts pretty much everything, from “brain stuff” like synaptic plasticity to “metabolism stuff” like glucose homeostasis. Sleep need is measured and sleep is triggered by the brain. To execute their functions, neurons consume a large amount of oxygen and cellular energy in the form of ATP. Thus, there is likely a basic metabolic function of sleep, enabling neurons to maintain the bioenergetic capacity for proper function. Most neurons do not divide once mature, so they must be carefully protected throughout the lifespan of mature animals.

Because animals carry out the bulk of their energy transformation via oxygen-based metabolism within mitochondria, sleep likely plays a critical role in maintaining mitochondrial function. That’s exactly what the latest and most detailed studies in fruit flies show. This one concluded that:

That study, titled Mitochondrial origins of the pressure sleep, used an unbiased transcriptomics approach in flies to characterize which genes are most affected by sleep deprivation within critical sleep-controlling neurons. Transcriptomics is when scientists measure all of the transcripts (mRNA molecules) in specific cells. When they measured which genes had clear expression-level changes following one night of sleep deprivation, two types of genes stood out: mitochondrial energy metabolism genes and synaptic transmission genes.

Sleep deprivation caused an upregulation (more expression) of genes encoding key components of the mitochondrial electron transport chain (reviewed here) and related metabolic enzymes; at the same it, deprivation caused downregulation of genes involved in synaptic plasticity. In essence, the sleep-deprived fly brain was trying to produce key components of mitochondrial energy metabolism, while simultaneously turning down production of proteins important for synaptic transmission and plasticity. A natural interpretation is that the sleep-deprived brain attempts to conserve mitochondrial energy metabolism by sacrificing synaptic transmission and plasticity to some extent—without the former, neuronal function would be totally compromised, so there’s no point in investing in learning new things.

Mitochondria have two cell membranes, each made of phospholipids containing fatty acids. Some of these are polyunsaturated fatty acids (PUFAs), which are prone to lipid peroxidation, an unregulated form of fat burning. Lipid peroxidation is when unsaturated fats get oxidized “on accident” by reactive oxygen species (ROS), largely produced by mitochondria. Thus, lipid peroxidation is inevitable, and mitochondria are both a primary source and primary target of lipid peroxidation within animal cells.

The longer an animal is awake and behaving, the more its neurons are active, and the more ROS are generated, driving lipid peroxidation. ROS are sort of like sparks. PUFAs are ignited by ROS, producing “toxic fumes” akin to the way the combustion engine in a motor vehicle produces exhaust. A gas-powered vehicle will necessarily produce exhaust and is specifically designed to manage and dispose of that waste, with as little direct exposure to the other vehicular components as possible. Similarly, our cells have evolved to manage and dispose of toxic waste within cells, such as oxidized fats.

As was recently discovered, “sleep neurons” in the fly brain have an exquisite mechanism that detects and stores a memory of how much lipid peroxidation has occurred during waking. A specific potassium channel detects toxic products of lipid peroxidation, stores a memory of this as a charge in a capacitor, and eventually discharges. When critical level of lipid peroxidation has been detected, “sleep neurons” fire in a way that activates the brain circuits that put the animal to sleep.

When deprived of sleep, more and more lipid peroxidation occurs, leading to oxidative stress. The “toxic fumes” of lipid peroxidation basically react with whatever they come in contact with, driving cell dysfunction. It’s waste. You sequester your daily waste at home, in specialized containers like toilets and trash bins. You don’t want that stuff touching everything else. Same idea.

When you look inside neurons of sleep-deprived flies, you find:

• Mitochondrial fragmentation

• Enhanced mitophagy

• Increase contact between mitochondria and the endoplasmic reticulum

Sleep deprivation causes mitochondria to become dysfunctional and break apart, requiring maintenance and recycling if cells are to remain energetically viable. What is the purpose of mitochondria contacting the endoplasmic reticulum (ER)? To replenish oxidized lipids. The ER is where mitochondria get “re-loaded” with fresh, unoxidized lipids.

So, lipid peroxidation throughout waking is the very signal the fly brain uses to measure sleep need, and peroxidized lipids within mitochondria need to be replenished following sleep deprivation. Without the replenishment that sleep provides, mitochondrial dysfunction gets worse. Eventually it can result in cell death.

Learn more about PUFAs, lipid peroxidation, and cell death:

• Article | Burning Down the House: Lipid Peroxidation, Oxidative Stress & Cell Death

• Podcast | Cell Death, Oxidative Stress, PUFAs & Antioxidants | Pamela Maher

Again, it’s the polyunsaturated fats (PUFAs) that undergo lipid peroxidation to produce the “toxic fumes” that break stuff. As in humans, flies cannot synthesize PUFAs. They must be obtaining from the diet, including the ω-6 PUFA linoleic acid, the most abundant fatty acid in modern industrial seed oils.

Think about what all of this means.

The reactive (toxic) compounds produced from lipid peroxidation (oxidation of PUFAs) are such a clear indicator of cellular stress and the need for recuperation that Nature keeps track of this, using it as a metric in to decide when to put the animal to sleep.

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If the chemical products of lipid peroxidation are so harmful, and they’re being produced throughout wakefulness, then cells have presumably evolved ways to deal with toxic waste, beyond just using its production as a metric for sleep need. As you’d imagine, cells are indeed equipped with ways to sequester and dispose of rancid (oxidized) fats.

Back to our garbage analogy: you produce trash throughout the day, in your home. Most of that trash is captured and sequestered for temporary storage in garbage containers, which have limited capacity. Once they become full, garbage can begin spilling out. Any garbage that isn’t efficiently captured and stored in specialized containers has the potential to damaging the structure or disrupting the functionality of your home—staining the carpet, attracting unwanted pests, or whatever.

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Nick Jikomes talks to Dr. Kristin Stanford about the ways parental exercise influences offspring health in animal models, emphasizing controlled studies that isolate effects of maternal and paternal activity on metabolism, the role of small RNAs in sperm, changes in milk composition, and placental function.

TOPICS DISCUSSED:

• Parental exercise & offspring metabolic health: exercise before and during pregnancy improves glucose tolerance and reduces fat gain in offspring.

• Paternal effects via sperm: moderate voluntary wheel running alters small non-coding RNAs, especially tRNA fragments, in sperm and enhances glucose clearance, with stronger benefits in female offspring.

• Maternal exercise mechanisms: benefits arise from in utero environment, placental changes, and breast milk composition rather than major oocyte alterations.

• Human milk oligosaccharides: exercise increases 3’-sialyllactose in milk, linked to better offspring microbiome and metabolic outcomes.

• Sex-biased & intergenerational effects: maternal exercise impacts male offspring metabolism more; effects can transmit to F2 generation depending on the transmitting parent’s sex.

ABOUT THE GUEST: Kristin Stanford, PhD is an associate professor in the Department of Physiology and Cell Biology at The Ohio State University Wexner Medical Center, where she serves as associate director of the Diabetes and Metabolism Research Center. Her lab investigates molecular mechanisms by which exercise enhances metabolic and cardiovascular health, with a focus on intergenerational effects.

RELATED EPISODE:

• M&M 145: Epigenetics, Endocrine Disruptors, Obesogens & Obesity, Inheritance of Acquired Characteristics | Bruce Blumberg

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Regular exercise before and during pregnancy supports better metabolic health in children, with benefits seen even from moderate activity.

• Paternal exercise can positively influence daughters’ glucose handling through mechanisms passed via sperm.

• Breast milk from active mothers contains compounds that promote healthier weight and glucose regulation in infants.

• Exercise benefits may extend to grandchildren, highlighting the value of consistent activity across life stages.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick speaks with Dr. Kevin Tracey about inflammation as a major driver of modern diseases, the vagus nerve’s role in balancing immune responses via reflexes, limitations of anti-cytokine drugs, and emerging bioelectronic medicine using targeted nerve stimulation.

TOPICS DISCUSSED:

• Inflammation is related to diseases that contribute to most deaths today: heart disease, diabetes, neurodegeneration, and cancer.

• Molecular signals involved in inflammation, such as cytokines.

• Homeostasis is maintained by push-pull mechanisms, with excitatory and inhibitory responses co-deployed in ways that maintains balance.

• The vagus nerve’s anatomy, sensory/motor fibers, and the inflammatory reflex that suppresses cytokine production in the spleen via acetylcholine and norepinephrine.

• Vagus nerve stimulation devices delivering brief daily pulses to reduce inflammation without broad immunosuppression, now FDA-approved for refractory rheumatoid arthritis.

• Challenges in measuring inflammation and oversimplifications online about “stimulating” the vagus nerve.

ABOUT THE GUEST: Kevin Tracey, MD is a neurosurgeon, president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, and professor of molecular medicine and neurosurgery. He discovered the inflammatory reflex, showing how the vagus nerve controls immune responses, and co-founded SetPoint Medical to develop FDA-approved vagus nerve stimulation for rheumatoid arthritis.

RELATED EPISODE:

• M&M 143: Gut-Brain Communication, Vagus Nerve, Fats & Sugars, Food Addiction, Gut Hormones & Weight Loss Drugs | Will de Lartigue

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Lifestyle habits that lower resting heart rate, including balanced diet, regular exercise, good sleep, and strong social connections, support vagus nerve tone and health.

• Patients with chronic inflammatory conditions unresponsive to drugs should discuss vagus nerve stimulation options with their doctors.

• Approach online vagus nerve claims cautiously; prioritize evidence-based methods over unverified techniques.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick & Dr. Alexis Cowan discuss non-image-forming effects of light on the body, from melanopsin-driven circadian signaling in the eye to UV-stimulated pathways in skin and brain that influence melatonin, cortisol, melanin production, and energy balance.

TOPICS DISCUSSED:

• Melanopsin & non-image-forming light: blue light signals daytime to the SCN master clock, suppressing melatonin and promoting alertness.

• UV light, POMC & peptide hormones: UVB exposure in skin and hypothalamus produces alpha-MSH (reduces appetite, boosts energy expenditure) and beta-endorphin (improves mood), independent of vitamin D.

• Mitochondrial effects of light: red/infrared supports function like a gas pedal; isolated blue light acts as brakes, impairing energy production and biophoton signaling.

• Artificial light: Evening blue light from screens inhibits melatonin, poisons mitochondria, and creates discordant timing signals versus balanced natural sunlight.

• Melanin beyond skin: produced via UVB, it harnesses energy, buffers oxidative stress, and links to dopamine pathways; low sun exposure ties to metabolic issues and conditions like Parkinson’s.

• Vitamin D as biomarker: supplementation shows limited benefits because it reflects broader UVB-driven processes, not a standalone fix.

ABOUT THE GUEST: Alexis Cowan, PhD earned her PhD in molecular biology at Princeton in the Rabinowitz lab, a leading metabolism research group, where she studied fasting, ketogenic diets, and exercise; she completed a postdoc at UPenn before shifting focus to circadian and quantum biology. She now educates on light, mitochondria, and quantum biology.

RELATED EPISODE:

• M&M 221: Regenerative Energy & the Light Inside You | Jack Kruse

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• View morning sunlight (ideally sunrise) and get midday sun exposure tuned to your skin type and latitude to support circadian alignment, mitochondrial health, and natural appetite regulation; use shade as needed instead of sunscreen.

• Minimize evening artificial blue light by using red/incandescent bulbs, candlelight, or dark-orange blue-blocking glasses to protect melatonin and sleep quality.

• Prioritize a seasonal, whole-foods diet low in processed seed oils to support skin resilience and reduce burn risk while building tolerance to natural light.

• Track vitamin D levels (aim 60-80 ng/mL via sun) as a proxy for adequate UVB exposure rather than relying on supplements alone.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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M&M written content is human-created, independently researched, and filled with resources to deepen your learning. Click here to see all the ways you can support this work.

Listen to the livestream that inspired this post:

• How to Lie With Science: Seed Oils & Inflammation

Modern liberal democracies operate according to a truth-by-consensus paradigm. On questions related to health and science, people often default to “the consensus.” Certain questions require specialized expertise to answer. Expertise is signaled by credentials issued by institutions with varying levels of prestige. Social prestige reflects the degree of trust a person or institution commands—essentially, how willing people are, on average, to accept what they say. The more prestigious the institution, the more faith people tend to place in it.

“The Science” is a relatively new phrase. It refers to the dominant viewpoints expressed by prestigious scientific institutions—the prevailing institutional consensus on any given subject. Are those viewpoints generally accurate? Do our institutions sometimes get things wrong? If so, how often?

Regardless of how one personally answers those questions, public trust in scientific and medical institutions has been declining. Fewer and fewer people have faith in The Science.

For any given institutional consensus, there are likely to be some credentialed experts who disagree with the dominant institutional view. For example, the dominant institutional view on seed oils is that ω-6 polyunsaturated fats are “heart healthy” and should be promoted for human health. This view is shared by the scientific leadership of nutrition departments at major universities, as well as “non-profit” organizations like the American Heart Association (AHA) and American College of Cardiology Foundation.

The dominant institutional view that ω-6 fats are “healthy fats” exists despite the fact that many experts, including scientists at major universities, keep finding new evidence that those very fats promote metabolic dysfunction and disease. For examples of recent scientific evidence on this, see the content below:

• Article | Seed Oils, Early-Onset Cancer & Human Metabolic Variability

• Podcast | Dietary Fats & Seed Oils in Inflammation, Colon Cancer & Chronic Disease | Tim Yeatman & Ganesh Halade

• Podcast | Soybean Oil: Obesity, Fatty Liver Disease, Gut Health, IBS & Colitis | Frances Sladek

A major factor in the decline of public trust in experts and institutions comes from the democratization of knowledge made possible by technology. Academic papers are available free online, one way or another. University lectures are on YouTube. Smart phones and Large Language Models (LLMs) enable anyone to engage in fact-checking with minimal effort.

But if people are losing faith in major institutions, what makes them think they can trust the output of LLMs?

As we’ll see, misleading answers provided by AI are rooted in misleading information published by prestigious people, from prestigious institutions. Junk food is sold to us as health food, because junk information is camouflaged as settled science, which AI algorithms ares designed to gobble up and regurgitate to the public.

Experts & Institutions: Placing faith in The Science™

People in our culture are inclined to place a lot of trust in people with prestigious titles, from prestigious places. I began to see first-hand as soon as I was accepted into a PhD program at Harvard. The moment someone learned of my association with Harvard, they would transform. Impressed. Inquisitive. “This guy will have the answers. He’s from Harvard.”

In the age of AI, we no longer need to take people at their word—not even credentialed experts, like physicians and professors. Fact-checking is easy. A second opinion is two seconds away. Technology is changing how people allocate trust. As the landscape of trust and prestige shift, conflict is generated.

A common internet memes captures that captures the spirit of this changing landscape:

Doctor: Don’t confuse your google search with my 4 years of medical school & 3 years of residency!

Patient: Don’t confuse the 1-hour lecture on my condition you got with my 30 years of living with it!

You may have AI in your pocket, but that information is not free from corruption. It’s fundamentally constrained by its training data. When ChatGPT gives you an answer, how does it know what words to string together? It must select text among many sources. It must rank and prioritize them. What are its criteria? The AI must have a notion of prestige, just as humans do.

Humans evolved as social primates. The drive for social status is more fundamental than the desire to explain reality. As a natural consequence, status-seeking is the strongest driver of the narratives that most humans create. Those narratives are composed of language. Modern neuroscience demonstrates that language is primarily a tool for communication rather than thought. Evidence indicates a double-dissociation between language and thought: you can disrupt linguistic ability without disrupting thinking and reasoning, and vice versa.

Similar concepts are explored in this M&M content:

• Article | The Purpose of (Public Health) Institutions

• Article | The Cholesterol Cult & Heart Mafia: How the process of science evolves into The Science™ of public policy

The words we select and the narratives we construct are first and foremost aimed at navigating our social environment, where our fate is determined by our social status. Our position within social status hierarchies determines how much attention we command, the level of influence we have over others and, ultimately, our mating potential. The stakes are high, so our stories need to be compelling.

A process I’ve called “narrative selection” plays out over time, as individuals and institutions selectively curate information to create narratives that serve their social interests. Whether or not those narratives explain reality or solve real-world problems is secondary. People will point to empirical results if and when it fits their preferred narrative, but are generally willing to ignore or distort empirical reality it threatens status-seeking objectives.

Large Language Models (LLMs) must select text in order to generate narratives that satisfy the end user. The better the LLM is at generating narratives you like, the more it get what it’s designed to extract from you: time and attention. Why does it “want” that? The social primates who designed the LLM engineered it that way. Attention is the currency of social networks. Social status is the ability command attention. Power is the ability to transform that attention into human action.

LLMs are programmed by social primates (humans) embedded within social networks. As a consequence, they are inherently biased to make prestige-weighted decisions about information sources and how to curate them. The algorithms are pre-configured to rank some sources higher than others, which influences which sources they select from. Notions of prestige have to be baked in, biasing LLMs to produce outputs that conform to narratives held by prestigious sources.

Imagine you ask your favorite LLM a health-related question, about what foods are healthiest. What sources will it select while it “thinks” about what particular string of words to feed you? Why those sources?

Here, let’s try.

Prompt: Are seed oils inflammatory and are omega-6 fats healthy? Consult scholarly sources and the best scientific literature on the subject, focusing on peer-reviewed science from reputable sources.

ChatGPT:

🧠 Bottom line (based on the best evidence)

• Seed oils are not inherently inflammatory in humans.

• Omega-6 fats (especially linoleic acid) are generally neutral or beneficial for health, particularly for cardiovascular disease.

• The “seed oils cause inflammation” claim is not supported by high-quality human evidence.

• The real issue in modern diets is more about ultra-processed foods and low omega-3 intake, not omega-6 itself.

What texts did ChatGPT draw from? It was asked to consult peer-reviewed science from reputable sources. Tufts University is a prestigious school, with one of the largest and most well-funded nutrition programs out there. They publish lots of highly-cited scientific papers. Those are good sources, right?

What if those sources, produced by high-prestige institutions, have been corrupted to some extent? How would an LLM know?

Consider the highly prestigious School of Nutrition Science and Policy at Tufts University. A whole team of experts from Tufts created their own scientific algorithm, called the “Food Compass.” It uses math and everything.

Here’s how the Tufts algorithm ranks some common foods:

How much faith are you willing to place in this expert-designed algorithm? How much faith does ChatGPT place in the Tufts University?

Large Language Models (LLMs) are feeding you answers to your health questions. The scientific literature is feeding the LLMs. As we will see, the literature contains “high-quality” papers that misrepresent what the data actually shows. Linguistic trickery is used to launder ideas that aren’t supported by the cited evidence, biasing the thoughts of physicians and the output of LLMs, both of which are guiding people’s health decisions.

Let’s look at how this is done, and by whom…

Learn more about Large Language Models & the nature of language:

• Podcast | Neural Basis of Language in the Human Brain | Ev Fedorenko

• Podcast | Computational Neuroscience, Machine Learning vs. Biological Learning, Large Language Models | Marius Pachitariu

The Hierarchy of Evidence in Mainstream Medicine: Picking from the top

Systemic reviews and meta-analyses sit near the top of the “hierarchy of evidence” of institutional science. In theory, the higher up the pyramid you go, the better the evidence gets and the more directly it should influence clinical practice. Systematic reviews are considered high-quality evidence, as they synthesize and summarize the results from many studies within a given domain.

Here is a recently published, “state-of-the-art” review paper, explicitly meant to serve as a guide for clinicians. It came to my attention recently, posted by large social media that repeated its conclusions. Because it’s a review paper authored by big names in nutrition science, it’s conclusions were taken on faith. We must all place our trust somewhere, and this is a state-of-the-art review paper, after all.

By placing faith in this hierarchy of evidence, people implicitly assume:

• The scholarship is honest and rigorous.

• Conflicts of interest are explicitly stated and the scholarship remains uncorrupted.

• Claims made accurately reflect what’s in the work cited to make those claims.

People must have some level of faith that the experts who produced this work engaged in honest, high-quality scholarship. Besides, who is psycho enough to read this stuff, look up the citations, and then read those papers?

For fun, I decided to look into one major claim the paper makes, in an area of the literature I was already familiar with: seed oils.

The experts at Tufts University and your favorite LLMs will tell you that seed oils are good for you, because they contain healthy ω-6 fats that reduce inflammation. I and others will tell you the opposite.

You will have to decide for yourself where to place your faith.

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Fact-Checking The Science

Right out of the gate in this review, in their basic overview of seed oils, we notice something interesting:

Canola oil and soybean oil are among the most studied seed oils. Each provide a balanced combination of healthy fats, including MUFA and both omega-6 and omega-3.

One has to be very familiar with the relevant biology to spot the linguistic sorcery at work here. Do you see it?

Canola and soybean oil are called out as among the most studied seed oils, and indeed they are. The text describes both oils as providing “a balanced combination of healthy fats,” with monounsaturated fatty acids (MUFAs) and omega (ω) polyunsaturated fatty acids (PUFAs) explicitly called out as “healthy fats.”

What’s strange about the statement is that canola and soybean oil do not have a similar balance of fatty acids. Both share the linguistic designation of “seed oils” because they are derived from plant seeds. Nonetheless, they have very different fat profiles. Canola and soybean oil share the name (“seed oil”) but they are not the same underlying thing.

The experts are playing language games by making it seem like canola and soybean oil both have a comparable balance of “healthy fats” because they’re both “seed oils.” But the various fatty acid classes—MUFAs, ω-3 and ω-6 PUFAs—all have distinct and sometimes opposing biological effects. Canola oil in particular has a very different mix of fats compared to soybean and other seed oils.

The authors of the review are obscuring those facts with their word choice, and they should certainly know better. If they don’t know better, they shouldn’t be writing papers. If they do know better, than they’re being either sloppy or deceptive.

To see what’s going on here, you need to understand how fatty acid profiles differ between various seed oils and other fats.

Learn more about dietary fats & the distinct effects of different fatty acids:

• Article | Eating Fat Like Never Before

• Article | Biological Consequences of Specific Dietary Fatty Acids

Fatty acid profiles of common seed oils, fruit oils, and other fats

The “classic” fat profile of seed oils is characterized by an abundance of ω-6 polyunsaturated fatty acids (PUFAs). Linoleic acid is the dominant ω-6 PUFA in most seed oils, usually present at much higher concentration than ω-3 PUFAs or MUFAs. Soybean and sunflower oil are two examples.

In contrast, oils derived from plant fruits, like olive or avocado oil, tend have an abundance of monounsaturated fatty acids (MUFAs), with much lower PUFA content. Most fruit-derived oils have have a fatty acid profile that’s different from most seed-derived oils. But this is biology. There are exceptions to most rules. Biological diversity is beautiful and fascinating, but also enables humans to obscure meaningful variation with language.

Remember what Feynman said: be careful not to confuse the name of something with the underlying reality.

Unlike most seed oils, canola oil has fat profile much closer to olive oil: abundant in MUFAs, with far lower ω-6 content than soybean oil, plus a more balanced ω-6:ω-3 ratio. Canola oil is named a “seed oil” because the oil is derived from plant seeds, not plant fruit. That’s it.

As you can plainly see, canola oil is an exception to the general rule that seed oils are dominant in ω-6 PUFAs.

More detail on why the relative ratios of these fatty acid classes matter can be found in this article. A short excerpt, to give you a sense:

ω-6 and ω-3 fatty acids tend to have opposing effects on various aspects of physiology including adipogenesis (fat cell formation), inflammation, and insulin resistance. In general, ω-6 overconsumption will promote those things (bad), while a more balanced ω-6:ω-3 ratio will do the opposite (good).

It’s important to remember that biology is complicated. Things are rarely so clean-cut as, “Omega-6 = 100% bad, omega-3 = 100% good.” Both ω-6 and ω-3 fatty acids are necessary for the proper, adaptive functioning of our inflammatory mechanisms.

The major problem people like me have with seed oils is the high ω-6 PUFA content. One common claim people debate: the high ω-6 content of seed oils promotes inflammation. To the extent that’s true, we would expect that lowering ω-6 PUFA intake, relative to other fats, would lead to less inflammation. If we tested this in a controlled trial, we’d expect to see inflammatory markers drop if ω-6 PUFA intake goes down, but not if ω-6 PUFA intake stays the same.

As we’ve already clearly stated, the fatty acid profile of canola oil has much lower ω-6 PUFA content than most seed oils, like soybean and sunflower oil. I’m repeating myself because many people are very confused about this. A major source of confusion comes from the word games that experts publish in peer-reviewed papers, which are then regurgitated by LLMs.

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Language Games: How Academic Experts Confuse People & Bias LLMs

Carefully read the claim the review paper in question makes about seed oils and inflammation:

The healthy fats in canola oil, especially the omega 6 PUFA, also improve blood glucose, insulin resistance, and insulin production. Consistent with these benefits and contrary to popular belief, canola oil and sunflower oil also reduce inflammation, with similar effects as olive oil.

(emphasis added)

In plain English, they identify ω-6 PUFA as the “heathy fats” in canola oil, stating explicitly that both canola and sunflower oil reduce inflammation, similar to olive oil.

Refer again to fatty acid chart. Like soybean oil, sunflower oil has very high ω-6 content, with much lower MUFA content than canola or olive oil. A single citation is used to make the claim that both canola and sunflower oil reduce inflammation. The authors of the review presumably view this citation is a very strong piece of evidence. They singled out that particular RCT, after all.

The citation is this randomized control trial (RCT) of 77 diabetic Iranian women. You may not be a diabetic Iranian woman, but it doesn’t matter—the trial results are flagrantly misrepresented by the review paper, which actually shows a drop in inflammation in response to a drop in ω-6 PUFA intake. The review paper’s own citation does not back up the claims they make.

Important context: Iran has high per capita seed oil intake. Iranians consume more sunflower oil than Americans do in the US, where soybean and canola are more common. In fact, the patients recruited for this RCT were women with high baseline sunflower intake. Here were the inclusion criteria:

“Female gender, records of type 2 diabetes of at least 6 months, and the routinely use of Sunflower Oil.”

The control group just kept consuming sunflower oil. The two other experimental groups were switched to either Olive oil or Canola oil, instead of Sunflower.

Let me repeat: the baseline condition and control group here is high sunflower oil intake. Sunflower oil has among the highest levels of ω-6 PUFA of any seed oil, much higher than either canola or olive oil. The fatty acid composition of the oils in the trial:

The sunflower oil contained about twice as much PUFA as canola oil and nearly 5x more than olive oil. The MUFA content of sunflower oil is also much lower than than canola or olive oil. Not shown in the table: within the PUFA category, canola oil has a much more balanced ω-6:ω-3 ratio than sunflower oil. Sunflower oil contains almost no ω-3 PUFAs, which are known to favor inflammation resolution.

You would expect ω-6 PUFA intake to drop substantially for both the olive and canola oil groups, which started with high baseline ω-6 PUFA intake from sunflower oil.

When you examine how diets changed during the intervention, you see just that:

• MUFA intake increased substantially for the Olive and Canola oil groups.

• MUFA intake does not change for the Sunflower group (control).

• PUFA intake drops substantially for the Olive and Canola oil groups.

• PUFA intake does not change substantially for the Sunflower group (control).

The result: a substantial increase in the MUFA:PUFA ratio for both the Olive and Canola oil groups, with no change for the Sunflower oil group used as a control. The numbers and how they changed:

CRP was the major inflammation biomarker measured. How did it change for each group? Remember: linoleic acid (ω-6 PUFA) is “seed oil fat,” which dropped for the Olive and Canola groups, but stayed the same for the Sunflower group.

• CRP dropped substantially for the Olive oil group.

• CRP dropped substantially for the Canola oil group.

• CRP did not change significantly for the Sunflower oil group (control).

Bottom line: The review paper above blatantly misrepresented the results of this study. Olive and Canola oil both led to a drop in CRP, and both saw a substantial drop in ω-6 PUFAs. Sunflower oil did not lead to drop in CRP, and so did not “reduce inflammation, with similar effects to olive oil,” as stated in the review paper above.

Again, the claim in the review is that “seed oils” are not inflammatory. The evidence cited was a single RCT, of diabetic Iranian women, where high sunflower oil intake was the baseline condition! The Canola oil group did indeed see a drop in CRP similar to Olive oil… but Canola oil has a similar fatty acid profile to Olive oil, with much lower ω-6 PUFA content than Sunflower.

Do you see what’s happening, and how we’re being deceived?

The people who wrote the review paper are (presumably) familiar with the literature. They hand-picked a single RCT and used it to make the false claim that sunflower oil reduced inflammation (it did not), while totally obscuring the fact that the baseline (control) condition of the trial was high sunflower oil intake in diabetic women.

This is how poor scholarship and language games are used to launder false claims into the literature, right to the top of the “hierarchy of evidence.” LLMs will naturally prioritize review papers like this, biasing the narratives they feed to people who don’t know any better.

Who wrote this review, anyway? What could be motivating them?

Learn more about the incentives that shape academic research:

• Podcast | How Science Really Works: Meta-Research, Publishing, Reproducibility, Peer Review, Funding | John Ioannidis

The Man Behind the Algorithm

Remember the chart from the beginning, ranking Count Chocula as healthier than ground beef? The ranking was generated by applying the “Food Compass” algorithm, originally described in this paper as a nutrient profile system that discriminates the “healthfulness” of foods. It’s publicly available and meant to guide consumer choice.

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Nick & Dr. Amita Sehgal talk about the latest science on why animals sleep. Using fruit flies, her lab shows that waking generates oxidized lipids in neurons that are shuttled to glia and then cleared by macrophage-like cells during sleep. This process protects mitochondria, supports memory, and links sleep to metabolic cleanup rather than just rest.

TOPICS DISCUSSED:

• Drosophila as a model: Fruit flies sleep with immobility, reduced responsiveness, and homeostatic rebound; their genetics reveal conserved mechanisms found in humans.

• Circadian vs homeostatic sleep: Circadian timing sets when we sleep; homeostatic drive builds need from prolonged wakefulness independent of time of day.

• Metabolic waste during wake: Neuronal activity oxidizes lipids in mitochondria; these damaged lipids transfer to glial support cells via apolipoproteins.

• Immune cells clear brain trash: Macrophage-like hemocytes dock at the brain during sleep, phagocytose oxidized lipids, and remove them; blocking this docking reduces sleep and impairs memory.

• Peroxisomes & oxidative stress: These organelles handle specific fats and rise with wakefulness; disrupting them increases brain oxidation that can be partially rescued by antioxidants like N-acetylcysteine.

• Sickness sleep differs from normal sleep: Infection-induced sleep redirects energy to immune defense and depletes rather than restores brain energy stores.

ABOUT THE GUEST: Amita Sehgal, PhD is the John Herr Musser Professor of Neuroscience at the University of Pennsylvania, an HHMI Investigator, and director of the Chronobiology and Sleep Institute. She uses Drosophila genetics to uncover basic mechanisms of circadian rhythms and sleep.

RELATED EPISODE:

• M&M 257: Sleep, Mitochondrial Metabolism & Oxidative Stress | Gero Miesenbock

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Prioritize consistent nightly sleep to allow the brain’s natural waste-clearance systems to operate and protect mitochondrial function.

• Recognize that afternoon dips in alertness reflect rising homeostatic sleep pressure; a short nap or break can help restore focus without fighting biology.

• Chronic short sleep accumulates metabolic stress that affects memory and longevity; treating sleep as essential maintenance supports long-term brain health.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Nick & Dr. Flynn McGuire discuss the surge in peptide use for injury recovery. They cover peptide basics, the preclinical evidence for BPC-157 and TB-500, mechanisms like angiogenesis and tissue repair, the lack of robust human trials, sourcing risks, regulatory bans, and the gap between anecdotal reports and scientific certainty.

TOPICS DISCUSSED:

• Peptide basics: Short amino acid chains (e.g., insulin, GLP-1 agonists); BPC-157 derived from gastric juice, TB-500 a fragment of thymosin beta-4.

• Rise in popularity: Driven by podcasts, social media, biohacking culture, and post-COVID distrust in institutions; “bro science” often precedes formal research.

• BPC-157 mechanisms: Pleiotropic effects including VEGF upregulation, nitric oxide pathways, angiogenesis, reduced fibrosis, and possible neuromuscular stabilization.

• TB-500 & “stacking”: Often combined with BPC-157 for presumed synergy; marketed as “Wolverine stack” for rapid healing.

• Evidence limitations: Strong rodent data for tendon/muscle repair, but almost no high-quality human trials; one small retrospective study and ongoing phase 2 trial in China.

• Safety and risks: Unknown long-term effects, potential cancer concerns via angiogenesis; no established dosing, potency, or administration route in humans.

• Sourcing & quality issues: Often obtained as “research chemicals” online; variable purity, stability concerns, no reliable regulation or third-party verification for most users.

ABOUT THE GUEST: Flynn Mcguire, MD is a physical medicine and rehabilitation resident at the University of Utah; he conducts clinical work in neurologic recovery and musculoskeletal care and has authored a narrative reviews on peptides for musculoskeletal healing.

RELATED EPISODE:

• M&M 252: Scarring, Fibrosis, Oxidative Stress, and Psilocybin & Aging | Louise Hecker

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the SUPPORT PAGE if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Peptides like BPC-157 show promising animal data for tissue repair but lack solid human evidence; anecdotal benefits may reflect placebo, natural recovery, or time.

• Be cautious about self-experimentation without medical oversight due to unknown risks (e.g., contamination, cancer promotion) and unregulated sourcing.

• Good science requires years of rigorous trials; internet claims often ususally spread before reliable data are available.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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Short Summary: Nick Jikomes and Tucker Goodrich expose misrepresentations in a 2026 review paper claiming seed oils reduce inflammation, using the cited trial, fatty acid chemistry, and conflicts of interest to highlight flaws in nutrition science.

About the Guest: Tucker Goodrich is a former Wall Street technology executive and systems engineer with expertise in fraud detection. Self-taught after personal health challenges, he is now an independent nutrition researcher, blogger, and consultant at Zero Acre Farms focusing on seed oil harms.

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Episode Summary: In this livestream, Nick Jikomes teams with Tucker Goodrich to fact-check a “state-of-the-art” review paper meant to serve as clinician’s guide on cardiovascular nutrition. They demonstrate how the paper falsely attributes anti-inflammatory effects to high-linoleic seed oils by mischaracterizing study results and fatty acid profiles, while uncovering industry funding ties.

Topics Discussed:

• Seed oil fatty acid profiles: typical ones like soybean and sunflower dominate in omega-6 linoleic acid unlike canola oil, which is higher in monounsaturated fats (similar to olive oil).

• Review paper critique: stated canola and sunflower reduce inflammation like olive oil, but cited RCT showed benefit only from switching to lower-PUFA oils.

• CRP as inflammation marker: binds oxidized omega-6 lipids akin to pathogens; rises with exercise damage or infection but signals sterile inflammation from seed oils.

• Oxidized lipid biology: fresh seed oils already contain rancid compounds; metabolites like 4-HNE and MDA from linoleic acid trigger cell death and immune activation.

• Author conflicts: Dariush Mozaffarian omitted Unilever funding for omega-6 projects; pattern of data adjustments obscuring seed oil links to obesity and diabetes.

• Historical research patterns: similar mislabeling and statistical tricks in prior papers on dairy fats and fried foods.

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Practical Takeaways:

• Always verify review citations against original trials, as the claims stated in papers might not match up with what the citations actually show.

• Reduce linoleic acid intake by choosing olive, avocado, or animal fats over typical seed oils to limit oxidized lipid exposure.

• Recognize personal variation in response; tracking symptoms after cutting seed oils can inform diet choices.

• Scrutinize author funding, as undisclosed industry ties from seed oil producers influence review conclusions.

Learn more:

• Podcast | Seed Oils & Heart Disease: Oxidized LDL, Cholesterol, Fat & Cardiology | Tucker Goodrich

• Article | PUFAs & The Palisades: Lipid Peroxidation, Oxidative Stress & Cell Death

AI-generated transcript below. Beware of mistranslations!

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TOPICS DISCUSSED:

• Historical views on obesity: In some cultures, like northern Africa or Stone Age societies, high body fat signaled status or attractiveness due to food scarcity, unlike today’s focus on leanness amid calorie abundance.

• Energy balance components: Metabolizable energy (95% absorption on average, but varying 1-11%) and unabsorbed nutrients excreted as waste significantly influence weight.

• Obesity resistance in animals: Inbred mouse strains show wide variation in weight gain on high-fat diets, often somewhat uncoupled from overeating, suggesting roles for feed efficiency, energy expenditure, or waste rather than intake alone.

• Genetic & twin studies: Monozygotic twins overfed 1,000 extra calories daily vary widely in weight gain (4-13 kg), indicating genetic influences, while mouse litter size affects lifelong obesity propensity via early-life programming.

• Bloodborne factors & hormones: Parabiosis studies led to leptin’s discovery for defending against weight loss, but evolutionary logic suggests systems also prevent excess gain, though modern environments may weaken this.

• Human thinness research: Constitutionally thin people snack more, move less, yet have better cardiometabolic health, but we don’t yet understand why.

• GLP-1 drugs & future directions: These slow gut transit and suppress appetite, but obesity’s root causes remain unclear; emerging thinness studies could inform prevention beyond drugs.

ABOUT THE GUEST: Jens Lund, PhD is a postdoctoral researcher at the University of Copenhagen’s Novo Nordisk Foundation Center for Basic Metabolic Research.

RELATED EPISODE:

• M&M 132 | Obesity Epidemic, Diet, Metabolism, Saturated Fat vs. PUFAs, Energy Expenditure, Weight Gain & Feeding Behavior | John Speakman

Listen or watch on your favorite platform:

• Audio version: [Apple] [Spotify] [Elsewhere]

• Video version: [YouTube]

Support M&M:

• Visit the support page if you find value in this content. Includes discount codes + links to affiliate partners.

PRACTICAL TAKEAWAYS:

• Consider diet quality over just calories: Opt for satiating foods to potentially improve energy absorption and weight management without strict counting.

• Recognize individual variation: Weight gain differs due to genetics, early-life factors, and biology, so avoid one-size-fits-all advice and track personal responses to diet changes.

SUBSCRIBER CONTENT BELOW: Reference paper + episode transcript.

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