Trying something new, thanks to the many issues with Blogger, and Google, in general.
New posts are going to be at the Substack I have set up, I'll make a more complete notice once I figure it out a bit better.
First one is the shownotes for this podcast, and links to the files.
Ep 9: Dave Feldman, Citizen Scientist—What Causes Heart Disease
"Today, Paul interviews Tucker Goodrich, Wall Street technology [exec] extraordinaire and independent researcher, and Jeff Nobbs, co-founder and CEO of Zero Acre Farms. They take a deep dive into the epidemic of seed oil consumption. They examine conflicting arguments, and then explain why seed oils are likely making humans fat, diabetic, and causing atherosclerosis."
tl:dr; Yes. This deserves a longer post, and will get it at some point, but for now this will have to do.
Gil Carvalho, a vegan MD/PhD, has a video out titled "Are Seed Oils Inflammatory?! (The *Evidence* No One Shows)" which I have not watched, and will not watch.
Carvalho is a movement vegan, and as such is presumed to be dishonest, based on the experience of myself and others (detailed here, here, and here on this blog).
But this video he has done seems to be misleading people about this topic, which is the intent, of course.
As I pointed out on Twitter, even Harvard has come around on this topic.
How can you identify a movement vegan? He's the last guy arguing that seed oils aren't a problem.
— Tucker Goodrich (@TuckerGoodrich) October 19, 2022
Even Harvard has come around.https://t.co/481Rhh1eZn
The only folks who are arguing that seed oils are NOT inflammatory are movement vegans, the flat-earthers of nutrition science.
Brad Marshall of Fire in a Bottle did watch the video, and did a nice analysis of the "misrepresentation" and "low-quality evidence" Carvahlo uses. Watch the whole thing. I did.
All this evidence was available when he wrote that. One can only conclude he’s completely unaware of the evidence on this subject. Spreading misinformation about an important health topic like this is not helpful and may prevent many people from undertaking an intervention that could provide significant benefits, as in these migraine sufferers.
Finally, we start to get to some actual science, and some claims we can evaluate beyond “no evidence provided!”:
“Let’s start with inflammation. The putative mechanism with regard to inflammation is that the omega-6 linoleic acid [LA] acts as a precursor to arachidonic acid [AA]; AA acts a substrate to form eicosanoids, and the eicosanoids AA is used to form may be pro-inflammatory. Ergo, as the logic goes, increasing PUFA – particularly LA – increases inflammation.”
Well, that’s not the most logical starting point, as one generally doesn’t start in the middle of the story, and of course he doesn’t quote anyone actually saying this. He continues:
“Except there is no evidence that either increasing or decreasing LA levels alters levels of AA in humans. A review of 36 human intervention studies [his link to (Rett & Whelan, 2011)] highlighted that neither increasing LA levels by up to 551%, or decreasing LA levels by 90%, altered concentrations of AA in plasma, serum, or red blood cells [erythrocytes], despite increasing LA intake resulting in increased membrane phospholipid LA content. Putative mechanism does not = biological effect. The following illustration helps to illustrate why:”
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| Image from (Flanagan 2020b) Red notation mine. |
See diagram to right (provenance unknown, he does not list a reference, but as it does not represent what he describes it as representing—see D6D—it’s unlikely that he created it).
This is, believe it or not, a necessarily drastically over-simplified version of metabolism and inflammatory pathways in which n-6 is involved! It leaves out quite a few well-recognized inflammatory pathways, however.
As that image makes clear, there are many different pathways, not just the one Flanagan provides the studies for. (Yes, this begins to look like another strawman, but we’re not keeping track!)
So let’s start by looking backwards, from the most well-recognized and effective marker/mediator of inflammation, C-reactive protein (CRP) (Watson et al., 2019)—which is not in the image above. CRP isn’t just a marker, it’s an active player in the body’s immune system:
“...it can be said that CRP possesses the functionality of a host defense molecule against not only atherosclerosis but against all diseases caused by proteins when proteins behave like a pathogen or a toxic molecule, in a life cycle that begins as free CRP in circulation and ends in ligand-bound mCRP at sites of inflammation...” (Singh & Agrawal, 2019)
Oxidized LDL (oxLDL) is such a toxic molecule, and indeed one of the roles of CRP is to bind to oxLDL and help remove it:
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| Figure 1 from (Deleanu et al.,2016), showing oxidation of n-6 fats in oxLDL. |
"...CRP also binds to the PC moiety of oxidized phosphatidylcholine [PtC] present in OxLDL and apoptotic cells, where CRP triggers the early steps of the classical complement pathway..."
“In addition, CRP only bound to unsaturated PtC in proportion to their degree of oxidation and unsaturation (Fig. 2A) and did not bind to the saturated PtC even if exposed to the same oxidizing conditions (Fig. 2A)." (Chang et al., 2002)
We’ve known since the 1980s that what is oxidizing in LDL is n-6 fats, (Deleanu et al., 2016) and:
“The nature of the substrate for lipid peroxidation, mainly the polyunsaturated fatty acids in lipid esters and cholesterol, is a dominant influence in determining susceptibility. As noted by Esterbauer et al. (52), there is a vast excess of polyunsaturated fatty acids in LDL, in relationship to the content of natural, endogenous antioxidants. The importance of the fatty acid composition was impressively demonstrated by our recent studies of rabbits fed a diet high in linoleic acid (18:2) or in oleic acid (18:1) for a period of 10 wk. LDL isolated from the animals on oleic acid-rich diet were greatly enriched in oleate and low in linoleate. This LDL was remarkably resistant to oxidative modification, measured either by direct parameters of lipid peroxidation (i.e., TBARS and conjugated dienes) or by the indirect criterion of uptake by macrophages (53)….
“In a recent study, human volunteers were fed a similar oleic acid-rich diet. When their
LDL was tested for susceptibility to oxidative modification, it was reduced albeit to a lesser degree than that noted in the rabbit studies (54). These studies demonstrate the feasibility of dietary modification of LDL fatty acid content in order to reduce its susceptibility to modification.” (Witztum & Steinberg, 1991)
Multiple studies have confirmed that dietary manipulation can alter the fatty-acid composition of LDL, and hence its susceptibility to oxidation (Abbey et al., 1993; Hargrove et al., 2001; Parthasarathy et al., 1990; Reaven et al.,1994; Spiteller & Spiteller, 2000).
Thus:
“In conclusion, our data show that Ox-LDL and hs-CRP levels correlate positively in ACS [acute coronary syndrome] patients, supporting the hypothesis that Ox-LDL and CRP may play a direct role in promoting the inflammatory component of atherosclerosis in these individuals.” (Zhang et al., 2012)
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| Table 4 from (Bemelmans et al., 2004) Image cropped to focus on CRP. |
Notably, while CRP is a reaction to inflammation, oxLDL is a cause of inflammation, due to its oxidized, dietarily induced n-6 fats (Hao et al., 2015; Kennedy et al., 2011; Norris et al., 2011; Que et al., 2018; Shapira & Pinchasov, 2008; Stiekema et al., 2019; van der Valk Fleur M. etal., 2016; Witztum, 2002) and ad nauseum, if you are interested.
So where does this get us as to diet and inflammation? (Bemelmans et al., 2004) looked at the question directly:
“Because of the lower CRP level, the present results suggest that a six-fold increased ALA intake may have anti-inflammatory effects, when investigated against an LA-rich background diet.”
While (Su et al., 2017) performed a systematic review and meta-analysis of RCTs in humans and found:
“However, in subjects with greater increase in LA intake, LA tends to increase the blood concentration of CRP.”
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| Attribution for CRP and OxLDL images at end. |
There are a number of caveats and conditions which are not discussed here, and a discussion of the scope of the inflammation induced via oxLDL is outside the need for a simple proof that it happens, QED.
So let’s go back to Flanagan. After introducing his little diagram above and his supporting studies, he states:
“This is where the buck just stops for the inflammation argument. There is no evidence that the putative mechanism is operative, nor that there is an inflammatory effect of dietary LA in actual Homo Sapiens.”
Well. Obviously that’s wrong.
Let’s discuss another pathway, demonstration of which is a little less involved than the above, although crucial, path from dietary LA to CRP. This pathway, unlike the rather more obvious one above, is in his diagram.
“Does inflammation have a role in migraine?”
“Migraine is a prevalent disorder, affecting 15.1% of the world’s population…. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system.” (Edvinsson et al., 2019)
This hypothesis was tested, in an animal model of course (we will get to why an animal model) in 2020:
“In preclinical models, HODEs, EpOMEs and DiHOMEs have been observed to participate in numerous (patho)physiological processes during inflammatory pain including mechanical and thermal hyperalgesia [excess pain]… We demonstrate two 11-hydroxy-epoxides increased proportions of responsive TNs [trigeminal neurons] in a concentration-dependent fashion, similar to PGE2. Further investigation revealed that exposure produced Ca2+ responses with high potency, at μM range, comparable to well-known pain mediators, LA and 9-HODE (Patwardhan et al., 2010, 2009).” (Doolen et al., 2020)
Here’s Flanagan’s diagram again, this time with the emphasized terms above circled. (I also highlighted soluble epoxy hydrolase (sEH), as this will be mentioned later):
Incidentally, LA is a “well-known pain mediator”? Hmm…
Now, they’re using “our rodent friends” here because they already demonstrated that reducing dietary linoleic acid in humans (and increasing n-3) reduces headache/migraine pain. In science, when one notices an effect in humans, one attempts to find out via an animal model what the mechanism is (Flanagan would probably still find this “odd”):
“In this randomized trial, the combination of increasing dietary n-3 fatty acids with concurrent reduction in n-6 LA (the H3-L6 intervention) produced statistically significant, clinically relevant improvements in headache hours per day, severe headache days, and headache-related quality of life compared to baseline, and compared to the n-6-lowering (L6) intervention. Prior to the intervention, this chronic headache population averaged 23 headache days per month and 10 headache hours per day, despite using an average of 6 different headache-related medications per subject.” (Ramsden, Zamora, et al., 2013b)
Now, before one jumps to the conclusion that it was the n-3 fats that had the effect and not the n-6 lowering, let’s look at another study, (Pradalier et al., 2001). The title will suffice, I think: “Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo.”
(While it’s outside the scope of this discussion, it’s important to note that the n-3 and n-6 fats interact, via some of the pathways above, and that increasing n-3 can replace n-6 in tissue, provided you also lower n-6. That may explain these results.)
“We hypothesized that hyperactive metabolism of n-6 linoleic (n-6 LA) and arachidonic (n-6 AA) acids, and insufficient metabolism of n-3 eicosapentaenoic (n-3 EPA) and docosahexaenoic (n-3 DHA) acids, contribute to headache pathogenesis."
The success of (Ramsden, Zamora, et al., 2013b) has led to a further, much larger, test detailed in (Mann et al., 2018), which is ongoing.
One of the really interesting findings in the study was:
“As expected, the L6 intervention reduced erythrocyte n-6 LA and a number of its pronociceptive [pro-pain] derivatives compared to baseline. Unexpectedly, the L6 intervention also reduced a number of pronociceptive HETEs compared to baseline, despite no change in their precursor n-6 AA in erythrocytes.”
So what this tells us is that Flanagan’s argument, that since AA didn’t change in blood, there was no effect possible on inflammation, was wrong.
“Although biochemical effects were less pronounced compared to the H3-L6 group, this L6 intervention did significantly alter erythrocyte fatty acids and their bioactive derivatives in a manner that we hypothesized would reduce pain.”
AA quantity seems to be tightly regulated in serum. Those studies were correct. But there are many other studies showing that the downstream metabolites of AA, like these HETEs, are still affected by dietary LA. This has been demonstrated in many other conditions with inflammatory components, which are outside the scope of this discussion.
I highlighted sEH in Flanagan’s diagram, because it was discovered by Bruce D. Hammock (Kodani & Hammock, 2015), who recently said:
“Seventy-five percent, by weight, of the drugs sold in the world work on a single pathway called the arachidonic cascade, where arachidonic acid is converted by cyclooxygenase into prostaglandins, which are strongly pro-inflammatory.” (Rice, 2020)
That’s the pathway detailed in Flanagan’s diagram. Overstimulation of that pathway arguably, is our biggest health problem. Aspirin, for instance, prescribed for cardiovascular disease prevention, works on that pathway. Obviously, one of the most common uses for drugs like aspirin is headache.
Hammock further commented, in a recent podcast:
"So we've got... a very fine-tuned biochemical system and we've sort of thrown the monkey wrench into it by eating too much of a good thing with [linoleic acid]." (Gornoski, 2021)
What was it Flanagan said again?
“This is where the buck just stops for the inflammation argument. There is no evidence that the putative mechanism is operative, nor that there is an inflammatory effect of dietary LA in actual Homo Sapiens.”
All this evidence was available when he wrote that. One can only conclude he’s completely unaware of the evidence on this subject. Spreading misinformation about an important health topic like this is not helpful and may prevent many people from undertaking an intervention that could provide significant benefits, as in these migraine sufferers.
Thoughts on 'Of Rats and Sidney Diet Heart...', Alan Flanagan's Post Defending Seed Oils
From that article:
"Highlights
- "The United States saw a catastrophic rise in heart disease during the mid-20th century most likely related to changes in dietary linoleic acid intake.
- "Researchers found a significant disparity in the incidence and prevalence of heart disease, with cultures eating pre-industrial diets having extremely low incidence, if any, compared to populations eating industrialized diets.
- "Before any human trials had been conducted, leading public health organizations assumed that lowering serum cholesterol levels and increasing seed oil consumption would lead to better health outcomes.
- "In the United States, steadily rising seed oil consumption drove linoleic acid intake up from 2% of calories in the early 1900s to around 8.9-9.4% by 2010.
- "By the late 20th century, research had revealed that the susceptibility of LDL particles to oxidation was a much better predictor of heart disease than changes in total cholesterol or LDL cholesterol levels.
- "Numerous human clinical trials demonstrate that, like smoking, increased seed oil consumption increases LDL’s susceptibility to oxidation, posing a major concern when it comes to cardiovascular disease.
- "Like smoking, seed oil consumption also induces oxidative stress, induces insulin resistance, damages the arterial endothelial wall, and increases oxidized LDL – a common mechanism that causes heart disease."
And if you are wondering, this is the puppy.
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| "Figure 3. Mendelian randomization analysis. A significant deviation from zero of the estimate of causal effect using all SNPs (solid red line) suggests a causal relationship between the metabolite and CHD." (Ganna et al., 2014) |
Oh dear. So sorry... *
"The Mendelian randomization analysis... suggested a weak, but positive causal effect of MG 18:2 on CHD risk (odds ratio, 1.05... per SD increment in MG 18:2; P-value = 0.05) and a lack of causal effect for LysoPC 18:1, 18:2 and SM 28:1."
Even worse:
"...In the multivariable analysis for association with CHD, we separately included two covariates in addition to the main cardiovascular risk factors: [CRP] and statin treatment. The associations between the four metabolites and incident CHD were essentially the same...
"Lysophosphatidylcholines were negatively associated with BMI, markers of inflammations and subclinical cardiovascular disease, while a reverse pattern was observed for MG 18:2."
“We found evidences [sic] for a causal effect of MG 18:2 on CHD independently of triglycerides levels."
And: "We observed a strong positive association between MG 18:2 and CHD."
So what are they saying? A few terms, so you can understand the jargon:
So they looked at metabolites of various things in the body (Metabolomics) and found a correlation between a form of linoleic acid (LA) and heart disease. LA is generally found in triglycerides (TG), but here they found the association with TG was weaker than that of LA with heart disease. TG is an established risk factor for heart disease.
Moreover they found that this effect became stronger as the amount of LA increased: “a weak, but positive causal effect of MG 18:2 on CHD risk (odds ratio, 1.05... per SD [standard deviation] increment in MG 18:2…” This is known as a dose-response, and suggests that causation is present (criteria 5 in the Bradford Hill list of criteria for determining possible causation from observed data).
More:
"Several observations suggest an involvement of MG 18:2 in the pathogenesis of CHD. First, MG 18:2 is central in the synthesis and breakdown of triglycerides and a causal effect of plasma triglyceride levels on CHD risk have recently been supported by a large Mendelian randomization analysis [11]. Although highly correlated, when both MG 18:2 and triglycerides were included in the same model, both showed independent significant associations with CHD. Moreover, when separately added to a model with main cardiovascular risk factors, MG 18:2 was a better predictor of CHD than triglycerides. Second, MG 18:2 was associated with higher levels of cardiovascular risk factors and markers of subclinical CVD and oxidative stress. Third, Mendelian randomization analysis suggested a weak, but positive causal effect of MG 18:2 on CHD risk. Several SNPs reported for association with CHD remained associated with MG 18:2 (in the PCSK9, HHIPL1, PLG, ApoE/ApoC1, COL4A1/COL4A2 regions, P-values,0.05), even after adj. for main cardiovascular risk factors.”
"Our study has several strengths. To our knowledge, this is the largest study investigating the metabolome in relation to incident CHD."
"In conclusion, in the largest study of the metabolome in relation to incident CHD to date, we identified [LysoPC]s 18:1, 18:2, monoglyceride 18:2 and sphingomyelin 28:1 as risk factors of coronary heart disease and suggested a causal effect for monoglyceride 18:2 on CHD."
So much for the claims there’s no epidemiology supporting the hypothesis that LA from seed oils is causal in heart disease.
"Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease" (Ganna et al., 2014)
Of course linoleic acid is hardly "novel"... The link between LA and heart disease goes all the way back to the 1950s:
“Our results are in accord with the recent work of [(Böttcher et al., 1960)] who showed conclusively that human atherosclerotic plaques have a high content of linoleic acid which increases with the severity of the disease….
“This result would support the view that linoleic acid is essential for the production of atherosclerotic plaques.” (Gresham & Howard, 1961)
If you want more information on the link between seed oil and heart disease, see our work here (Zero Acre Editorial Team, 2022)
I discussed with Prof. Tom Brenna the importance of choline and phospholipids in the metabolism of fat in the body (Goodrich,2022), and I find it very interesting that the correlations between LA in phospholipid form (LysoPC 18:2) and triglyceride form (MG 18:2) is different. Monoglycerides can have very distinct effects on the body (Poursharifiet al., 2017), this may be such a case.
So what's the most messed up thing about this analysis?
They never mention the word "linoleic," or any part of it.
I found this while pulling threads, I never would have found it looking for any useful search term.
* Came across this paper today, while working on something concerning diabetes (Al-Sariet al., 2021). Really, you shouldn’t have to dig into something like this (ChEBITeam, 2018) to find a pretty important paper, but the Tower of Babel story is true in every important way, except perhaps for not actually having happened.
** I have some serious issues with MR, which I will not go into here, but since I have been told that there is no evidence using MR that LA causes CVD, I found this satisfying.
Al-Sari, N., Schmidt, S., Suvitaival, T., Kim, M., Trošt, K., Ranjan, A. G., Christensen, M. B., Overgaard, A. J., Pociot, F., Nørgaard, K., & Legido-Quigley, C. (2021). Changes in the lipidome in type 1 diabetes following low carbohydrate diet: Post-hoc analysis of a randomized crossover trial. Endocrinology, Diabetes & Metabolism, 4(2), e00213. https://doi.org/10.1002/edm2.213
Böttcher, C. J. F., Woodford, F. P., Romeny-Wachter, C. C. T., Houte, E. B., & Gent, C. M. V. (1960). Fatty-Acid Distribution In Lipids Of The Aortic Wall. The Lancet, 275(7139), 1378–1383. https://doi.org/10.1016/S0140-6736(60)91153-3
ChEBI Team. (2018). Phosphatidylcholine 35:4 (CHEBI:91322) [Informational]. European Molecular Biology Laboratory; Chemical Entities of Biological Interest. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:91322#25502724
Ganna, A., Salihovic, S., Sundström, J., Broeckling, C. D., Hedman, A. K., Magnusson, P. K. E., Pedersen, N. L., Larsson, A., Siegbahn, A., Zilmer, M., Prenni, J., Arnlöv, J., Lind, L., Fall, T., & Ingelsson, E. (2014). Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease. PLoS Genetics, 10(12), e1004801. https://doi.org/10.1371/journal.pgen.1004801
Goodrich, T. D. (2022, September 1). Podcast Ep. 5: Prof. Tom Brenna on Omega-3 and Omega-6 in Human Health—with Dr Brian Kerley [Blog]. Yelling Stop. http://yelling-stop.blogspot.com/2022/09/podcast-ep-5-prof-tom-brenna-on-omega-3.html
Gresham, G. A., & Howard, A. N. (1961). The Effect of Dietary Fats and Synthetic Glycerides on the Production of Atherosclerosis and Thrombosis in the Rat. British Journal of Experimental Pathology, 42(2), 166–170. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082415/
Poursharifi, P., Madiraju, S. R. M., & Prentki, M. (2017). Monoacylglycerol signalling and ABHD6 in health and disease. Diabetes, Obesity & Metabolism, 19 Suppl 1, 76–89. https://doi.org/10.1111/dom.13008
Zero Acre Editorial Team. (2022, August 12). Seed Oils as a Driver of Heart Disease [Advertisement]. Zero Acre. https://www.zeroacre.com//white-papers/seed-oils-as-a-driver-of-heart-disease
Dr. William Li is a physician and research scientist at his institute, the Angiogenesis Foundation in Massachusetts.
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| Eat to Beat Disease: The New Science of How Your Body Can Heal Itself |
“EAT TO BEAT DISEASE shows you how to integrate the foods you already love into any diet or health plan to activate your body’s health defense systems —Angiogenesis, Regeneration, the Microbiome, DNA Protection, and Immunity —to fight cancer, cardiovascular disease, diabetes, neurodegenerative disease, autoimmune disease, and other debilitating conditions.”
It’s an interesting book, and a bit different from any I’ve seen before, in that he starts from what he says are the five functions essential for health and repair: Angiogenesis, Regeneration, the Microbiome, DNA Protection, and Immunity, and then backs into foods that support those functions. This leads to his 5 x 5 x 5 “framework” for eating better. It’s not meant to be a strict program of eating, but is a series of guidelines to pick better foods in your day-to-day life, while allowing for flexibility and not requiring perfect behavior. Aside from the list of foods, it’s also not complicated.
He starts from a presumption which should be self-evident, that medicine has made many advances, “But, despite all of the success, the sobering fact is that the rates of new disease are skyrocketing.”
He attributes this, correctly I think, to our diet, and to Medicine’s lack of attention to it:
“Not many doctors know how to discuss a healthy diet with their patients. This is through no fault of the individual doctors, but rather a side effect of how little nutrition education they receive. According to David Eisenberg, a professor at the Harvard T.H. Chan School of Public Health, only one in five medical schools in the United States requires medical students to take a nutrition course. On average, medical schools offer a mere nineteen hours of coursework in nutrition, and there are few postgraduate continuing education classes on nutrition for doctors already in practice.”
Being at root a physician of the vascular system, he starts there (which of course allows him to look at every system in the body, since all depend on the vascular system to some extent). Angiogenesis is the process of the body growing new blood vessels. Surprisingly, this takes place regularly, and is involved in wound healing (good), and atherosclerosis, cancer, and blindness; and is an area in which Dr. Li is a pioneer.
“The goal of an angiopreventive diet is to keep the body’s angiogenesis defense system in a healthy state of balance. This sometimes becomes a point of confusion among Western-trained doctors, because balance is not typically part of their lexicon for disease treatment. Balance is a more familiar concept in Ayurvedic and traditional Chinese medicine, in which the focus is on balance for preventive health. Health is viewed in those systems as the presence of balanced systems in body and mind.”
Lack of balance leads to dysregulation, where the homeostatic systems that are supposed to keep things in balance (within reason) get out of order, leading to the chronic diseases.
It’s an approach I whole-heartedly agree with.
The book is presented logically, in an easy-to-follow manner. He goes through each “5” of the framework, so the first five chapters cover the topics mentioned above (angiogenesis, etc), and so on.
He offers a suggestion of surviving in the kitchen, and a bunch of recipes. You have to like a book about food where this is the first recipe!
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| From Eat to Beat Disease. |
Li seems to approach this with a strong “plant-based” (aka vegan) view. (“Vegan” appears in the text nine times, and “plant-based” 32, “paleo” appears eight times, "red meat" appears 13 times (mostly negatively), and “carnivore” does not appear at all.) However, while I think it is fair to say that Li is biased in that direction, or at least influenced by that school of thought; he is open-minded. He is somewhat critical of the Paleo diet (calling it an “elimination” diet, a critique he does not level the vegan or vegetarian diets he discusses, but he also describes the success of Loren Cordain’s autoimmune protocol, a Paleo-based diet geared towards reducing autoimmune disease. He expresses some concerns (unfounded, I think) about the ketogenic diet, but also describes some successes of that diet for treating cancer.
“Glioblastoma was used to study the ketogenic effect, in part because of the importance of cancer stem cells in this disease. Even if this cancer is successfully removed or treated initially, the glioblastoma stem cells help it return aggressively. Avoiding added sugar and adhering to a ketogenic diet are strategies that may be helpful in fighting brain tumors.”
Many of the papers he cites or discusses start with an assumption that a plant-based diet is optimally healthy, and even those that he has authored himself make this claim:
“A plant-based diet is increasingly becoming recognized as a healthier alternative to a diet laden with meat.... We suggest that a shift toward a plant-based diet may confer protective effects against atherosclerotic CAD by increasing endothelial protective factors in the circulation while reducing factors that are injurious to endothelial cells.” (Tuso et al., 2015)
Another paper contrasts a “plant-based” diet to a Western diet (Fotsis et al., 1993), and that’s a comparison where the PB diet will win (in the short term, at least) as nothing seems worse than a Western diet.
But this is not a vegan or plant-based diet book, by any means.
“Because the 5 × 5 × 5 is a framework, not a prescription, it is adaptable to whatever diet plan you’re currently following, whether it’s Paleo, Whole30, Ornish, low-carb, plant-based, gluten-free, allergen-free, or ketogenic—and it’s easy to adopt if you don’t follow a plan at all.”
Many of the foods he recommends as part of his list of prescribed foods are indeed fish, but the only meat is dark chicken. He does not proscribe red meat, although he certainly discourages it.
Ultimately the cons to this approach are quibbles. The pro is that it’s a flexible, relatively easy-to-follow diet plan that you can overlay on whatever you are currently doing. Adding foods that are healthy—and it’s fair to say they are all healthy, and he includes beer and wine in moderation—will make any diet better, so even if you are on a junk-food Modern American Diet your diet will improve.
“For the 5 × 5 × 5 framework you first create your own personalized preferred food list (PFL) based on foods you actually enjoy. You create your list from the master list of all of the foods that follow.”
It’s a long list, so I won’t reproduce it here, but the sections are:
Three sections only contain one item, and these sections tell you the most about this framework: Meat is only dark chicken, Oil is only extra-virgin olive oil (EVOO), and Sweets are only dark chocolate.
He obviously doesn’t like red meat, and recommends dark chicken, along with lots of cheeses, because of the vitamin K2—which is what your body needs, not the vitamin K found in vegetables. K2 is thought to be important to vascular health. He does recommend not eating the chicken fat. Li is not a fan of organ meats, although he does recommend oysters, the liver of the ocean.
Recommending only EVOO is due to Li not being a fan of omega-6 seed oils. While this is a major pro in my view, it’s also a con, as he doesn’t explicitly say so.
Instead, one must read between the lines:
“Tilapia has a high unhealthy ratio of omega-6 to omega-3 PUFAs, making it a less desirable fish from a health perspective.”
And:
“There was no cancer-risk-reducing benefit seen with seed oils.
And:
“For cancer protection, researchers have found that the higher the overall intake of marine omega-3 in the diet, the greater the benefit. In contrast, higher omega-6 PUFA consumption in relation to omega-3 PUFA (the omega 6:3 ratio), which comes from vegetable oil, for example, is linked to unhealthy inflammation and an increased risk of disease.”
I fully agree with those ideas, but I would have been helpful if he had been more explicit. (I asked him about this in the interview, he was quite explicit there.)
And by recommending only dark chocolate for your sweets, what I do personally, he is recommending against too much added sugar, something he discusses at length in the book.
I would have liked to have seen a similar discussion of omega-6 fats, which I think are a much bigger health issue than sugar.
His recommendations on meat are unfortunately not well-founded in science, unfortunately. He is concerned that meat can increase the production of TMAO, a chemical which is often cited in the vegan literature as a reason not to eat meat. However, “Among food groups, TMAO directly correlated with the intake of fish, vegetables, and whole-grain products, but not meat, processed meat, and dairy products,” which is from a paper titled, “Plasma TMAO increase after healthy diets: results from 2 randomized controlled trials with dietary fish, polyphenols, and whole-grain cereals” (Costabile et al., 2021). Li’s diet is indeed a healthy one, and it will indeed raise your TMAO. Fish is the single biggest source of TMAO production. It’s not a reason to avoid Li’s framework, or red meat. The biggest issue with red meat consumption that I’m aware of is when it is consumed with high levels of omega-6 fats (Guéraud et al., 2015; Pierre et al., 2003), which, happily, Li steers his readers away from.
Quibbles aside, if you follow Li’s framework, and increase your consumption of fruits, vegetables, fish, dairy, and avoid seed oils and sugar, you will surely improve the quality of your diet immeasurably.
When David suggested interviewing Dr. Li, it was at the suggestion of his listeners. Frankly, I was rather dreading it, as it pretty quickly became apparent that he was on the plant-based side of things as I did my initial research.
So I was quite happily surprised when I went through his book, and in speaking to him. While we have some disagreements, it’s a well-founded book that takes a reasonable approach to nutrition, and is more cognizant of the science behind a lot of the issues in the Modern American Diet than, say, the Dietary Guidelines.
I’d recommend this book to anyone that is looking to fix their diet for the first time, as it’s a good introduction to some basic principles of diet and health, or to someone who is simply looking to expand their understanding of what makes a healthy diet, and is looking for a more holistic view. From either perspective he has a better approach than a typical physician with little interest or training in the subject. The advantage of Li’s background in vascular health is that he starts from a holistic view, and thus makes a series of very practical recommendations.
The recommendations in Li's book reminds me of both a traditional Japanese diet, with its emphasis on fish and vegetables, while avoiding fat and sugar; and also of Dr. Terry Wahls’ excellent Minding My Mitochondria (Wahls, 2010), also heavily focused on plant nutrients and from a vegetarian background.
I recommend Eat to Beat Disease, it’s a helpful addition to a happily burgeoning literature of how diet can improve health..
Costabile, G., Vetrani, C., Bozzetto, L., Giacco, R., Bresciani, L., Del Rio, D., Vitale, M., Della Pepa, G., Brighenti, F., Riccardi, G., Rivellese, A. A., & Annuzzi, G. (2021). Plasma TMAO increase after healthy diets: Results from 2 randomized controlled trials with dietary fish, polyphenols, and whole-grain cereals. The American Journal of Clinical Nutrition, nqab188. https://doi.org/10.1093/ajcn/nqab188
Fotsis, T., Pepper, M., Adlercreutz, H., Fleischmann, G., Hase, T., Montesano, R., & Schweigerer, L. (1993). Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proceedings of the National Academy of Sciences, 90(7), 2690–2694. https://doi.org/10.1073/pnas.90.7.2690
Guéraud, F., Taché, S., Steghens, J.-P., Milkovic, L., Borovic-Sunjic, S., Zarkovic, N., Gaultier, E., Naud, N., Héliès-Toussaint, C., Pierre, F., & Priymenko, N. (2015). Dietary polyunsaturated fatty acids and heme iron induce oxidative stress biomarkers and a cancer promoting environment in the colon of rats. Free Radical Biology and Medicine, 83, 192–200. https://doi.org/10.1016/j.freeradbiomed.2015.02.023
Pierre, F., Taché, S., Petit, C. R., Van Der Meer, R., & Corpet, D. E. (2003). Meat and cancer: Haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats. Carcinogenesis, 24(10), 1683–1690. https://doi.org/10.1093/carcin/bgg130
Tuso, P., Stoll, S. R., & Li, W. W. (2015). A plant-based diet, atherogenesis, and coronary artery disease prevention. The Permanente Journal, 19(1), 62–67. https://doi.org/10.7812/TPP/14-036
Wahls, T. L. (2010). Minding My Mitochondria 2nd Edition: How I overcame secondary progressive multiple sclerosis (MS) and got out of my wheelchair. (2nd edition). TZ Press. https://amzn.to/3v6G03s
This turned out to be quite an interesting interview, much more so than I had anticipated. I think in some ways it's the best interview David and I have done.
"William Li MD on Seed Oils, Cancer, and Food as Medicine"
"David Gornoski and Tucker Goodrich sit down with Dr. William Li, an internationally renowned physician, scientist, and author of the New York Times bestseller Eat to Beat Disease. The discussion revolves around why we are seeing cancer rates skyrocketing in the US, anti-VEGF treatment for neovascular eye disease, seed oil consumption, the cause of angiogenesis dysregulation, the right diet for a strong immune system, and more."Video:
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| Eat to Beat Disease: The New Science of How Your Body Can Heal Itself |
“EAT TO BEAT DISEASE shows you how to integrate the foods you already love into any diet or health plan to activate your body’s health defense systems —Angiogenesis, Regeneration, the Microbiome, DNA Protection, and Immunity —to fight cancer, cardiovascular disease, diabetes, neurodegenerative disease, autoimmune disease, and other debilitating conditions.”
