Sometimes, it takes what seems to be a really good idea, a long time to proliferate through the paleosphere, and into the mainstream. Sometimes, even though we’re all super-smart over here in Paleo-land, we actually get things wrong.
Only slightly less than a year ago, it was the standard recommendation of each of the Paleo “leaders” (if there is even such a thing), that everybody take supplemental fish oil, or cod liver oil as part of a healthy diet based upon the Paleo Template. It took a while, but finally we began to see this recommendation filtering down into the mainstream. Suddenly it seemed everything on TV was about the amazing health benefits of Omega-3’s. EPA this, DHA that…..it’s everywhere now…..
But it seems that we have a bit of problem there, because now that the mainstream has caught on to what we were once preaching, the Paleo powers-that-be have since moved on to something else, and decided that fish oil supplementation may not be the best idea after all. What if Omega-3’s cause cancer?
Back in 2011 on April 11th, Paul Jaminet co-writer of The Perfect Health Diet, published a lengthy article on his blog site called, “Omega-3s, Angiogenesis and Cancer: Part II” that looked into some of the problems with Omega-3s.
What is Angiogenesis?
“Angiogenesis performs a critical role in the development of cancer. Solid tumors smaller than 1 to 2 cubic millimeters are not vascularized. To spread, they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes.
Beyond the critical volume of 2 cubic millimeters, oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor, causing a state of cellular hypoxia that marks the onset of tumoral angiogenesis.
New blood vessel development is an important process in tumor progression. It favors the transition from hyperplasia to neoplasia i.e. the passage from a state of cellular multiplication to a state of uncontrolled proliferation characteristic of tumor cells.
Neovascularization also influences the dissemination of cancer cells throughout the entire body eventually leading to metastasis formation.The vascularization level of a solid tumor is thought to be an excellent indicator of its metastatic potential.” – Angioworld.com
This article is the second of a set of three, so we’re picking up in the middle, which may make some of the references and points seem misplaced and poorly explained, so I’ll try to do my best to keep it on point. Paul started out by talking about an article called the “Brasky Paper” that was earlier commented upon by Denise Minger…
“Denise Minger wrote a commentary on this paper for Mark’s Daily Apple, which is excellent. Her conclusion – “given the oxidation-prone nature of all polyunsaturated fats, a massive intake of omega-3’s – despite their brilliance in moderation – could potentially do more harm than good” – is the proper one.
A few of Denise’s observations, however, could stand elaboration.
The study measured the fraction of serum phospholipid fatty acids in various polyunsaturated and trans-fat species, not dietary intake. This is the right parameter to measure, as fatty acid profiles can be measured precisely while dietary intakes assessed through questionnaires are notoriously unreliable. Also, phospholipids are the fats in cell membranes, and these are the ones involved in the inflammatory signaling pathways long thought to drive cancer risk. So cell membrane lipid measurements have the best chance to demonstrate a link to cancer risk.
Denise makes the important point, however, that the connection between dietary fish oil intake and serum fatty acid profile is not simple. Higher DHA intake raises phospholipid DHA levels, but lower intake of non-omega-3 fats also raises the DHA fraction. She points to a study  comparing a low-fat diet (20% fat, 6.7% PUFA, n-6:n-3 ratio 11.1) to a high-fat diet (45% fat, 15% PUFA, n-6:n-3 ratio 12.3). The low-fat diet had more of its fat in the form of long-chain omega-3s, but the specific DHA intake on the diets was not reported. Membrane DHA ended up 28% higher on the low-fat diet.
So if DHA is dangerous, low-fat dieters will be in the most trouble. Another reason to eat a high-fat diet!”
“Here are a couple of possible explanations for this pattern:
1. DHA is bad: DHA doesn’t drive early cancer development but does drive late-stage cancer growth – i.e. the transition from low-grade to high-grade cancer. So the DHA consumers got the high-grade cancers. Angiogenesis does, in fact, drive the shift from low-grade to high-grade cancer, so a DHA-angiogenesis association would be consistent with this explanation.
2. Hospital diet advice is bad: DHA was a marker at the start of the study for conscientious, educated, disciplined persons who followed health advice and ate fish oil. When these people were diagnosed with low-grade cancer, they followed the dietary advice of their cancer dietitian. The dietitian’s advice? Eat lots of wheat, whole grains, legumes, and vegetable oils. It could be the conscientious folks who followed bad diet advice from the hospital dietitian who got the high-grade cancers.
So there is a possible confounding effect.”
At this point, Paul talked about the fact that there were an abundance of studies on the effects of DHA that either showed a small protective nature against cancer, or no effect at all.
“So the score was 4 studies finding that DHA is associated with less cancer, 1 that it is associated with more, and a boatload that it had no association.
Now there are two ways of interpreting this general insignificance of DHA against cancer. One is to note that there are slightly more studies showing DHA to have benefits than harm, and therefore to judge that DHA might be helpful against cancer.
But another, equally plausible, interpretation is this. Most Americans eat far too much omega-6, and their omega-6 to omega-3 tissue ratio is too high, which is pro-inflammatory via the COX-2 pathway. Eating omega-3s including DHA reduces inflammation by downregulating the COX-2 pathway. This accounts for the well-attested benefits of DHA against cardiovascular disease. Now, cancer is promoted by COX-2 pathway inflammation, which is why COX-2 inhibitors such as aspirin and ibuprofen are protective against cancer.  DHA’s action to downregulate this pathway must generate an anti-cancer effect. But, unlike aspirin and ibuprofen, DHA has no observable effect on overall cancer risk. This suggests that DHA has other effects, unrelated to its anti-inflammatory activity, that are cancer promoting. These counterbalance the benefits from its anti-inflammatory effect. If DHA has pro-angiogenic effects that are independent of COX-2 mediated inflammation, then this could account for the observations”
“DHA and Angiogenesis in Macular Degeneration
Let’s start by going back to 2003 and a paper on the role of a compound called carboxyethylpyrrole (CEP) in age-related macular degeneration (AMD).  AMD is an eye disease caused by improper angiogenesis. Basically, malformed blood vessels overgrow the eye, causing retinal detachment and blindness. It afflicts 35% of those over age 75, and is the leading cause of blindness in developed countries.”
“CEP is uniquely produced by oxidation of DHA, not other PUFAs. Its abundance depends on DHA abundance, availability of retinyl proteins, and the level of oxidative stress.
CEP is elevated in AMD. The correlation is strong: a person in whom the immune system is trying but failing to clear elevated CEP levels almost invariably has macular degeneration (AMD)”
“So CEP is a great marker for AMD. Is it causal?
Well, first it’s worth noting that the retina is uniquely vulnerable to DHA oxidation:
Although rare in most human tissues, DHA is present in ~80 mol % of the polyunsaturated lipids in photoreceptor outer segments (13). The abundance of DHA in photoreceptors, the high photooxidative stress in retina, and the fact that DHA is the most oxidizable fatty acid in humans (13) suggests that DHA oxidation products may have possible utility as biomarkers for AMD susceptibility. ”
“DHA, Immunity, and Angiogenesis
This is a rich paper. Briefly, CEP has a physiological function: it is transiently elevated in wounds and recruits immune cells from bone marrow to the site of the wound. These immune cells further increase oxidative stress and promote angiogenesis; CEP levels are highest at the time of peak angiogenesis. CEP is highly elevated in cancers. Unlike in wounds, where CEP is elevated for a few days, in cancers CEP elevation is chronic.”
“You can accelerate angiogenesis and wound healing by adding CEP to the wound.”
“If you administer CEP-neutralizing antibodies to a normal wound, wound healing takes more than twice as long. This confirms that angiogenesis driven specifically by CEP (and therefore by DHA oxidation) is part of healthy wound healing.
Tumors use these same pathways to generate vessels and feed their growth.”
“Connection to Vitamin A
DHA is oxidized to a compound called HOHA which then combines with a protein, generally a retinyl (vitamin A-derived) protein to form CEP.
Cancers generate lots of CEP from DHA, and perhaps one way they do that is by generating lots of retinyl proteins. Cancers are known to have disturbed vitamin A biology with lots of retinyl”
“haven’t looked much into this literature but it may speak to higher cancer risk with excessive vitamin A intake. Thus high-vitamin A cod liver oil may be a double risk for cancer patients.”
I have to break in here, because that final statement really struck me. High-vitamin A cod liver oil may actually work to assist in cancer growth…..how’s that for a kick in the teeth!?
It looks like we have a recipe for angiogenesis:
DHA + retinyl + oxidative stress = angiogenesis
This recipe is invoked normally and properly during wound healing. But it is also invoked excessively in pathological contexts – notably in cancers and age-related macular degeneration, probably also in other angiogenesis-associated diseases such as arthritis, rosacea, obesity, psoriasis, endometriosis, dementia, and multiple sclerosis.
In the case of cancer, DHA oxidation to CEP might transform miniscule, harmless cancers to high-grade, life-threatening cancers.
Should this possibility affect our dietary omega-3 recommendations? Well, we need to know the relative importance of the three ingredients on the left side of the above equation in producing angiogenesis. Chris Kresser wondered in the comments Tuesday whether oxidation may be the key factor:
I question whether DHA supplementation would truly play a causative role in the absence of a *pro-oxidative environment*.
In other words, perhaps in someone eating a SAD, not exercising, under a lot of stress, etc. DHA is more easily oxidized and thus potentially carcinogenic.
But in someone that is keeping all other oxidative risk factors low (i.e. they’re avoiding n-6, exercising, managing stress, reducing exposure to chemical toxins, etc.) I tend to doubt that supplementing with DHA could cause significant harm.
That’s the last piece of the puzzle: how do we minimize the level of oxidized DHA?
As I replied to Chris in the comments, low-carb Paleo dieters are not out of the woods in regard to oxidative stress. Oxidative stress is generated normally during metabolism, immune function – and by cancers. If anti-oxidant minerals like zinc, copper, and selenium and vitamins like vitamin C are deficient, then oxidative stress can be very high on a low-carb Paleo diet.
At the moment, I think it’s prudent to eat no more than 1 pound of salmon or similar cold-water fish per week, to avoid further EPA/DHA supplements, and to avoid low-fat diets which tend to elevate membrane DHA levels. Moderate omega-3 consumption is especially important for those suffering from diseases of pathological angiogenesis – especially cancer. DHA is essential for good health – but in excess, it is probably dangerous.”
So there we have it. I think that Paul presents a good case against the combination of DHA, Retinyl (Vitamin A), and oxidative stress, which basically equates to the Standard American Diet plus fish oil.
Just for additional value, here is the conclusion from the subsequent and final article in the series “DHA and Angiogenesis: The Bottom Line”:
At the moment there’s some puffs of smoke but no fire. Observational studies weakly link high DHA, high vitamin A, and low antioxidant status to diseases of angiogenesis such as cancer.
This pattern would be consistent with the idea that the natural pathway used in wound healing to trigger angiogenesis – DHA oxidation and combination with retinyl protein to trigger TLR-2 pathways – is also important for cancer progression.
It suggests a strategy of reduced fish oil and vitamin A consumption and increased intake of certain antioxidants (such as lycopene, zinc, selenium, or NAC) may be helpful against cancer.
However, this idea needs testing. No study in animal cancer models has tested this dietary combination.
Given the many proven benefits of moderate amounts of fish oil, I don’t see a reason yet to alter our recommendation that healthy people should eat a pound of fish per week. That said, I do think very high intakes of fish or fish oil are ill advised. And I’m intrigued by the idea that dietary changes may have the potential to play a powerful role in recovery from diseases of angiogenesis such as cancer.”
This is another example of a situation where the standard American diet, and the American way of life can turn a potentially positive (although probably neutral) element, and turn it into something that could actually be harmful.
According to Dr. Ray Peat, another reason that these fish oils are seen as being beneficial in so many studies is that they actually suppress the immune system, which downregulates inflammation, and histamine production. This gives the appearance that they are making things “better”, but at what cost? A suppressed immune system isn’t a good thing, no matter how you look at it. Check out this article by Ray Peat for more info: Oils In Context.
Personally, I have completely stopped recommending fish oil supplements, including cod liver oil, and I stopped taking them myself a while ago. In light of this kind of evidence and much more that I have seen, I no longer see any benefit to supplementing with Omega-3 oils.
I think that a much more logical approach would to be to focus on eating meats that have a type of fat that is more compatible with our warm bodies. The fats found in fish are unsaturated so that the fish can swim around in cold waters, and their fat doesn’t become solid from the cold and make them sink to the bottom. These unsaturated fats oxidize very quickly at higher temperatures like we find inside our own bodies, which logically makes them a poor match for our biological environment. Is it any wonder that the stable saturated fats are the healthiest fats for human kind to eat?
Dr. Ray Peat also asserts that the “essential” status of these polyunsaturated fats is questionable at best. He says that there is only one poorly conducted study from the 1930s by Burr, Burr and Miller, that proposes that EPA and DHA are “essential” fatty acids. Check out the article here.
Sure, I still intend to eat some fish, but I’m not going to worry about getting my 3 servings of fish per week, when I can easily focus on eating meats that are inherently more compatible with my body like beef and lamb. Those animals with ruminant stomachs filter all of the polyunsaturated fats and turn them into saturated fats, which is exactly what I want. They eat the grass, so I don’t have to. What about you…..does any of this info change your mind on fish or fish oils? Let me know!
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Barry Cripps is a Paleo-based, Certified Nutrition and Wellness Consultant, who operates out of Bowling Green, Kentucky.
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