Watch Your Six
OnIn supplemental circles, omega-6 fatty acids are not very popular. They have been linked to chronic inflammation, and all the many health conditions driven by chronic inflammation. The fact that so many of these diseases have increased – by up to 10-fold since 1900 (ie 1) – roughly over a period during which our intakes of omega 6 fatty acids increased by up to a thousand-fold (2), has led many nutritionists and nutritional scientists to connect those two trends.
I tend to do so myself, although chronic inflammation is a complex process and there are many other factors, dietary and otherwise, which also affect inflammation (ie 3). You can’t blame it all on omega-6 (3), and I’m not against omega-6 fatty acids per se. I don’t like them when consumed in excess, as routinely occurs today.
The omega-6 arachidonic acid (AA) has always been in our diet, in animal products from eggs and meat to dairy. Its precursor linoleic acid (LA) has always been there too, in plant foods such as nuts and seeds and also in animal products. LA is an essential fatty acid, the essential precursor for AA and essential in its own right for the function and health of skin (4), brain (5, 6) and other tissues including the gonads (7). But it becomes harmful, as all nutrients do, when consumed in exaggerated amounts (i.e., 8).
How, then, do we know what is the right amount of LA for us?
The omega 6:3 ratio has long been considered a meaningful way of judging and optimizing your PUFA intake. Recently however professor William Harris, an acknowledged expert on dietary fatty acids, has argued for a shift away from the 6:3 ratio as a marker of ie cardiovascular risk to the omega-3 index (ie 9), deeming the latter to carry more overall prognostic weight.
I believe that Harris is correct, but only in the context of the current fish oil market.
It is possible to have a seemingly healthy 6:3 ratio while being depleted in both 6- and 3-PUFAs, a configuration I have often seen in patients suffering from medically ill-advised ultra-low-fat diets. They typically have supra-normal levels of palmitic, stearic, and oleic acids, all of which we can synthesize from acetyl-CoA, and frequently present with dermatological, musculoskeletal, and other inflammatory problems.
Less common is an apparently good 6:3 ratio combined with very high levels of both 6- and 3-PUFAs, which I have seen, very occasionally, in keto-dieters taking very large doses of fish oil. Given the increased oxidative stress such individuals are likely to experience, I don’t believe this to be a healthy configuration either. (NB I have only seen blood data, and cannot comment on ratios in other tissues).
These two very different configurations show that the 6:3 ratio and the 3-index can be effectively uncoupled, and this leads me to suspect that Harris may be throwing the baby out with the bathwater. The 6:3 ratio has indeed been used in some studies of fish oil and found to have insufficient prognostic value, but the trial populations were almost certainly heterogeneous. Furthermore, almost all those trials used fish oils stabilized with the ‘wrong’ antioxidants, namely ascorbyl succinate, d-alpha tocopherol or astaxanthin.
Apologies to the old hands for repetition, but the following is important for new readers.
Firstly, the commonly used (and inappropriate) antioxidants do not support good secondary bioavailability of the 3-HUFAs (10).
Secondly, while these compounds slow oxidation of the highly oxidizable omega-3 PUFAs in the capsule or, for that matter, the steel holding tank, they do not prevent the formation of omega-3 peroxidation products in the far more aggressive environment they encounter when ingested. Once swallowed, EPA and DHA are exposed to inter alia extremes of pH, high pp O2 values as they pass through the pulmonary circulation, various forms of iron and other pro-oxidant species including oxidized vitamin E (ie 11).
That is why standard fish oil formulations produce significant levels of peroxidation products in the body (12-15), which exert pro-inflammatory, cytotoxic and arrhythmogenic effects (16-20). As these breakdown compounds are generally not measured during fish oil trials, or within routine assays of omega-3 and omega-6 fatty acids in the blood, here is another likely reason why the 6:3 ratio has not been more useful and why fish oil supplements have not fulfilled their early promise (21, 22).
The chaperones selected by the evolutionary process to protect the omega-3 PUFAs during their transition through the marine food webs are the phlorotannins (23, 24).
Due at least in part to the peroxidative problems, fish oils without amphiphilic polyphenols generally fail to achieve good secondary bioavailability (10, and below). The omega 3 index is not sufficiently elevated and the 6:3 ratio does not decline sufficiently, making it impossible for standard fish oils to achieve clinical benefits. This is the Cochrane Collaboration’s perspective (25, 26 and see 27 also), which I must agree with (10, 23, 24).
My experience with the fish oil / high-polyphenol olive oil blend is very different.
The Balance self-use test measures the 6:3 ratio, the omega-3 index and the major saturated and mono-unsaturated fatty acids in the blood. We use it to test those taking either standard fish oil, or a blend of fish oil and high-polyphenol olive oil in which olive-derived amphiphilic polyphenols mimic the amphiphile phlorotannins.
Our in-house library of circa 1.6 million samples shows that both olive and algal polyphenols are extremely effective in achieving good secondary bioavailability, where the standard antioxidants fail (10, 23, 24, 27, 28).
NB This collection of references provides only circumstantial but I think persuasive proof.
The library indicates that standard fish oil supplements bring the European average 6:3 ratio of 15:1 down to 10:1. which is insufficient to manifest an anti-inflammatory effect (10). In contrast, eating fish or consuming a fish oil / olive oil blend at a dose adjusted to body weight (29) routinely drops the 6:3 ratio below 5 (10), the threshold where anti-inflammatory benefits emerge. And as the 6:3 ratio falls in this group, the omega-3 index inevitably rises.
The Balance test is also used dynamically, to monitor changing lipid levels. In those taking the fish oil / olive oil blend, falling 6:3 ratios and a rising omega-3 index both consistently predict the reduction or removal of inflammatory symptoms (30), and the move towards pharmaceutical independence is seen in the majority of subjects who use the blend (30).
If a correctly designed fish oil formulation is used, providing the omega-3’s with good secondary bioavailability, the 6:3 ratio must fall as the omega-3 index rises because the 6:3 ratio and the 3 index are mechanistically coupled.
To recap, I believe that Harris’ view of the 6:3 ratio as ‘flawed and unhelpful’ and the omega-3 index as being the correct marker is correct, but only in the context of the widespread use of badly formulated fish oils. If used with oily fish or oily fish in liquid form (10, 30, 31), the 6:3 ratio remains very useful indeed, and corroborates the predictive value of the omega-3 index.
In related news, other scientists have found evidence which supports the continuing relevance of the 6:3 ratio when fish oil is consumed as fish.
In a recent prospective and large-scale population-based cohort study, derived from the famous UK Biobank (31), higher 6:3 ratios were associated with significantly raised risk of all-cause, cancer and cardiovascular death. This was not specifically a supplementing population (although many were taking fish oil supplements) but a general population who also ate fish and were therefore taking at least some of their omega-6 PUFAs correctly, ie with phlorotannins.
Other pro- and anti-inflammatory factors (3) in the Biobankers’ diets were not considered, and it is certainly possible that the fish-eaters were eating a generally healthier diet, but the Biobank findings are in line with an earlier and even larger study (32) which found a similarly strong association between fish consumption and lowered all-cause, cancer and cardiovascular death.
In other words, eating fish appears to improve health, whereas fish oil supplements do not (i.e., 33, 34).
The amphiphile polyphenols in fish exert anti-inflammatory and health-protective benefits that not only complement those of the omega-3 PUFAs (35) but also prevent the in vivo formation of harmful PUFA peroxidation products (23, 24, 36). They are highly effective at doing this. One study found that as fish consumption goes up malondialdehyde, a marker of 3- and 6- PUFA peroxidation, goes down (37)!
This is somewhat in line with other research that found that while both oily fish and fish oil supplements get omega-3 PUFAs into the bloodstream (the easy part), the downstream metabolic effects of these two interventions are quite different (38).
Back to omega-6, where we started.
There is evidence that moderate doses of LA exert positive effects in the body (ie 39, 40), but there is also inverted evidence that high intakes lead to increased levels of potentially harmful LA oxidation products known as OXLAMs. When humans are put onto reduced LA diets, as opposed to a standard high-LA contemporary diet, levels of OXLAMs in their blood fall (41).
As some of the OXLAMs have been provisionally linked to various pathologies (ie 42-45 but see also 46), and to increased sensitivity to pain (47-49), lowering LA intakes from their currently unnaturally high levels seems like a reasonable idea. This means cutting down on vegetable oils, with the exception of oils which either have a low 6:3 ratio or only very small amounts of omega-6. These include canola and olive, peanut and coconut oils.
Is this a safe strategy? I think so.
Nutritional biochemistry contains a significant amount of redundancy, meaning that changes in the input of one dietary component can often be compensated for, at least partially, by changes in other inputs. Redundancy improves the reliability of complex systems and enhances at least short-term resilience and adaptability, which explains why the evolutionary process has built this principle preferentially into life forms which must survive in more variable nutritional environments (50).
Resilience and adaptability are closely related and overlapping conditions. Resilience describes the ability to absorb change. Adaptability, which requires resilience, describes the ability to change in response to that external alteration in order to better survive under new conditions.
Being opportunistic omnivores has been a good long-term survival strategy for us, but one which requires considerable metabolic resilience and adaptability. This is presumably why humans display a high degree of metabolic modularity and cross-talk between metabolic pathways (51); within the metabolome there is a highly conserved but still flexible core group of enzymes involved in multiple reactions across different pathways which modulate each other.
This general approach crosses over into food design. Specifically, it should be possible to make LA and the oils that contain it safer by adding amphiphilic polyphenols to the oil. If these polyphenols chaperone LA in the body as effectively as they do EPA and DHA, reduce excessive OXLAM production and provide additional anti-inflammatory benefits, the therapeutic index of soy, corn and other vegetable oils might be increased.
This is not exactly metabolic modularity, but is analogous to it. You could call it nutritional modularity, of the kind displayed in any good cookbook. Although the approach might not work so well in vegetable oils used for shallow and deep frying, it seems worth considering when those oils are to be used as ingredients in ultra-processed foods such as industrial mayonnaise, hummus, salad dressings, margarine and vegan ice cream.
Such an approach might help to produce healthier cross-talk between metabolic pathways, and healthier outcomes.
Endnote. I have long followed William Harris’ important contributions to this area of nutritional science, which have added immeasurably to the field.
Next week: Are you becoming more endangered, or is it just me?
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