Eat Your Fish Oil and Digest it, Too (Unoxidized!) | DHA:EPA Ratio of 1:1 Minimizes Oxidation, Maximizes Uptake | Plus: Fishes that Come Close are Sardines, Rainbow Trout, ...

The often-heard "the more DHA, the better"-rule is - like so much you'll read about fish oil online - not the evidence-based truth it seems to be. Some extra EPA may keep the oil from getting oxidized before you even absorb it.

No, I am not a fish oil fanboy, that's for sure. But how can you be if your chances to get already oxidized fish oil are 100% if you buy any of the US TOP-sellers (and assume that it's not different in Europe). Speaking of which: There's new research allowing us to add two new and potentially important criteria to the inofficial SuppVersity-"How to buy and use your fish oil" guide.

The corresponding research comes from an international team of researchers and was first published in 2017. It is thus not exactly revolutionarily new but in view of the fact that I haven't seen the results being addressed anywhere before still SuppVersity newsworthy (Dasilva 2017).

You can learn more about omega-3 & co. at the SuppVersity

Fish Oil Makes You Rancid?

POPs in Fish Oils are Toxic!

N3/N6 Ratio Doesn't Matter

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

In the paper, the authors followed up on their own research showing that increasing the proportion of DHA in marine lipid supplements significantly reduces associated health benefits (in terms of lipidomic biomarkers of oxidative stress and inflammation) compared with balanced EPA:DHA supplementation (Dasilva 2015). In conjunction with evidence suggesting that these difference may be brought about during the digestive process, where the rate of oxidation and subsequently impaired uptake may be a function of the ratio of DHA:EPA.

The scientists starting hypothesis was thus that EPA and DHA molecules "might have differential resistance to oxidation during gastric digestion, and the oxidation level achieved could be inversely correlated with intestinal absorption and, hence, with the resultant health benefits" (Dasilva 2017).

Figure 1: TIM system, simulating the upper gastrointestinal tract for fat digestion studies (Domoto 2013). In the study I grabbed this illustration from, it was used to demonstrate and quantify the improved absorption of phospholipid- vs. triglyceride bound omega-3s I wrote about as early as in 2012 (read the #SVClassic)

To really get to the bottom of the underlying mechanisms, the scientists decided to test their hypothesis by investigating the degree of oxidation in the stomach, and the levels of bioaccessible lipids, of varying molar proportions of DHA and EPA (2:1, 1:1, and 1:2) using the well-established dynamic gastrointestinal tract model TIM-1.

Tumor-free status according to age. Description of the results in the text.

Less surprising but noteworthy: Fish oil is more potent than plant sources of omega-3s when it comes to the prevention of breast cancer, a recent study from the University of Guelph and the McGill University shows. While we are dealing with rodent data, it is newsworthy that the scientists were able to assess the potency of ALA (plant omega-3) vs. DHA+EPA (as in fish oil) for the first time. Their estimates show "that ALA was 1/8 as potent as EPA+DHA" (Liu 2018).

As usual, though, it makes sense to look beyond the abstract and at the data in the Figure on the left!

The mice receiving 7% safflower + 3% fish oil (FO) developed the virally programmed tumor significantly later than those on either 7% safflower + 3% flax (3%FS) or the control diet with 10% safflower, but the higher dosed (more omega-3, but in form of ALA vs. DHA/EPA) 10% flaxseed diet (10%FS) outperformed them all. That doesn't change the overall conclusion that - gram by gram - fish oil is more important, but it highlights that ALA, the plant form of omega-3s, is a pretty potent anti-tumor agent, as well.

TIM-1 (see Figure 1) was particularly designed to simulate the upper gastrointestinal tract for fat digestion studies (Guerra 2012; Verwei 2016).

Figure 2: Graphical abstract of the study design (Dasilva 2017).

Figure 2 illustrates the methodology at the most basic level. With TIM-1 being designed to adequately simulate the human digestion process, the scientists obviously had to prepare "test meals"... what? Yeah, the artificial digestive tract is meant to test the absorption of fats from real-world(-ish) food matrices. Accordingly, the scientists mixed a commercial rodent chow (caloric composition: 22% from protein, 66% from carbohydrate, and 12% from fat) with either soybean oil as a control (source of ω-6 LA), or with different proportions of the two main ω-3 FA from fish oils (1:1, 2:1, or 1:2 EPA:DHA) - and surprise, unlike the products in the previously mentioned study, the commercial fish oils had a peroxide value of below the 5 meq O2/Kg of oil cut-off, the 2.84 mg tocopherol/g oil (see "How much vitamin E do you need to consume with PUFAs" | read it) added an extra protective effect.

DHA/EPA and total fatty acid composition of the test diets.

The study used the regular triglyceride-bound versions of EPA & DHA: It is not irrelevant to say that the scientists used the cheap(er) triglyceride-bound forms of DHA and EPA you will find in almost every regular fish oil capsule/bottle. Why's that relevant? As previously hinted at, the phospholipid (PL) versions are better absorbed - the results could thus have been different and, since few people actually use krill oil and other sources of PL-bound DHA & EPA, less practically relevant.

Moreover, the scientists blended regularly available commercially fish oils from AFAMPES 121 EPA (AFAMSA, Vigo-Spain), EnerZona Omega 3 RX (ENERZONA, Milano-Italy) and Oligen liquid DHA 80% (IFIGEN-EQUIP 98, Barcelona-Spain) - another factor that adds to the real-world relevance of the study at hand... speaking of "real-world" the natural ratio of DHA/EPA ratio in Atlantic salmon is 2:1,... you can find better choices like rainbow trout & others in the bottom line.

As a control, the authors used plain cold pressing unrefined organic soybean oil from Biolasi S.L. (Ordizia, Guipuzcoa-Spain). All diets were high in PUFAs, and delivered approximately 42% of calories from fat (34% from PUFAs of the supplements and 8% from the chow), 43% from carbohydrates and 14% from proteins (the figure in the red box has some details about the individual fatty acid composition if you're interested in that).

Figure 3: Concentrations of conjugate dienes (CD) and conjugate trienes (CT) evolution during the in vitro stomach digestion in TIM-1 for supplements 1:1, 2:1, 1:2 DHA:EPA, and soybean oil (Dasilva 2017).

Again, the "diets" were not fed to rodents or human beings but digested in the artificial gut from Figure 1, in which the scientists observed a really significant increase in the formation of conjugate dienes and trienes (Figure 3), which signify increased peroxide levels only with the 2:1 oil - exactly those oils supplement companies are going to seel most expensively.

What about phospholipid bound (krill oil) and other funky forms of advanced fish oils? You will be laughing, but DIY fish oil gummies could be king... While for many the jury is still out there, krill oil, in which the N3s come mostly in form of phospholipid- instead of triglyceride-bound fatty acids, seems to have a slightly higher bioavailability but also differential effects I discussed in previous articles.

The previously alluded gummy bears were - in research terms - gelled emulsions in which the DHA and EPA are also available in triglyceride form but protected by a gelatin matrix (gelled emulsions) that is created by heating and mixing commercial gelatin powder with water at 68°C, letting it cool to 50°C and then mixing it with the fish oil by applying a homogeniser.

The easily prepared "fish oil gummies" from Haug et al's 2011 RCT will deliver more (~40-50%) DHA + EPA and it will do so faster (C_max and time to C_max not shown)

In the corresponding small scale RCT, the scientists observed an impressive 44.9 and 43.3% increase in cumulative absorption and a 100.4% and 105.6% increase in peak levels compared to the same 5g in soft gel capsules for DHA and EPA, respectively - not bad... if you want to make your own fish oil gummies, the authors mixed ~260mg of omega 3s with 56.7 mg of gelatin, added, 37.0 mg gum arabic, and flavored the 'gummies' with 103.6 mg sorbitol, 241.7 mg xylitol , as well as 5.9 mg citric acid, and 1.2 mg flavour ;-)

The difference between 1:2 and 1:1, i.e. the medium- vs. lowest-price fish oils you will see on the virtual and real shelves (obviously you also pay for brand names, but in general the high DHA fish oils are simply the most expensive ones), on the other hand, wasn't statistically significant, though.

Figure 4: Lipid metabolism of 1:1 EPA*:DHA and 1:1 EPA:DHA* (TOP). of 2:1 EPA*:DHA and 2:1 EPA:DHA* (middle) and 1:2 EPA*:DHA and 1:2 EPA:DHA* (bototm). Data are expressed as percentage of each lipid class by total lipids. | Please mind that I used the DHA:EPA ratio in previous graphs and throughout the article, i.e. 2:1 EPA:DHA = 1:2 DHA:EPA.

In view of the fact the researchers also found a tendency toward higher amounts of bioaccessible lipids at all-time points in jejunal dialysates for the soybean and 1:1 EPA:DHA diets, compared with the 2:2 and 1:2 diets (differences were significant at 1-2 h, when jejunal absorption principally occurs), it will not be a total surprise to hear that...

• with 2:1 DHA:EPA, the uptake was maximally reduced, i.e. by 21-23% at 2-6h, 
• with 1:2 DHA:EPA there was still a relatively high reduction of 18-14%, and 
• with the 1:1 DHA:EPA the intestinal cells the scientists fed left only 8-5% of the N3s. 

In relative terms that means that you lose 3x more DHA + EPA from the 2:1 DHA:EPA mixture compared to the balanced one. Unfortunately, the study at hand cannot answer a far more important question for sure: How bad is the oxidation and potential incorporation into blood lipids and cell walls, really?

Speaking of needing more fish oil - Your genes may predispose you to lower absorption, too: A study that has been published only a few days ago shows that carriers of the T allele at FADS1 rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele (Juan 2018). Study doesn't say that if those people simply don't need such high EPA/DHA levels, however.

What the scientists were able to show is that the uptake of oxidized DHA and EPA is generally reduced by -19% and -15% over 6h. This, however, doesn't tell us anything about the biological/health effects of the slightly differential rates of incorporation/occurrence of oxidized DHA and EPA in trigs, phospholipids, fatty acids and diglycerides as depicted in Figure 4 and downstream effects on cell walls inflammation, etc..

Without the answer to these questions, it is not possible to tell if you just have to take more fish oil to make up for the increased loss, of the corresponding increase in the amount of oxidized PUFAs in your blood and cells will do more harm than good.

Current evidence seems to suggests: The less oxidized junk omega-3s you have in your blood and, even more importantly, your cell membranes, the better.

We can thus still not say how "bad" the non-balanced fish oils are - or, as the scientists have it "by which [mechanisms] the oxidative stability of the PUFAs may be correlated with their metabolic fate" and downstream effects on cell integrity and metabolic health, in general - but we can say for sure that "the balanced 1:1 diet showed the lower oxidation level and minor metabolite changes after oxidation" (Dasilva 2017).

Table 1: DHA, EPA and their ratio in fish products (USDA 2005).

Why haven't I heard about this before? I guess that's because the whole omega-3 hype is heavily pushed by the industry whose margins are maximized if they manage to con you into buying highly purified high DHA, low EPA products. If there's no financial interest involved, science news rarely make it to the mainstream media outlets... even if they deal with one of everybody's darlings like fish oil or vitamin D... well, whatever the reasons may be, unless you need DHA-only for whatever funky science- and not marketing based reason, you will hopefully buy the medium-priced fish oils with a ratio of DHA:EPA of roughly 1:1 to make yourself, not the fish oil manufacturers happy and, obviously, "to eat your fish oil and digest and absorb it, too" ;-)

Speaking of eating: The currently available research suggests that you are more likely to see significant health-benefits from consuming (fatty) fish vs. fish oils or other omega-3 supplements, anyway. Against that background you may be interested to hear that wild rainbow trout, sablefish, sardines, or flatfishes (ratio 1.1) come very close to the 'magic ratio' - according to USDA data (Table 1), the Atlantic wolffish is yet unique with it's 1.0 DHA/EPA (with natural variations of ±20% it's not necessarily 'the best' or significantly better than a whole host of fish in the tabular overview on the right, though) | Comment!

References:

• Dasilva, Gabriel, et al. "Healthy effect of different proportions of marine ω-3 PUFAs EPA and DHA supplementation in Wistar rats: Lipidomic biomarkers of oxidative stress and inflammation." The Journal of nutritional biochemistry 26.11 (2015): 1385-1392.
• Dasilva, G., et al. "Relative levels of dietary EPA and DHA impact gastric oxidation and essential fatty acid uptake." The Journal of Nutritional Biochemistry (2017).
• Domoto, Nobuhiko, et al. "The bioaccessibility of eicosapentaenoic acid was higher from phospholipid food products than from mono‐and triacylglycerol food products in a dynamic gastrointestinal model." Food science & nutrition 1.6 (2013): 409-415.
• Guerra, Aurélie, et al. "Relevance and challenges in modeling human gastric and small intestinal digestion." Trends in biotechnology 30.11 (2012): 591-600.
• Haug, Ingvild J., et al. "Bioavailability of EPA and DHA delivered by gelled emulsions and soft gel capsules." European journal of lipid science and technology 113.2 (2011): 137-145.
• Juan, et al. "Joint effects of fatty acid desaturase 1 polymorphisms and dietary polyunsaturated fatty acid intake on circulating fatty acid proportions." The American Journal of Clinical Nutrition 107.5 (2018): 826–833. 
• Liu, et al. "Marine fish oil is more potent than plant-based n-3 polyunsaturated fatty acids in the prevention of mammary tumors." Journal of Nutritional Biochemistry 55 (2018) 41–52.
• Verwei, Miriam, et al. "Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms." International journal of pharmaceutics 498.1-2 (2016): 178-186.
• USDA. "The Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans, 2005 > Appendix G2: Original Food Guide Pyramid Patterns and Description of USDA Analyses; Addendum A: EPA and DHA Content of Fish Species" (2005). 

3/3 TOP-Selling US Fish Oils Exceed Maximal Peroxide and Total Oxidation Levels - Levels Roughly 4000% Higher Than in Medical Grade N3 Supplements, Harvard Study Shows

The US' favorite fish oil supplements: Dirt cheap and still not worth the money. Better buy fish - fresh fish.

"I told you so!" That's how someone else in my position would probably start today's blogpost. In view of the fact that "smartassing" is not exactly an effective means of education, I will yet refuse from reminding you that I've been reporting about unwanted side effects of the gold-ish pills that claim to have "fish oil" in them on various occasions.

And guess what!? The publication of a recent study by scientists from the Cardiovascular Division, Brigham and Women's Hospital at the venerable Harvard Medical School, gives me yet another reason to rant against the evermore popular fish oil supplements.

You can learn more about omega-3 & co at the SuppVersity

Fish Oil Makes You Rancid?

POPs in Fish Oils are Toxic!

N3/N6 Ratio Doesn't Matter

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

In their study, the scientists analyzed 3 commonly available fish oil dietary supplements and found that (a) their level of omega-3 fatty acids varied significantly, that (b) they contained tons of other fats that you would ask to be paid for to consume if you knew about them and, that (c) the caps were so full of oxidized fats that they exceeded international standards and may (d) may harm, rather than help with your health.

No, we're not talking about cheap Chinese internet purchases, bro!

The Harvard scientists bought the "three top-selling fish oil DS [dietary supplements] in the United States and to examine the extent of oxidative damage in the DS as compared with chemically characterized standards with respect to purity and ability to prevent human sdLDL oxidation in vitro" (Mason. 2016). The commonly heard excuse that this is "just a problem with the cheap Chinese stuff" is thus as useless as it is ridiculous in view of the data from the study at hand.

Figure 1: The TOP3 US fish oil products are rancid... well, mostly (right hand side) and they have almost no ability to prevent human LDL particles from oxidation, as the results of the MDA test on the left indicates (Mason. 2016).

Compared to the medical grade control, the US top-sellers look as if they had been tainted with motor oil from a fishing cutter. Speaking of which: I would not guarantee that the 34%, 21% and 24% of "other oils" in this so-called dietary supplements do not include at least tiny amounts of mineral oils.

Your fish oil contains 4000% more oxidized fats than prescription fish oil! That's a huge problem, because many of the studies you're so fond of, because they seem to prove how healthy fish oil is, have been done with medicinal grade fish oils. Accordingly, the results of these studies have ZERO predictive power with respect to what your "machine oil" fish oil will do to your health. Speaking of "your" - it is not impossible that the oxidative damage occured during storage, which reminds me to remind you NEVER to use fish oil in a bottle that's constantly exposed to pro-oxidative oxygen, whence you've opened the bottle. Note: If stored in the fridge (4°C) the shelf life of the fish oil in fresh fish is, as Boran et al. show in their 2006 paper in Food Chemistry ~ 90 days.

In fact, the scientists measured not just primary oxidation products, as the highly elevated peroxide levels, an indicator of high levels of primary oxidation and hydroperoxides, confirm, but also secondary products of the decomposition of the primary oxidation products during continued exposure to oxidative conditions, as they ar detected in the p-anisidine test.

Figure 2: Indeed, there was also some "fish oil" in the caps - emphasis on "also" and "some" (Mason. 2016)!

The total oxidation levels in Figure 1 were then derived from the peroxide and anisidine values indicate without fail that "[a]ll three DS exceeded the recommended maxima for peroxide and total oxidation values (5 meq/kg and 26, respectively) when normalized to 1 g OM3FA (based on the number of capsules needed to achieve 1 g of OM3FA)" (Mason. 2016). The latter is particularly shocking in view of the fact that the prescription product of pure OM3FA did not contain significant levels of these oxidation products under identical test conditions. Any studies on the health effects of fish oil - mostly conducted with medical grade capsules - is thus meaningless for the average consumer who shies away from the exorbitant costs of LOVAZA and co. - a bad mistake, as it turns out, now, that the Harvard scientists' study shows that EPA and DHA containing oxidized trash fats from the dietary fish oil supplements have a >77% reduced ability to protect your LDL oxidation from (>90% protection for pure products, a meager 21 ± 4% for the "fish oil" you have probably been buying for years).

Speaking of "for years": Is it possible that you've done more harm than good in the past years of consuming copious amounts of fish oil to your health? Yes, it is, but in view of the fact that even the "motor oil" version of fish oil in the average US dietary fish oil supplement (the brand names are obviously undisclosed = not mentioned in the paper) was still anti- and not pro-oxidative, it's more likely that you have only wasted time and money.

Only three brands, but unfortunately in line with previous research: The scientists make no secret of the fact that a major limitation of their study "is that, although [they] evaluated the top-selling DS in the United States, [they] only assessed three products given the scope of this initial investigation" (Mason. 2016). Bad luck for fish oil fans: e results of this study are consistent with previously published analyses of DS with respect to content and oxidative damage" (ibid.) - studies that didn't just find oxidized fatty acids, but also heavymetals and cholesterol in the pills.

So what do we make of these results? Well, I guess it depends on how indoctrinated you've already been about fish oil being an essential supplement (the word "supplement" already implies that it cannot be essential). If you actually believe in the magic of fish oil (imho bogus for healthy individuals), you should go and buy pharma grade fish oil spending your whole monthly supplement budged on fish. If, on the other hand, you've any sanity left, you simply do what I've been recommending for years: eat your fatty fish once or twice per week (doesn't have to be wild-caught | Farmed Fish is Less Poluted and Has More Omega-3) | Comment!

References:

• Boran, Gökhan, Hikmet Karaçam, and Muhammet Boran. "Changes in the quality of fish oils due to storage temperature and time." Food chemistry 98.4 (2006): 693-698.
• Mason, PR and Sherrat SCR. "Omega-3 fatty acid fish oil dietary supplements contain saturated fats and oxidized lipids that may interfere with their intended biological benefits." Biochemical and Biophysical Research Communications - Available online 21 December 2016 | In Press, Corrected Proof

The Good Krill & Salmon Oil That's Bad For You: Increased Risk of Metabolic Syndrome in Men Who Supplement

Recent Human Cross-Over Trial Puts "?" Behind Super-Supplement Status of Omega-3 Supplements

Increases in omega-3 intake are among the"small dietary modifications" doctors and nutritionists like to suggest to their patients in their common battle against obesity that are comparatively easy to achieve. It is thus no wonder that millions are enthralled by the cheap fish, krill, cod and salmon oil caps you can buy in every supermarket, these days.

The often (namely when they're rancid) disgustingly tasting content of the pills is believed to offer absolution from all your dietary sins, because epidemiologic (Villegas. 2011; Djoussé. 2011) and animal evidence suggested that these n–3 PUFAs may in fact improve insulin sensitivity and metabolic risk.

You can learn more about omega-3 & co at the SuppVersity

Fish Oil Makes You Rancid?

POPs in Fish Oils are Toxic!

N3/N6 Ratio Doesn't Matter

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

For most people the marketing and the existence of the previously cited non-relevant studies (what we want are randomized, double-blinded clinical human trials) are exciting enough to forget about the existing conflicting evidence from randomized controlled trials (Mori. 1999; Ramel. 2008; Tsitouras. 2008):

"A systematic review that included 11 randomized controlled trials and 618 participants concluded that n–3 PUFA supplementation did not influence insulin sensitivity (Akinkuolie. 2011). However, the individual trials were highly heterogeneous and included participants with and without type 2 diabetes and used a wide range of n–3 PUFA sources, doses, and control oils" (Albert. 2015).

What? You don't know about that? Well. I am not surprised, because all you hear about in the mainstream science outlets are the exciting studies, where fish oil is added on top of a weight loss regimen (Mori. 1999; Ramel. 2008), so that no-one can tell you if it's the diet or the fish oil or the fish oil in conjunction with the diet that does the insulin sensitivity improving magic.

Figure 1: Overview of the study design (Albert. 2015).

For krill oil, which is an increasingly popular source of marine n–3 PUFAs that differs from fish oil, because its n–3 PUFAs are predominantly in phospholipid form, while those in fish oil are triglyceride bound (Schuchardt. 2011). In view of the fact that krill oil also contains astaxanthin, which is a carotenoid pigment and powerful antioxidant (Shahidi. 2010), it is thus not surprising that differential effects of krill and fish oils have been described in mice (Burri. 2011).

Something to ponder on: I think it is worth mentioning that the control oil in the study at hand was canola oil. An oil that has actually a quite favorable fatty acid composition compared to stuff like soybean oil or corn oil. So, if you see a study with different results, make sure you check what oil the scientists used in the placebo group.

What is surprising, though is that the effect of krill-oil supplementation on insulin sensitivity in humans has not been reported..., well, at least before Albert et al. investigated whether supplementation with a blend of krill and salmon (KS) oil would lead to changes in insulin sensitivity in a double-blind, randomized, controlled, crossover human trial.

"The design was a randomized, double-blind, controlled crossover trial. A total of 47 men with a mean 6 SD age of 46.5 6 5.1 y, who were overweight [body mass index (in kg/m2) from 25 to 30] but otherwise healthy, received 5 1-g capsules of KS oil or a control (canola oil) for 8 wk and crossed over to another treatment after a 8-wk washout period. The primary outcome was insulin sensitivity assessed by using the Matsuda method from an oralglucose-tolerance test. Secondary outcomes included lipid profiles, inflammatory markers, 24-h ambulatory blood pressure, and carotid artery intimamedia thickness [...]"

The active treatment contained krill oil (88%) and salmon oil (12%). This combined oil was 42.1% of phospholipids by weight, and each 1000-mg gelatin capsule contained 46 mg EPA and 31 mg DHA. Participants were instructed to take 5 capsules as a single dose, once a day, with a glass of water, which equated to a daily supplementation with 400 mg n–3 PUFAs (including 230 mg EPA plus 154 mg DHA). The control intervention consisted of 1000 mg canola oil, which was also presented in a gelatin capsule that was minimally coated in fish oil (,5 mg) to match odor and flavor" (Albert. 2015).

What the scientists (and probably most of you) didn't expect was that the insulin sensitivity (per the Matsuda index) was 14% lower with the KS oil than with the control oil (canola | P = 0.049) - and that despite the fact that the KS oil had a peroxide value (PV) below the lower limit of detection of 0.3 mEq/L and an ansidine value (AV) of 11.0, which indicated a Totox value < 11.6 and indicates that it was as fresh or fresher than any of the best products you can buy.

Figure 2: Primary outcome - Insulin sensitivity (Matsuda index, low values are bad | Albert. 2015)

If you are still not questioning the "health halo" of fish oils, you should know that a mediation analysis the scientists conducted showed that, after controlling for the likely positive effects of blood EPA and DHA (i.e., the omega-3 index), the reduction in insulin sensitivity after KS-oil supplementation was more marked [27% lower than with the control oil (P = 0.009)]. Even the improvements in blood lipids (Total cholesterol, LDL, HDL, Triglycerides, Apolipoprotein A & B) many people who take fish oil are sure they would get, were not observed.

What should be said in favor of the omega-3 supplement is that only the acute insulin sensitivity as it is measured in the Matsuda test was messed up from the krill + salmon supplement. For HOMA-IR and fasting glucose the scientist didn't find a sign. difference... which reminds me that I should mention that this is often the only measure of glucose control in scientific studies (esp. in fish oil studies). In spite of the fact that the Matsuda index provides a much better assessment of how your body actually handles incoming glucose (Matsuda. 1999).

There's something fishy about high dose fish oil supplementation. Increased inflammation and beginning fatty liver disease and a dose-response curve for EPA + DHEA that's U-shaped | read more!

So, basically, the study at hand suggests that the more you increase your omega-3 index, i.e. the total weight of EPA + DHA in your red blood cells divided by the weight of the red blood cells, or, put simply, the better your krill oil + salmon supplement works, the worse it's going to be for your insulin sensitivity.

That's a surprising, but not a contradictory results. After all previous tightly controlled clinical trials on fish oil were unable to confirm any benefit on blood glucose management, too. And in view of the fact that clinical human trials for krill + salmon oil that could contradict the results of the study at hand are non-existant, it's hard to argue with the conclusion the researchers from the University of Auckland and the University of Newcastle draw: "[K]rill-oil supplementation in overweight adults could exacerbate risk of diabetes and cardiovascular" (Albert. 2015).

Things to keep in mind, though are (a) the fact that the subjects were overweight, results in both obese and lean individuals may thus differ (the same could go for the dosage, although 5x1,000mg caps is not much considering the low EPA + DHA content of the oils), (b) the fact that previous studies have shown sign. differences between the effects of fish and fish oil supplements with the former always having the upperhand and (c) the selected measure of insulin sensitivity, the Matsuda index (Matsuda. 1999), which is excellent, but different from static measures like fasting blood glucose or quasi-static ones like HOMA-IR. Data that does not in all cases reflect one's ability to handle glucose correctly; and data to which  the previously cited epidemiological studies are usually limited | Comment on Facebook!

References:

• Akinkuolie, Akintunde O., et al. "Omega-3 polyunsaturated fatty acid and insulin sensitivity: a meta-analysis of randomized controlled trials." Clinical nutrition 30.6 (2011): 702-707.
• Albert, Benjamin B., et al. "Supplementation with a blend of krill and salmon oil is associated with increased metabolic risk in overweight men." The American journal of clinical nutrition (2015): ajcn103028.
• Burri, Lena, et al. "Differential effects of krill oil and fish oil on the hepatic transcriptome in mice." Frontiers in genetics 2 (2011).
• Djoussé, Luc, et al. "Plasma omega-3 fatty acids and incident diabetes in older adults." The American journal of clinical nutrition 94.2 (2011): 527-533.
• Matsuda, Masafumi, and Ralph A. DeFronzo. "Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp." Diabetes care 22.9 (1999): 1462-1470.
• Mori, Trevor A., et al. "Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects." The American journal of clinical nutrition 70.5 (1999): 817-825.
• Ramel, A., et al. "Beneficial effects of long-chain n-3 fatty acids included in an energy-restricted diet on insulin resistance in overweight and obese European young adults." Diabetologia 51.7 (2008): 1261-1268.
• Schuchardt, Jan Philipp, et al. "Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations–a comparative bioavailability study of fish oil vs. krill oil." Lipids Health Dis 10.145 (2011): 1-7.
• Shahidi, Fereidoon, and Ying Zhong. "Lipid oxidation and improving the oxidative stability." Chemical Society Reviews 39.11 (2010): 4067-4079.
• Tsitouras, P. D., et al. "High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults." Hormone and metabolic research 40.3 (2008): dh199-205.
• Villegas, Raquel, et al. "Fish, shellfish, and long-chain n− 3 fatty acid consumption and risk of incident type 2 diabetes in middle-aged Chinese men and women." The American journal of clinical nutrition 94.2 (2011): 543-551.

Revisiting the Fish Oil is Good For Heart & Brain Mantra: SU.FOL.OM3 Trial Says High Omega-3 Good For the Heart, High Arachidonic Acid (LC N6-PUFA) Good for the Brain!

I never believed that it was a good idea to pay for and consume for the capped extract of what has long been the useless waste of the fishery industry and is now called "fish oil". Fishing, and eating real, whole fish, on the other hand, is something I wholeheartedly recommend.

I am, as most of you should know, no real fan of correlation analyses such as the one SuppVersity reader Roy Nelson, recently pointed me to, but in view of the fact that they are the best we have, when it comes to the assessment of the long-term effects of high vs. low omega-3 intakes (actually rather serum levels), I still decided to give the SU.FOL.OM3 trial a go.

The study is after all "more controlled" than your usual epidemiological guesswork and with 2,263 patients who were enrolled in the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acid trial (SU.FOL.OM3) sufficieently powered (meaning it has enough subjects to provide relevant results and determine even smaller inter-group differences relatively reliably).

You can learn more about omega-3 & co at the SuppVersity

Fish Oil Makes You Rancid?

Are All Fats Bad For You?

N3/N6 Ratio Doesn't Matter on SAD Diet

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

The intention of the researchers fro the Cnam, Université in France was to check, whether the number of major cardiovascular, cardiac and cerebrovascular events between those patients who had been randomized to receive the said combination of "health supplements" and their counter-parts in the placebo arm would differ during the 4.7 years of follow up.

By now you should be throwing your hands up in despair! 

It's of course total bullocks to use the data from a stud using a multi-ingredient supplement (Folate, vitamin B6 + b12 and omega-3) to draw any conclusions with respect to the cardioprotective effects of one of the ingredients. Luckily, the scientists appear to have realized that as well. Accordingly, their criterion was not "active" vs. "placebo" treatment, but rather "high" vs. "low" serum omega-3 levels, they adjusted for the fish oil and B-vitamin supplements (no idea how they did that) and to spice things up a bit, they included a bunch of other serum fatty acid levels in their analysis, too.

Another study suggests: Maybe it's not even about the fats you eat! Usually we assume that the fatty acid composition of our blood would be determined by the fats we eat. According to a recent study from the University of Eastern Finland, the type and amount of fat we eat is yet only one of at least two factors which determine the amount and ratio of fatty acids in our body.

Table 1: The associations of food consumption w/ fatty acids in plasma cholesteryl esters (Venalainen. 2014)

In particular, the Finnish researchers were able to prove that there is a highly signicant association between the amount of "garbage" carbohydrate foods (highly processed, low dietary fiber content) and the amount of oleic acid (MUFA) in the blood of 512 children 6-8 years of age from the city of Kuopio.The researchers explain this effect based on carbohydrate induced increases in hepatic delta-9-desaturase activity and a consequent increase in the conversion of saturated to mono-unstaturated fatty acids (Venäläinen. 2014).

What they found were significant risk increases for both types of major events (heat and brain) with high total fatty acid levels (+54%), which did yet lose their significance, when Fezeu et al. adjusted for tobacco smoking, alcohol consumption, systolic blood pressure, diabetes status, plasma cholesterol (HDL and LDL), triglycerides, n-3 supplementation and homocysteinemia.
That's in contrast to the positive effects 2nd and 4th quartile palmitic acid levels, as well as the borderline significant risk decrease (-21%) in those subects with the highest long-chain omega-3 levels (EPA + DPA + DHA) in their blood.

In spite of the fact that the overall brain + heart protective effects of omega-3 are obviously pretty pathetic (without DPA, high total N-3 and high DHA + EPA levels did not even correlate with reduced risk), the scientists heart-specific analysis would seem to support the hype around the holy omega-3s and their ability to save our fat asses.

Both, high stearidonic acid (C 18:4 n – 3) and DHA levels appear to have be associated with 37% and 16% reduced risks of incident cardiac events. In view of the absence of a clear trend (= more omega-3 = lower risk) for DHA and considering the fact that a high omega-3 to omega-6 ratio did not have the significant protective effect everybody believes it would have, the the public (in many countries even "official") hype does eventually appear to be over the tops.

Figure 3: Partially (age, BMI, initial e- vent, gender) and fully adjusted multi- variate hazard ratios for associations between baseline plasma lipid profile and incident cerebro-vascular events in the SU.FOL.OM3 study - high value = high risk with the given profile; e.g. -36% with high AA levels

If omega-3s are not so protective, maybe omega-6s are not so bad? In the end, the study at hand does confirm just that. There are no significant risk increases for either cardiac or cerebrovascular events associated with any of the various forms of omega-6 fatty acids, the scientists tested. On the contrary, very high amounts of the "big bad" long-chain omega-6 fatty acid arachidonic acid are actually associated with a -56% reduced risk of cerebrovascular events the amount of long-chain omega-3 fatty acids (DHA, EPA, DPA), on the other hand, is not.

Now this does not imply that omega-3 fats are junk and I have to admit that I am a bit skeptic how the scientists were able to "adjust for" the supplemental omega-3s. For me, the study at hand does nevertheless confirm that the "proven benefits" of omega-3 fatty acids should rather be considered "proven benefits" of high omega-3 foods.

Practically speaking this means: Keep eating your salmon, grass-fed beef, nuts, etc., but don't fool yourself to believe that popping a pill with waste-products of the fishery industry (that's what fish oil was for decades, before someone instigated the hype and people started to pay for the waste) will have you live healthily ever after.

References: 

• Fezeu LK, et al. "Baseline Plasma Fatty Acids Profile and Incident Cardiovascular Events in the SU.FOL.OM3 Trial: The Evidence Revisited." PLoS ONE (2014): e92548.
• Venäläinen, Taisa, et al. "Cross-Sectional Associations of Food Consumption with Plasma Fatty Acid Composition and Estimated Desaturase Activities in Finnish Children." Lipids (2014): 1-13.

No Magic Numbers: The Omega-3:Omega-6 (N3/N6) Ratio - Higher is Better, But as Part of the Standard American Diet Even a 1:1 Ratio Won't Protect You Against Diabesity

Eating "like an American" makes you fat and sick. No matter what the omega-3 to omega-6 ratio of your diet may be.

It is a pity. Yeah, if the latest study from the University of South Carolina was a human study, it would finally provide a definitive answer to the question how much omega-3 we actually need. Well, I should clarify: It would provide an answer to the question how much omega-3 we need with a given baseline omega-6 intake.

In view of the fact that the study duration was 20 weeks, it would yet take more than 60 (human) years to find out, whether the ratio of n-3/n-6 in the diet is in fact as irrelevant as the reslts Reilly T. Enos et al. present in their latest paper would suggest.

You can learn more about omega-3 & co at the SuppVersity

Fish Oil Makes You Rancid?

Are All Fats Bad For You?

Fish Oil & GLA vs. Acne

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

Over those 20 weeks the scientists from the Departments of Pathology and Chemistry and Biochemistry fed their previously healthy C57BL/6 mice diets that contained either the regular rodent chow or one out of four high fat diets with omega-3 to omega-6 ratios of 1:1, 5:1, 10:1, and 20:1. As the scientists point out, the percentage of calories provided by each of the three macronutrients and the ratio of monounsaturated FAs (MUFAs) to PUFAs (MUFA:PUFA) were identical for the HFDs and were designed to be similar to the standard American diet.

Table 1: Diet composition of treatment diets.SFAs, Saturated Fatty-Acids; MCSFAs, Medium-Chain Saturated Fatty Acids; LCSFAs, Long-Chain Saturated Fatty Acids; USFAs, Unsaturated Fatty Acids; MUFAs, Monounsaturated Fatty Acids; PUFAs, Polyunsaturated Fatty Acids (Enos. 2014)

The only significant difference among the HFDs was the omega-6:omega-3 (The control diet (AIN-76A Mod) was used in order to match the MUFA:PUFA and omega-6:omega-3 of the 20:1 HFD.)

Ok, the rodent thing is not the only problem

None of the diets contained any long-chain omega-6 or omega-3 FAs. In human terms this would mean that we are not testing a high fish, high grass-fed beef, but a high omega-3 vegetarian diet with tons of alpha linolenic, but no Docosahexaenoic acid (DHA) or Eicosapentaenoic acid (EPA), which is the "stuff" (=long-chain omega-3 fatty acids) you would find in meats of grass-fed beef and, of course, fish.

Figure 1: Changes in body weight, visceral fat weight and adipocyte size during 20 weeks on modified "standard American diet" w/ different ratios of omega-3 to omega-6 fatty acids (Enos. 2014)

And still, based on the current paradigm, the scientists expected to see significant differences in metabolic health parameters between the high and low omega-3 to omega-6 ratio groups - at best even a complete revision of the metabolic damage the rodents suffered due to consuming a high energy + high fat diet.

It does not always work that way.

In reality, though, any therapeutic benefit produced by reducing the omega-6:omega-3 was evident only when comparing the 1:1 to 20:1 HFD. Yep, that's true, the mice on the 1:1 HFD had a lower total to HDL (TC:HDL-C) ratio and a decreased adipose tissue CXCL14 gene expression and adipose tissue macrophage infiltration, both of which would indicate that they had a lower risk cardiovascular disease.

As a SuppVersity reader you know very well that "A Meta-Analysis Says: Fish Oil Does Not Help You Lean Out!" you do yet also know that the there are also a bunch of arguments "Why It's Still Worth Having Fatty Fish 1-2x/Week" | more

But there were benefits, weren't there? Yes, there were! In fact, there was even a direct link between higher EPA:AA (AA: arachidonic acid, the allegedly inflammatory and thus "bad" long-chain omega-6 fatty acid) and DHA:AA in the adipose tissue phospholipids. 

The net outcome on the other hand, was profoundly disappointing: "[...]despite these effects, and independent of the omega-6:omega-3, all HFDs, in general, led to similar levels of adiposity, insulin resistance, and AT [adipose tissue] inflammation" (Enos. 2014) - in short, it's a sad, but actually not surprising fact that the standard American diet (SAD) will make you fat and diabetic, no matter how much omega-3 fatty acids you are shoveling down.

References

• Enos, Reilly T., et al. "Reducing the Dietary Omega-6: Omega-3 Utilizing α-Linolenic Acid; Not a Sufficient Therapy for Attenuating High-Fat-Diet-Induced Obesity Development Nor Related Detrimental Metabolic and Adipose Tissue Inflammatory Outcomes." PLOS ONE 9.4 (2014): e94897.