Some Things Fishy: Oxidized Fish Oil Totally Benign!?Plus: The Inflammatory Side of EPA and Peroxide & Alkenal Levels in Commercial Fish and Vegetable Oils.

Image 1: Surströmming, a Swedish delicates is essentially rancid fish and it stinks exactly like that. Now, the results of a recent study show that the rancidity does probably not compromise the health benefits of the fish... so if you like it, go for it!

You know that whenever something is so (over-)hyped like fish oil or vitamin D that rings an alarm with me and when I hear "experts" on popular podcast say things along the lines of "as long as you take your fish oil that can compensate for a whacky diet", this is totally burning me up. Yes, there is conclusive evidence that for someone who has damaged his/her body by years and years of omega-6 over-consumption the inclusion of even "high" dose (I consider 5-6g high!) fish oil supplements can make sense, but NO, it will neither allow you to keep eating the same crap that has brought you to where you are at now, nor (and I think this is even more important for most of the SuppVersity readers) is there conclusive evidence that a healthy, active and lean human being is not way better off by limiting his total PUFA intake instead of popping grams of highly oxidizable n-3 fatty acids from fish oil caps.

Highly oxidizable? Yes! Dangerous? Surprisingly not!

A pros pos "highly oxidizable", the argument that polyunsaturated fatty acids (PUFAs) are readily oxidized not only in your body, but even at the shelves of your nutrition store, is one of the few possible caveats of fish oils supplementation even fish oil enthusiasts will acknowledge. After all previous animal studies have shown that diets rich (5%) in rancid (=oxidized) fish oils lead to increases in thiobarbituric acid-reactive substances (TBARS) levels and elevate liver specific transaminases, as well as the alkaline phosphatase (ALP) levels in the plasma of rats (detrimental effects which can by the way be ameliorated by taurine supplementation, cf. Hwang. 2000). The results of a recent study by Inger Ottestad and colleagues from Norway may thusly surprise the "pro-fish oil"-faction about as much as they surprised me (Ottestad. 2011): The ingestion of 8g of oxidized (peroxide value: 18mEq/kg; ansidine value: 9) fish oil (1.6g EPA+DHA) did not have any unfavorable short term-effects in previously healthy individuals.

Figure 1: Serum (left, 8-iso on secondary axes was measured in urine) and erythrocyte (right, GPx on secondary axes) markers of oxidative stress in 68 healthy subjects who were randomly assigned to ingest 8g of "fresh" fish oil, oxidized fish oil or high oleic-acid sunflower oil per day for before (pre) and after (post) the 7 week intervention (data adapted from Ottestad. 2011)

If you take a closer look at the measured levels of serum (4-hydroxy-2-hexenal: 4-HHE, 4-hydroxy-2-nonenal: 4-HNE, alpha-tocopherol,  high-sensitive C-reactive protein: hsCRP and 8-iso-PFG2a, the latter in urine) as well as erythrocyte (total GSH, 4-hydroxy-2-nonena: GR, CAT and glutathione peroxidase: GPx) markers of oxidation before and after the 7-week intervention (cf. figure 1), it is quite obvious that there were no statistically significant oxidation-related changes in the concentrations of the measured markers of oxidative stress, of which the scientists state that they are the current, yet debatable, "gold standard" for in vivo studies.

Figure 2: Changes in n-3 and n-6 levels and the n-6/n-3 ratio (small graph) in the course of the study period (data calculated based on Ottestad. 2011)

It is thus not really surprising that both fish oil groups experienced virtually identical (and highly favorable) -50% reductions in the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids. Moreover, ...

[a]fter 3 and 7 weeks of intervention, the plasma level of EPA, docosapentaenoic acid and DHA were significantly increased in both fish oil groups compared to the HOSO group, but no significant difference in EPA, doc-osapentaenoic acid and DHA between the FO and oxFO groups was observed.

The scientists are thusly right to conclude that their results do not support the often-heard hypothesis that higher intakes n-3 long-chain fatty acids could increase in vivo lipid peroxidation and more importantly, that ...

[...] the content of hydroperoxides in fish oil supplements, even with a PV that exceeds the European Pharmacopeia for marine n-3 oils, does not apparently influence the plasma level of n-3 FA.

With regards to the obvious differences to previous animal studies, the scientists state that secondary oxidation of hydroperoxides, which are then absorbed in the intestine has until now been observed in animal and cell studies. In view of the relative short duration of the study and the reliance on healthy subjects, it is also questionable whether identical results would have been achieved, when sick patients (the usual customer group at least for the pharma-grade n-3 supplements) had been treated with the same product for years.

Oxidized fats in fish oil and beyond

It is also worth mentioning that Ottestad et al. are not sure, whether their "aritifically oxidized" fish oil (oxidation was achieved by sparkling pure oxygen through the oil for 20 min twice a day for 21 d) was an appropriate model for commercially available (oxidized) fish oils. After all, there could be major differences in the composition of the oxidation products, when the oils go rancid over months or get damaged by heat etc. While I obviously cannot answer this question without setting up my own lab, I can however tell you that another recent study by Halvorsen et al. who examined the peroxide and alkenal (one of the major products of secondary oxidation) content of fish and vegetable oils, found average peroxide levels in 33 commercially available fish oil products (mean PV: 3.61mEq/kg) that were ~500% below the ones of the oxidized fish oil (18mEq/kg) in the Ottestad study.

Figure 3: Mean peroxide and alkenal values of 33 commercially available fish and 35 vegetable oils (Halvorsen. 2011).

In this regards, fresh vegetable oils, obviously are way in front, as the data from a study by Bente Lise Halvorsen and Rune Blomhoff clearly shows, that they have lower peroxide and much lower alkenal levels than fish oils (cf. figure 3). Interestingly, vegetable oils are also less prone to being oxidized during storage, something Halvorsen and Blomhoff conclude based on the absence of the "negative correlation (r=−0.557, p<0.001) [...] between the number of days until expiry and the PV [peroxide value]" they observed in the marine omega-3 oils.

Figure 4: Peroxide (PV in mEq/kg) and alkenal (in nM/ml) levels in fresh vegetable oils and after being heated for 25 minutes at 225°C in an oven (data adapted from Halvorsen. 2011); solid red line - maximal peroxide value for olive oils, dotted red line - maximal peroxide values for fish oils as suggested by Turner et al. (Turner. 2006)

Contrary to fish oils, which are usually taken "fresh" and in a capped form, the main fate of vegetable is however to be (ab-)used as cooking / frying oils. During the heating process, the amount of secondary lipid oxidation products, the alkenals, doubles or quadruples depending on the type of oil (cf. figure 4). In that, it may at first seem counterintuitive that, when the scientists heated the samples for 25 minutes at 225°C in an oven, the amount of primary oxidation products was slightly reduced in most, but not all (e.g. soy bean oil) of the 11 vegetable oils. If you do yet take into consideration that the latter are the "raw material" for the secondary oxidation products, it becomes quite clear that this is not a desirable process ;-)

Image 3: Extra virgin olive oils (EVOOs) have generally higher peroxide values than the cheap refined stuff, and yet, EVOOs and not refined oils have been shown to exhibit numerous health benefits.

Putting peroxide values (PV) into perspective: All potential health hazards aside, it may be interesting to know that the general "rule of thumb" says that a fat is rancid when the PV is about 10 meq/kg (the fish oil in the study with PV=18 was thusly "rancid"). A fresh and refined product on the other hand should have PV below 1 meq/kg (Gunstone. 1996). That being said, it may surprise you that for high quality extra virgin olive oils, the PV limit is 20meq/kg, while for "regular" olive oil it is only 10 meq/kg. If you know look at studies related to the health benefits of refined vs. extra virgin olive oil, you will have to admit that - quite obviously - fish oil apparently is not the only oil, where increased peroxide levels do not negate the beneficial health effects of the oil.

So, if pure vegetable oils are generally "fresher" than fish oils does that mean that as long as you do not heat them, they are the better choice? No, they are not! I mean, look at the research that is out there... the abundance of n-6 fatty acids in the "healthy" vegetable oils that are getting pimped especially by the US government, is at the heart of an epidemic of which the authorities still claim that it was caused by high cholesterol levels. Instead banning all saturated fats from YourPlate (which should never look like the governments MyPlate ;-), you should rather incorporate more coconut oil and saturated fats from butter, beef etc. into your diet. Select (vegetable) oils that are relatively high in mono-unsaturated fatty acids, like extra virgin olive oil (don't care about its high peroxide value, cf. red box above) and try to reduce the amount of n-6 fats you ingest - you will get more than enough even from grass-fed meats, olive and other oils and any processed foods that may still be part of your diet, anyway.

Image 4: Not all Omega-3 are created equal. We know for some time that DHA (not EPA) is what your brain needs and a recent study from Norway suggest that eicosapentaenoic acid (EPA) is actually pro- not anti-inflammatory at a cellular level. It may yet well be that this in turn triggers a beneficial hormetic response which would support my "fish oil = exercise in a pill hypothesis"

Although this is not directly related to the topic of oxidation I still want to add that another study appears to confirms my long-cherished skepticism towards EPA (most fish oils have a 2:1 EPA to DHA ratio), which, as a recent study from Norwegian scientists shows (Myhrstad. 2011), is not really "beneficial super-antioxidant" people are led to believe. In their trial the scientists fed 14 healthy female volunteers test meals. The cakes the participants ate were enriched with either flaxseed, cod liver or coconut oil and the intention of the study was to elucidate differential effects of meal fatty acid composition on inflammatory markers. Not to my, but probably to the scientists surprise the "evil" saturated fat from the coconut oil turned out to be similarly benign as the flaxseed cake. Only the EPA-laden cod liver oil cake produced a statistically significant increase in IL-8 mRNA levels 6h post ingestion. Similarly, incubation of peripheral blood mononuclear cells with EPA, yet not ALA lead to >3x increase in IL-8 and >2x increases in IL-6 mRNA expression.

While I am not quite sure what to make of these observations, these results stand in line with previous studies reporting differential effects of EPA vs. DHA rich fish-oils, where across the board, the DHA appeared to be the major driving force of the beneficial health effects people hope to be getting from their fish oil caps (e.g. brain health, Engström. 2009).

Fish oil caps can be a good addition to this regimen specifically for those who are just about to start out on a low omega-6 diet to offset the skewed n-6 to n-3 ratio (something that takes its time). They are yet by no means obligatory for someone who eats fish on a regular basis and invests the extra bucks into grass-fed beef and eggs from pastured chicken. If you thusly satisfy your (anyway low) dietary DHA requirements... and most importantly, taking fish oil will not compensate for eating shitloads of processed foods and lack of exercise, even if the aforementioned pro-inflammatory effects of EPA support my previously uttered hypothesis that fish oil has some resemblance to "exercise in a pill".

Pimp My Olive Oil! When Virgin is not Phenol-Rich Enough: The Pharmacokinetics of Phenol-Enriched Virgin Olive Oil.

Image 1:  "If we have not somehow pimped it, it can never be good enough!" appears to be one of the credos with which mankind approaches almost every health-remedy nature has provided for us. In the past this approach was not particularly healthy, though... is phenol-enriched olive oil going to be the exception to the rule?

Being the health-conscious person you obviously are (why else would you visit the SuppVersity ;-), chances are that olive oil, or, to be specific, extra virgin olive oil is one if not primary source of of mono- and polyunsaturated fats in your diet. But do you actually know why? I mean why olive oil? And why extra virgin? What? "Mediterranean diet", "high MUFA content", "lower incidence of coronary heart disease and cancer"? All right, you have done your homework on olive oil, but what about the "extra virgin"? The polyphenols, right. The phenolic content is in fact what distinguishes a "good" olive oil. The phenolic alcohols, the secoiridoid derivatives, the phenolic acids, the lignans and the flavonoids in concert have been reported to have anti-oxidant, anti-inflammatory, anti-atherogenic and anti-carcineogenic properties and are probably as, if not more important for the beneficial health effects of the Mediterranean gold than its fatty acid profile (Covas. 2007; Covas. 2008).

So, if those polyphenols are the "active ingredients" in olive oil, wouldn't it be nice if we had an oil that had even more of these beneficial healthy secondary plant metabolits in our oils, right?

Now we have tons of polyphenols, but does that make a difference?

The thought, that a souped up version of the already phenol-rich virgin olive oil would be an even more potent health promoter must have occurred to a group of researcher from Spain, as well. Back in 2010 already, Manual Suárez and his coworkers published a paper in the Journal of Argiculture and Food Chemistry in which they describe the development of a "phenol-enriched olive oil with phenolic compounds from olive cake" (Suárez. 2010). In essence, the scientists just put back some of the pulp (an extract to be precise) that is produced when the oil is squeezed from the olives into the end-product. In a more recent study the scientists did now try to evaluate how much of these (additional) health promoters in 30ml of regular virgin olive oil (VO) and the enhanced virgin olive oil (EVOO) actually make it into the blood of 16 (8 men, 8 women) healthy subjects in a randomized, controlled, cross-over trial (Suárez. 2011).

Figure 1: Compositional differences (phenol-enriched vs. standard virgin olive oil) in polyphenol content (data calculated based on Suárez. 2011)

If you take a look at the compositional differences between the regular and the "phenol-enriched" virgin olive oil, it is quite obvious that, from a mere quantitative point of view, Suárez' product with on average 3.3x more secondary plant metabolits should be the more potent health promoter. After all, numerous previous studies have shown that those olive oils with (naturally!) particularly high phenol-content exhibit the most pronounced beneficial health effects (Samanego Sanchéz. 2007). This would yet require adequate absorption of the respective compounds from a now obviously more dense solution, which, according to the results of this study, does not seem to be the case for all compounds - and more importantly, all subjects:

The in vivo study showed that the concentration of fourteen of twenty-four compounds detected was higher in the plasma samples from the EVOO than after ingestion of VOO. Among these, two of them, hydroxytyrosol sulphate and vanil-lin sulphate, were statistically significant in attending their pharmacokinetic parameters, demonstrating the suitability of enrichment. In general, a displacement of the time to reach the maximum concentration is observed in the samples, which indicates that more time is needed to absorb the higher phenolic content. However, inter-individual variabilityin the concentration of the plasma phenol metabolites shows that it is difficult to show statistically significant differences between the VOO and the EVOO.

The scientists thusly conclude that the "metabolism of phenols is affected first by the individual". So until we actually know which influence these are, the label "phenol-enriched" on olive oils and other products has little meaning for you as an individual. And even if you belong to the "lucky" high-absorbers, only two, namely vanillin sulphate and hydroxytyrosol sulphate will reach what the scientists call "pharmocokinetic" levels, if you ingest two tablespoons of the super-potent "phenol-enriched" virgin (and still relatively natural) olive oil.

Figure 2: Changes in total antioxidant activity (TAA) of experimental oils subsequent to heat treatment (from Pellegrini. 2001)

Note: Common Internet wisdom would suggest that you have to be particularly cautious with those "phenol-enriched virgin olive oils", when respective products hit the market (and I bet this won't take long). After all, you will all have heard how heating those oils damages the healthy polyphenols - and while that may to some extend be the case, a 2001 study by Nicoletta Pellegrini et al. found that the total antioxidant value of olive oil does not only increase with increased polyphenol content, but that those polyphenols are also "stabilizers of R-tocopherol during olive oil heating, thus contributing to the nutritional value of cooked foods" and "the prevention of antioxidant activity decay in olive oil during realistic heating conditions" (Pellegrini. 2001), which ranged from 30min at 160°C to 120min at 190°C. The latter happens to be at the upper end of the regular deep-frying temperature and would thus suggest that the commonly heard recommendation not to use extra virgin olive oil for frying is not valid, at least when we focus exclusively on its total antioxidant capacity as measured by Trolox essays (cf. figure 2). In that it should be mentioned that, with its relatively high content of highly oxidizable omega-6 fats, olive oil still isn't the "ideal" frying oil - notwithstanding that frying does not constitute the healthiest way of preparing your food anyways ;-)

And though a recent study has shown that the latter conjugates with LDL and thusly protects it from oxidative damage (González-Santiago. 2010), it remains to be verified whether the consumer variety of the olive oil in this study will actually provide any health benefits. And this is particularly true in view of the fact that the food giants will, as they already do it in the case of "normal" virgin olive oil, minuscule amounts this probably expensive ingredient into their otherwise unhealthy convenient products, just to be able to put the highly marketable "contains phenol-enriched virgin olive oil" on the label... but, hey! I guess, this is just the never-ending story of complete nutritional idiocy ;-)

SVSR: Supplement-Drug Interactions, Exercise & Your Pysche, Running vs. O-Lifting vs. Heart Health, N3-to-N6 Ratios, CYP Enzymes, Cannabinoids & Telomeres

The SuppVersity Science Round-Up every Thursday live on Carl Lanore's Super Human Radio -- tune in live at 1PM (EST=  6PM GMT)!

I hope that most of you have already had a chance to listen to yesterday's installment of the SuppVersity Science Round Up on Super Human Radio. In case you didn't, or have been waiting for me to post the link to the podcast (just a reminder: you can always download the latest show, from the navigation bar on the right, where it says: "Physical Culture for your Ears"), I'd suggest you go and download the podcast either now, or after going through today's SuppVersity Science Round Up Seconds.

The "Seconds" are as the name implies no "leftovers", but actually yet another selection from the selection of god knows how many interesting newsbits I usually pile up for the short 1h show, Carl and I are doing every Thursday. I would therefore encourage everyone to do both, listen to the podcast and read the "Seconds" one day later. After all, the things Carl and I discuss on the air won't reappear here, they are "SHR exclusives", so to say ;-)

Apropos, in yesterday's show, the topics we did cover were

• premature ejaculation, and how only two hormones seem to make a difference,  
• peptides as prostate cancer vaccine, and how Harvard scientists build them from scratch,
• supps vs. medications, and how fatal commonly overlooked interactions can be, and
• copper, and why it may well matter than raw milk has 2-3x more than pasteurized milk

and before we go on with the actual "seconds", I must acquit myself of a promise -- the promise to provide you with more information on #3 on the above list.

Supplemental data: Supplement vs. drug interactions

Figure 1: Important supplement drug interactions based on Tsai (2012)

Those of you who have already listened to the podcast will probably be waiting eagerly for the supplemental material with more information about the potential pitfalls with supplement-drug interactions, Carl and I have been talking about on yesterday's show. With some digging, typing, searching, excerpting and formatting on my part, I have actually come up with a quite comprehensive and for people who are not familiar with all the funky drug names, probably even more understandable version (see figure 1) of the tabular overview H.H. Tsai and colleagues from the China Medical University Hospital and the College of Pharmacy at the University of Illinois at Chicago have included in their latest review of the literature (Tsai. 2012).

What I left out are the two pages (!) part on St. John's wort. With 147 drug (!) interaction ranging from "A" as in "amiodarone" to "W" as in "warfarin" and covering almost every drug type from anti-depressants, protease inhibotors, calcium channel blockers, PDE-5 inhibitors (viagra & co), SERMs, proton pump inhibitors, etc.. In view of the fact that these are only the known interactions, it would be easier to list those drugs with which St John's does not conflict, anyway. So, unless you have a study at hand which conclusively shows that St. John's is no problem, I would rather err on the side of caution, than end up in the ER.

Top 5 of the most frequent interactions observed with medication that act on (ranked by frequency, figure in brackets indicates percentage of all drugs in the study; based on Lin. 2012):

1. nervous system (19.6%)
2. cardiovascular system (17.7%)
3. antiinfectives for systemic use (14.7%)
4. alimentary tract and and immunomodulating agents (12.2%)
5. musko-skeletal system (6.4%)

As far as the supplement list in figure 1 goes, the most frequent potential side effect due to supplement-drug interactions affected drugs / supplements that play a role in blood coagulation. Danshen, evening primrose, gingko, glucosamine, white willow bark, garlic, vitamin E, fish oil to name only the most common ones, they all can increase the risk of bleeding not only, but specifically in patients who are taking warfarin (aspirin, ibuprofen, heparin and others were on the list, as well).

"What’s wrong with telling a patient, 'If you don’t hear from us with your lab results a few days, give us a call'? The answer is plenty, if that patient is receiving warfarin therapy. Because warfarin has a narrow therapeutic range and complex pharmacology, insufficient monitoring or errors in dosing can lead to severe and possibly life-threatening bleeding and clotting in patients receiving it." (Bush. 2002)

In view of the "top 5" above, this certainly sounds counter-intuitive, but we are dealing with a practical research bias here. As I mentioned on the air, there is simply an overabundance of research on potential interaction with warfarin, because finding the right dosage and adapting it appropriately is already hard even when there are no confounding variables, so that a sudden supplement-drug interaction and subsequent increase in the risk of bleeding can potentially be fatal (see the quote in the red box to the right)!

Regardless of what medication you may be on, rules that apply for a healthy individual that does not take any medication chronically (not even 'harmless' NSAIDs), don't apply to you! So please for one, follow the recommendation you find on each and every supplement to "talk to your medical practitioner" before you add another 'harmless' supplement on top of the 'harmless' over-the-counter or prescription drugs you are taking.

The Seconds: Interesting news that have been missing from yesterday's show

After this pretty lengthy addendum, let's get to three other items I had actually planned to have on the show, two of them are exercise, while the third one is a health and supplementation... and, when I come to think about it, obviously also diet related news-item:

• Exercise makes you happy and puts an end to the greed for money! That's not exactly the result of a recently conducted study from the Charité in Berlin (Bothe. 2012), but it is more or less what follows from the differential response Bothe et al. observed in their untrained and highly trained subjects to monetary stimuli after they had completed a standardized running exercise (30 min at 60-70 % VO2max, T) or placebo (P).
  

  

  Who would have thought that: Exercise reduces the anticipatory response to monitary incentive delay (MIT) test (Bothe. 2012)

  "Acute exercise was found to influence gain anticipation. In the P compared to the T group a more pronounced anticipation-related BOLD response was found in mesolimbic and mesocortical dopamine-innervated regions like the VS, hippocampus (Hipp) and subgenual anterior cingulate cortex (sgACC). [...] Additionally, several brain structures potentially associated with motor preparation (primary and supplementary motor areas) as well as structures belonging to the ventral (lingual gyrus) and dorsal (cuneus, precuneus) visual pathway showed stronger BOLD responses to gain anticipation in the P group compared with the T group." (Bothe. 2012)

  Moreover, according to the paper which is going to be published in one of the upcoming issues of Medicine and Science in Sports and Exercise, all 43 healthy men between the age of  20 - 32 years who participated in the study showed similar increases in mood (effect size F=11.70).
  
  With both, the beneficial outcome of the positive and negative affect schedule and the decrease in anticipatory signalling (= the greedy "I am about to win!") in the psychological testing session (the so-called monetary incentive delay) in an fMRI brain scanner, being identical it becomes evident that you don't have to be an athlete to monetize (all puns intended ;-) on the beneficial psychological effects of exercise.

• 

  Figure 1: Changes in total lean mass, aerobic fitness, strength (mind the scaling with x10!), right ventricular mass and end-diastolic volume in subjects in the endurance (runners) and strength training arm (O-lifting) of the 24-week study (based on Spence. 2012)

  Changes to the heart (right ventricular) due to exercise are mild, and if anything more pronounced in response to endurance than resistance training! " Left ventricular (LV) adaptation to exercise training has been the focus of 'athlete's heart' research to-date, information regarding right ventricular (RV) adaptation is sparse, due to its complex structure and imaging technique limitations." (Spence. 2012) So scarce, in fact, that this recent study that has been conducted by researchers form the The University of Western Australia, the University of Leeds, a and the Liverpool John Moore's University is the first to take a closer look at the impact endurance or resistance training have on the morphology of the RV.
  
  For their randomized trial, the researchers recruited twenty-three young untrained men.. The men were assigned to either
  
  • endurance training (E; n = 10)  - consisting of a progressively overloaded program of walking/jogging/running, divided into three training phases over the 24-week period, or
  • resistance training (R; n = 13) - with a focus on periodised R program was Olympic weightlifting with incorporated assistance exercises (e.g. deadlift, squat, bench press, overhead press) to develop overall strength and technique
  for a total timespan of 6 months, in the course of which body composition, aerobic fitness, muscular strength, RV morphology (MRI) and function (speckle tracking echocardiography) were continously monitored.
  
  The results Spence et al. are going to publish in one of the future issues of Medicine and Science in Sports and Exercise refute even two pieces of common "knowledge". Firstly, a still totally benign, right ventricular hypertrophy was exclusively observed in the endurance training group, yet not in the heavy lifters who were doing their squats, deadlifts and military presses (by 2.7g following E and by 1.4 g  following R training). Secondly, both strength and size gains were no prerogative of the lifting weight group. Contrary to the increase in total lean mass (+1.3 kg vs. +2.1 kg), the strength increase of +53.8 kg vs. +35.3 kg was yet much significantly more pronounced in the weight lifters.
  
  On the other hand only the endurance training group saw significant statistically improvements in their aerobic fitness level. This correspondence of endurance exercise, mild ventricular hypertrophy and increased fitness levels is unquestionably telling in terms of "how bad" a physiologically enlarged heart where the ratio of left-to-right ventricular  mass remains intact (which was the case in the study at hand), don't you think so?
• Omega-3s, omega-6s, telomere length, CYP enzymes, endogenous cannabinoid and the liver you need all of them to see the complete picture While the epidemiologists are still debating who will and who won't benefit from omega-3 supplementation, those who still care about how our bodies works and why their colleagues over at the epidemiology department are still debating, have made quite some progress as far as the underlying health benefits of rectifying the omega-3 to omega-6 balance are concerned.
  
  
  Why are endocannabinoids problematic? One of the answers is: "They will make you fat!" Basically we have known that forever, but a recent study which tracked the conversion of dietary linolic acid (n-6) to it's endocannabinoid metabolits, 2-AG and anandamide has recently confirmed not just that, but also that the provision of no more than 1% of the total energy of the diet in form of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) can already make a huge difference (Alvhem. 2012). With the addition of the long-chain omega-3s, the rodents in the study had a 8:1 ratio of linolic acid (LA) to long-chain omega-3 fatty acids in their diets. Still much higher than what you will hear is necessary, but sufficient to reverse the overabundance of arachidonic acid, in the phospholipids of liver and erythroctes, and the +200% increase in endocannabinoid levels that had been brought about, when the researchers had increased the linolic acid content of the diet from 1% to 8% of the total energy intake. In view of the fact that the same goes for the increased food intake, feed efficiency, and adiposity the mice had developed on the 60% fat (total) diet with a high linolic acid content, this study - despite being done on rodents - clearly shows that it does not necessarily have to be a 1:1 ratio to grasp major health benefits.
  
  If you get down from  30:1 to 8:1 you've come a tremendous way, already; and guess what: The easiest way to achieve that is to just cut out all seed and vegetable oils as well as processed foods that contain them.
  In a recent review on the differential effects of fatty acids on human metabolism in the Italian journal Medical and surgical pediatrics G. Caramia emphasizes the role of omega-6 derived endocannabinoids:
  

  "[E]ndocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol [that arise from the enzymatic conversion of linolic acid by enzymes from the cytochrome P450 family at the liver are] capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both [of the] cannabinoid receptor present on nervous and peripheral cell membranes." (Caramia. 2012; my emphases)

  Unfortunately, the same enzymes which are responsible for the generation of those endocannabinoids, are also responsible for the conversion of n-3 PUFAs into more potent metabolites of EPA and DHA, which will actually do most of the the vascular- and cardioprotective magic that is commonly ascribed to "fish oil".
  
  And how does all that relate to telomeres?
  
  These competitive effects in turn segue directly into the observations of a double-blind 4-month trial that involved 106 healthy sedentary overweight middle-aged and older adults. The participants supplemented their diets with capsules containing either (1) 2.5 g/day n-3 PUFAs, (2) 1.25 g/day n-3 PUFAs, or (3) a placebo that mirrored the proportions of fatty acids in the typical American diet.
  
  Now, it's not news that this led to decreases in inflammatory markers. I am not going to bore you with those, don't worry!
  
  What is news, and in my eyes very important, is that neither the provision nor the dosage of additional long-chain omega-3s had an effect on telomere length, the only variable that mattered was were the changes in the n-6:n-3 PUFA plasma ratios, which "helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios (p= 0.02)" (Kiecolt-Glaser. 2012).

That's it as far as today's seconds go... you want more? Man, I could certainly give you more, but you know that gluttony was once considered a sin, right? Tomorrow is another day, and if you can't wait, just head over to the SuppVersity Facebook wall, which is always bursting from the seems with the latest tidbits from the realms of health, exercise and nutrition sciences.  

References:

• Alvheim AR, Malde MK, Osei-Hyiaman D, Hong Lin Y, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity (Silver Spring). 2012 Oct;20(10):1984-94.
• Bothe N, Zschucke E, Dimeo F, Heinz A, Wüstenberg T, Ströhle A. Acute Exercise Influences Reward Processing in Highly Trained and Untrained Men. Med Sci Sports Exerc. 2012 Oct 10.
• Bush J. Preventing errors in your practice. Reducing risks for patients receiving warfarin. Fam Pract Manag. 2002 Jul-Aug;9(7):35-38.
• Caramia G. [Essential fatty acids and lipid mediators. Endocannabinoids]. Pediatr Med Chir. 2012 Mar-Apr;34(2):65-72.
• Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2012 Sep 23. pii: S0889-1591(12)00431-X.
• Spence AL, Carter HH, Murray CP, Oxborough D, Naylor LH, George KP, Green DJ. MRI-derived Right Ventricular Adaptations to Endurance versus Resistance Training. Med Sci Sports Exerc. 2012 Oct 15.
• Tsai HH, Lin HW, Simon Pickard A, Tsai HY, Mahady GB. Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review. Int J Clin Pract. 2012 Nov;66(11):1056-1078.

TTA + Fish Oil Revisited - Increased Intramuscular Omega-3 Levels Compromise Heart and Skeletal Muscle Performance: -40% Endurance & -54% Total Work Capacity in 9 Weeks

Image 1: It is hilarious this picture was probably shot and (ab-)used to propagate the unhealthy message that you could never get enough omega-3 fatty acids from your diet, because that would mean you had to eat such nasty stuff as fish - pah, better pop some pills, I mean we are in the 21st century right!?

I guess you will remember my previous blogpost,  "TTA + Fish Oil - Fat Burning Superfats or Hepatoxic Pro-Oxidants?", on the 2012 study by Vigerust et al. which did show that TTA could ameliorate the hepatoxic side effects of fish oil, which, when it is administered in amounts higher than 1-2g per day over an extended time period, begins to accumulate in the liver (see also "Too Much of a Good(?) Thing: When Fish Oil Starts Clogging Your Arteries and Fattening Up Your Liver"). Moreover, the addition of ~912.4mg (human equivalent) TTA to the "long-term fish oil = fatty liver"-equation turned produced a pretty potent fat burning and anti-obesity stack. Based on previous reports on the unwanted side effects of TTA-based fatburners in the past, I deliberately selected the subtitle "Why You Better Avoid Large Amounts of Omega-3 and Tetradecylthioacetic Acid in the Long Run" and explicitly cautioned against the (over-)use of this fat loss combo for an extended period of time - as one of the most recent article in the journal Lipids in Health and Disease suggests, more than rightly so (Strand. 2012)!

TTA a can save your liver, but it will exasperate the shift of n-3 into your heart

Image 2 (Knuuti. 2008): a globally, well-perfused and (top) a compromised heart with a maximum perfusion of 1.3 ml/g/min (bottom)

As the data the scientists from the Haukeland University Hospital in Bergen, Norway, collected clearly suggest. A similar combination of fish oil and TTA of which Vigerust et al. found that it ramps up fatty acid oxidation in the liver and clears your most important detoxification organ from long-chain polyunsaturated fatty acid junk (not or incompletely oxidized omega-3s) fails to elicit similar effect in the heart of 8-10 weeks old male Wistar rats, who were kept for 50(!) weeks on one the following four 25% fat diets which differed only in terms of their individual fatty acid composition:

• control diet - 23% lard, 2% soybean oil
• TTA - 0.375% TTA, 22.6% lard, 2%
• fish oil - 10.4% fish oil (42% EPA / 21% DHA), 12.6% lard
• TTA & FO - 0.375% TTA, 10.4% FO, 12.2% lard, 2% soy

With both, fish oil and TTA being potent peroxisome-proliferator receptor (PPAR) agonists the scientists were mainly interested in the long-term effects of this touted "anti-diabesity" (i.e. countering diabetes and obesity) agents on the deposition and distribution of different fatty acids in various tissues. A special focus was on the heart and the downstream effects of fatty acid metabolism and myocardial function and performance.

N-3 accumulation in the heart? Wait that's a good thing, right? NO!

For the laymen who has been bamboozled by the fish oil craze this may initially sound counterintuitive, but the profound accumulation of omega-3 fatty acids in the myocardium (heart) of the rodents (see figure 1) is about as bad as it can get for the critters heart health.

Figure 1: PUFA composition (wt%) in heart of rats after 50 weeks of diet administration (Strand. 2012)

Similar to what we have seen for Zinc (cf. "Zinc: 15mg Are Plenty - After 120 Days Rodents on Diets Containing 2xRDA of Zinc Develop Metabolic Syndrome") and alpha lipoic acid (cf. "Lean & Muscular With Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out 'Nutrient Repartitioner'!"), the PPAR-agonists fish oil and TTA, both of which have been shown to exert beneficial effects in certain sick (as of yet still sub-)groups of the population, like diabetics (e.g. Khalid. 2011) and patients with dilated cardiomyopathy (e.g. Nodari. 2011), exert diametrically opposed effects in a rodent model that is probably more accurate for the average healthy human being than his/her sedentary, obese and metabolically deranged peers.

Keep away from your obese neighbors' supplement stash, damn it!

Independent analyses such as a 2009 paper by Dijkstra et al. do not support the commonly held conviction that fish oil or a higher intake of omega-3 fatty acids was beneficial for the general non-diabetic public anyway (Dijkstra. 2009). And it does not take all too long to find numerous reports of in parts serious side effects from the consumption of high-dosed TTA-based fat-burners in the archives of popular fitness and bodydbuilding boards, before the respective supplement producers got scared and pulled them voluntarily and under the pre-text that they had found more effective formulations off the market.

Figure 2: Enzyme activity (nmol/min/mg) in heart of rats after 50 weeks of diet administration (based on Strand. 2012)

Probably a smart move if you look at the combined increases in enzymes that oxidize (ACOX) and enzymes that synthesize and store  fatty acids (FAS and GKAT) in the heart muscles of the rodents in figure 2. Together the synergy of increased storage and increased oxidation could create a perfect storm, which due to the overall "limited capacity of heart to metabolize the poorly oxidizable n-3 PUFA compared to SFA [...] might altogether indicate a reduction in cardiac efficiency" (Strand. 2012).

Reduced cardiac efficacy = reduced muscular efficacy

It's quite funny that we could actually have known that all along, after all, one of my favorite "holy omega-3 vs. bad omega-6" studies by K.J. Ayre and A.J. Hulbert was published in 1997 already. Ayre and Hulbert wanted to elucidate the effects of different dietary fatty acid compositions on the exercise capacity of rodents and found (way before the fish oil craze and therefore not so much to their surprise) that compared to a coconut (EFA deficient) or sesame oil (high omega-6) the n-3 enriched test diet led to a profound decrease in exercise capacity (see figure 3)

Figure 3: Endurance and total work capacity (left) and soleus and EDL fatty acid composition (right) of rats after 9 weeks on diets containing almost no essential fatty acids , a high n-6 or a high n-3 content (Ayre. 2012)

Similar to the detrimental effects on the efficacy of the heart muscle, the decreases in endurance -40% and -54% in endurance and work capacity in the n-3 group went hand in hand with profound increases in the soleus and extensor digitorum longus omega-3 content.

In view of the fact that TTA appears to increase the existing fatty acid recompositioning effects of an overload of dietary omega-3 fatty acids in the diet, and against the background that the observed negative side effects came about in no more than 9 weeks and were not reversed after 6 weeks on standard chow, it appears more than questionable if the few lbs of body fat you may be able to shed with the aforementioned TTA+fish oil double whammy over say 4-8 weeks are actually worth taking the risk of permanent or at least only slowly reversible changes in the intracellular fatty acid composition of your heart and skeletal muscle.

"And what about fish oil supplementation alone?"

Aside from the fact that the usefulness of fish oil caps in healthy individuals is questionable (Dijkstra. 2009) and anything beyond 1-2g of fish oil per day could well lead to increased not decreased oxidative damage in athletes and physical culturists (cf. "Omega-3 Fatty Acids Pro-Inflammatory in Athletes"; Filaire. 2010), you don't necessarily have to throw away your fish oil. After all, I would hope that no one here is getting 50% of his/her daily fat intake from fish oil caps - which was basically what Strand et al. fed their rodents to make sure that the shift in myocardial fatty acid levels would be profound enough. Still the Ayre study, where the n-3 content of the diets was much lower (16% of total fat intake, ~8.8g of fish oil if you consumed 2,000kcal/day), does indicate that the intramuscular changes in fatty acid composition can be profound and not without detrimental consequences even without the addition of TTA and in response to amounts of omega 3 fats of which we all know that thousand of supplement junkies still believe would be nothing but beneficial for their health.

Image 3 (woschie): What would these guys say, if everything they caught was a handful of fish oil caps? "Look! I have caught the best part of the fish. lucky me, so I don't have to take it, squeeze it and bath it in all sorts of chemicals to separate the good fats from the bad protein I would then have to process to fish meal!"

In the end, it all comes, as so often, by the way, back to two very common motifs here at the SuppVersity motif A which I have already implied in one of the subheadings is the simple truth that what has been show to work for the obese type II diabetic does not necessarily work for a healthy human being, let alone such an extraordinary specimen as you are ;-) And that does in fact segue perfectly into motif B which revolves around the notion of balance and is basically the foundation of my repetitive advice to always prefer real foods over supplements, where the latter is possible - and contrary to creatine of which even a meal-loving carnivore like myself could never get enough from his diet to see any of the scientifically well-established benefits, eating fish spending a couple of extra-bucks on grass-fed beef from time to time and simply avoiding the omega-6 laden vegetable oils will make the use of those nasty fish oil caps obsolete, anyways.

References:

1. Ayre KJ, Hulbert AJ. Dietary fatty acid profile affects endurance in rats. Lipids. 1997 Dec;32(12):1265-70.
2. Dijkstra SC, Brouwer IA, van Rooij FJ, Hofman A, Witteman JC, Geleijnse JM. Intake of very long chain n-3 fatty acids from fish and the incidence of heart failure: the Rotterdam Study. Eur J Heart Fail. 2009 Oct;11(10):922-8.
3. Filaire E, Massart A, Portier H, Rouveix M, Rosado F, Bage AS, Gobert M, Durand D. Effect of 6 Weeks of n-3 fatty-acid supplementation on oxidative stress in Judo athletes. Int J Sport Nutr Exerc Metab. 2010 Dec;20(6):496-506.
4. Khalid AM, Hafstad AD, Larsen TS, Severson DL, Boardman N, Hagve M, Berge RK, Aasum E. Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H2116-22. Epub 2011 Mar 18.
5. Knuuti J, Bengel FM. Technology and guidelines: Positron emission tomography and molecular imaging. Heart 2008;94:3 360-367
6. Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, Gheorghiade M: Dei Cas L: Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol 2011, 57:870–879.
7. Strand E, Bjørndal B, Nygård O, Burri L, Berge C, Bohov P, Christensen BJ, Berge K, Wergedahl H, Viste A, Berge RK. Long-term treatment with the pan-PPAR agonist tetradecylthioacetic acid or fish oil is associated with increased cardiac content of n-3 fatty acids in rat. Lipids Health Dis. 2012 Jun 27;11(1):82.
8. Vigerust NF, Cacabelos D, Burri L, Berge K, Wergedahl H, Christensen B, Portero-Otin M, Viste A, Pamplona R, Berge RK, Bjørndal B. Fish oil and 3-thia fatty acid have additive effects on lipid metabolism but antagonistic effects on oxidative damage when fed to rats for 50 weeks. J Nutr Biochem. 2012 Jan 3.

Body Fat Modulation with Corn Oil & L-Carnitine: What You Can Learn From Your Schnitzel

Its quite remarkable that, primates aside, swine are among the best models of human metabolism. So, even if you do not feel piggy at all, the fact that pigs just as humans are omnivores, makes them a much better model for metabolic disease than rodents. It is thus not too unrealistic to assume that we can learn something about ourselves from the results of a very recent study published in the Journal of Animal Science (Apple. 2011).

Figure 1: American Pork Cuts; quality is determined by corn-oil and carnitine intake of the swine.
What lessons can you learn from our pink relatives?

Investigating the effects of l-carnitine supplementation on the quality characteristics of fresh pork bellies from pigs fed three levels of corn oil, J.K. Apple and his co-workers observed a linear trend towards decreased belly-firmness with increasing amounts of corn oil (0, 2 or 4%) in the diet. If you look at the average American, his/her high corn oil consumption and their respective (pot-)bellies, this should not surprise you. All aesthetic considerations aside, those feisty pot-bellies are nothing but the outward sign of metabolic derangements that - without appropriate lifestyle interventions - have their owners suffer from diabetes, high blood pressure, chronic inflammation, and all the other players in the (eventually) deadly "game" of metabolic syndrome.

[...] belly firmness decreased linearly (P < 0.001) with increasing dietary OIL, but there was no (P ≥ 0.137) effect of CARN on any belly firmness measure.

Now, did the touted fat-burner l-carnitine prevent these effects? No, it didn't. Yet, what it did do is it increased the amount of saturated (SFA) and mono-unsaturated (MUFA) fatty acids and decreased the amount of polyunsaturated fatty acids (PUFA) in the belly tissue:

Dietary CARN increased (P < 0.05) the proportion of total SFA in the intermuscular fat layer, increased (P < 0.05) the proportion of total MUFA in the primary and secondary lean layers, and decreased (P < 0.05) the proportion of total PUFA in the intermuscular fat and secondary lean layers of pork bellies.

In view of the finding that increasing the amount of corn oil in the diet tended to increase the PUFA content of the belly tissue, while depositing the highly oxidative polyunsaturated fatty acids preferentially in fat and not lean layers, one must acknowledge that L-carnitine, despite not being able to prevent the outwardly visible (and touchable) negative effects of a diet high in omega-6 rich corn oil, was yet able to modulate the effects of excess PUFAs on intra-tissue body fat composition.

Against the background of the recent changes in the scientifically accepted perspective on the previously vilified saturated fatty acids and possible beneficial effects on cell stability and inflammation the significance of these results goes beyond profane insights into the management of pork quality and solidify the foundation of my previous recommendation to avoid omega-6 instead of increasing the overall PUFA load by additional omega-3 supplementation. What's new, however, is the role l-carnitine supplementation may play in your efforts to get rid of overly high tissue levels of omega-6, since the reduced storage in fat tissue and the increased storage in muscle could be able to (a) decrease inflammation of the fat tissue and, at the same time, (b) increase oxidation of PUFAs in exercised muscle tissue. Yet, without appropriate dietary changes and the incorporation of regular exercise sessions into your  new, healthier lifestyle all carnitine in the world won't help you, if you insist on eating too many breaded and fried schnitzel with French fries and a boatload of mayonnaise and ketchup.

The Pro-Diabetic Effects of Shark Liver Oil - Plus: Can it Be Coincidence that the Omega-6-Laden Nigella Sativa Oil has Just the Opposite Effects on Blood Glucose & Triglycerides

Image 1: Even if you kill him, he will take revenge and increase your blood glucose and triglyceride levels. And if you don't die from the negative side effects of the oil from his liver the neurotoxins from his fins will take care of the rest (cf. Science Daily)

"Healthy fats"... not to long ago even the combination of these two words was an oxymoron (an intrinsic contradiction). "How on earth can fats be healthy?" Was what the blank stares were telling you, when you set out to explain how and why people should not buy the latest and greatest "no fat" products from their local grocery stores. As of late the tides have changed and even mainstream media is jumping on the "healthy fats"-bandwagon - unfortunately, in a similarly single-sided way as before, with the "healthy polyunsaturated fats" on the one side of the divide and the "unhealthy saturated fats" on the other. Now, we all know that this distinction is flawed, but are really all fats made equal? Probably not, after all the overall message in the blogosphere has been changing from "limit omega-6s and get as much fish oil as you can" over "avoid omega-6s alltogether and make sure you get enough fish oil" to "avoid all PUFAs, but make sure that you get a decently low omega-6 to omega-3 ratio from the PUFAs you cannot avoid".

Sharks vs. blackseed - round 1: Fight!

A recently published study from the Faculty of Medical Sciences at the University of Science and Technology in the Republic of Yemen does yet provide further evidence that even this may not be the answer to everything. After all, the (formerly ;-) healthy 18 subjects (age: 23-31 years) in Doa’a A. Ibraheem study did not react particularly favorable to 2 weeks on 500mg of omega-3 fatty acids from an American shark liver oil product (Vitex  Pharmaceuticals).

Figure 1: Changes in glucose and lipid metabolism in 18 healthy volunteers in response to 2-weeks on either 500mg of omega-3 rich shark liver oil or 1,200mg of omega-6 rich nigella sativa oil (data calculated based on Ibrahiim. 2011)

As you can see in figure 1, the GMP certified "healthy" fish oil variety from shark livers did exactly what people who pop tons of cod-liver or regular fish oil want to avoid: It increased the fasting blood sugar and triglyceride levels - and if Mr. Ibraheem had had the financial resources to measure their insulin levels, I would bet any money that those were elevated as well.

The "bad" Nigella Sativa Oil of which the "poor" subject ingested even 1,200mg per day for another 2 weeks (in fact this trial was done 4 weeks before the SLO trial with an appropriate wash-out period in-between), with its 13% saturated fat, 25.5% MUFA and 58.5% of the dreaded omega-6s (it has only 1% omega 3) did not only induce a significant drop in fasting blood glucose, it also left the lipid parameters untouched.

And what about fish oil?

Now, despite the fact that shark liver oil is not identical to either fish, or cod liver oil, and that some if not all the health benefits of nigella sativa could be induced by other (micro-)nutrients than , I would hope that results like this will make more people question the "revised" perspective on "healthy fats", according to which all omega-6 acids are like vampires, that must be parried with garlic... ah, pardon omega-3 ;-)