Complete Meals & GI (Non-)Sense, Glutamine & GLP-1, Low Thyroid & High Trigs, N-3 vs. N-6 Interactions, Optimal DHA Dosage in Kids W/ NAFLD, Selenium vs. Aluminum Toxicity

While this is not the exact combination of chicken breast, mashed potatoes and salad in the first one of today's news items, it's more than likely that the predicted GI (and thus probably what you would find if you looked it up in a table) overestimates the postprandial glucose response to this meal by ~50% and says absolutely nothing about the insulin response. It looks like complex meals and over-simplified theories, don't mix well, at all ;-)

78% that's the SuppVersity Figure of the Week and actually part of the additional information I provided on one of today's On Short Notice items. It's the increase in coronary heart disease risk women with subclinical hypothyroidism have compared to their peers with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). In conjunction with other more or less recent studies, such as Mitchel's, Hsu's and Sahai's paper confirming the previously often talked about but not well-established 2-fold increase in congenital hypothyroidism from the early 1990s to the first years of the new millennium (Mitchel 2011), the predictive value of high TSH levels in the first trimester (early pregnancy hypothyroidism) for adverse pregnancy outcomes (Schneuer. 2012), the 30% risk increase in all-cause mortality in both women and men with subclinical hypothyroidism Tseng et al. reported in their paper earlier this year or the impairment of spatial working memory (Yin. 2012), Asvold's results only add to the evidence that the potential pitfalls of an increasingly prevalent metabolic dysfunction may have been ignored way too long.

• More GI lovin' - On the menu today: Mashed potaoes with chicken, rapeseed oil or both (Hätönen. 2011) - I thought a mini-follow-up on Friday's post on the GI would be nice, 'cause some of you have not without reason been complaining that not everyone would eat pure white bread, like my students do.
  
  

  

  Figure 1: The real (=measured) GI of a meal does differ significantly from the theoretical prediction. So, even if the concept was worth bothering, the GIs of complete meals simply wrong, if they are not measured (Hötönen. 2011).

  Moreover, the mere fact that the scientists from the Department of Lifestyles and Participation at the National Institute for Health and Welfare in Helsinki, Finland, found that the addition of chicken breast, rapeseed oil and a salad, individually and in combination, had the GI of a meal containing six mashed potatoes (this was the parameter that was held constant) induced more than twofold changes in GI, with the addition of chicken breast having the greatest deviation from the predicted value in this group of 11 (initially 12) healthy subjects, three men and nine women, aged 36.2 (SD 14.1) years with a BMI of 21.3 (SD 1.7) kg/m² and normal glucose tolerance (see figure 1).
  
  Now given the fact that most data on the GI of complete meals has never been measured, but is actually based on the same predictions the scientists used, it stands to reason that...
  

  [...] this highlights the problems encountered when predicting the GI values of mixed meals. The protein com-ponent of the mixed meal evoked the largest insulinaemic responses and markedly increased the II of the mixed meal containing protein. However, introducing fat into the meal decreased the effect of protein on the insulinaemic responses (Hätönen. 2011)

  So, this does not simply bust the idea that you could calculate the GI, it does likewise show you that people who are still overtly scared of insulin (which is hillarious as long as you are insulin sensitive) are doing he exact wrong thing, when they make food-choices based on GI: Whey protein would in that case be in as much a no-go as simply eating a chicken breast with your mashed potatoes would be, because other than what most people believe, it does increase the insulin spike and thus reduce the glycemic index by allowing your body to clear the glucose more efficiently from the circulation.
  
  Suggested reads: The red box in the "Whey is More Insulinogenic than White Bread" post on the partitioning effects of BCAAs and yesterday's Facebook post on the anti-Alzheimer's effects of insulin.

• 

  Suggested read: Amino Acids for Super Humans the purported ergogenic effects of l-glutamine

  30g of oral glutamine have similar effects on GLP-1 as 75g of glucose (Greenfield. 2008) - Still a follow up on the GI discussion, I think you may be interested in. If you are someone who follows the questionable practice of ingesting large boluses of glutamine in the futile believe that this would increase your gains or speed up recovery, you may be pleased to hear that only 30g of oral l-glutamine produced an increase in the "Fat Burning Satiety Hormone GLP-1" (read more on GLP-1) that's on a gram to gram basis more pronounced than in response to insulin (0.41pmol/L per gram glucose vs. 0.75pmol/L per gram of glutamine; in 8 healthy subjects).
  
  Before you go and buy tons of glutamine, you should however consider that GIP, the pro-insulinogenic peptide and glucagon (ramps up gluconeogenesis in the liver) were likewise increased by the ingestion of this bolus of glutamine. It is therefore no wonder that glutamine has never been shown to be a "fat burner". Nonetheless, a 1999 study by Bowtell et al. would suggest that it may come handy to replenish liver and muscle glycogen after a workout (8g alone did increase glucose storage after a workout to a similar degree as a 18.5% glucose polymer solution and additional 25% glucose storage mostly in the liver, when both were coingested; cf. Bowtell. 1999). And if you don't care about that - your gut integrity could also be a reason to consider supplementation in the vicinity of particular strenuous or length workouts (see "Shedding Some Light on the Leaky Gut <> Exercise Connection") 

• Practical relevance? Based on data from a 12-year longitudinal study, even women with subclinical hypothyroidism have 76% risk for coronary heart disease (p = 0.005), than women with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). And even women well within in the "normal range" (TSH of 1.5-2.4mU/l) have a 41% higher risk of heart disease, although this is only borderline significant (p = 0.08). For men the TSH level alone had not predictive value. Spec. w/ regards to T3, there are also reports of increased incidence of ventricular disfuntion (Cassetti. 2009), increased cardiac death in CVD patients (Iervasi. 2003) and impaired recovery after a stroke (Alevizaki. 2007). We do yet have to be cautious, here as "low T3" syndrome could as well be the consequence of overall inflammation and the association does not tell us anything about what's the chicken and the egg.
  Low thyroid, high triglyceride (Hashimoto. 2012) -- If you are wondering why on earth your trigs won't come down, it may well be that it's the absence of sufficient amounts of thyroid hormone. I a soon-to-be-published paper in Endocrinology scientists from the Gunma University in Maebashi, Gunma, Japan, report that thyroid hormone regulates the expression of a Stearoyl-CoA desaturase-1 (SCD-1) which controls the production of trigs from carbohydrates.
  
  Surprisingly the 75% increase due to hypothyroidism and the 75% decrease in SCD-1 mRNA expression (both compared to a euthyroid state) the scientists observed in rodents in response to the administration of T3 were not mediated by receptor binding, but simply as a down-stream effect of direct modifications of the SCD-1 gene promoter between -124 and -92 bp by T3.
  
  On a related side note: It is actually the last mentioned mechanism which is the major new finding in the study at hand and not the fact that T3 can reduce the conversion of carbohydrates to triglicerides that is the actual news here. After all, the latter is something scientist should know, but obviously like to forget about ever since the late 1999s (Waters. 1997)

• Omega-6 intake and not low omega-3 intake is the problem (Liou. 2007) -- Another older study, but one I am posting in response to a discussion some of you are having about omega-3 (ALA) intake in the post about safflower oil and DHT, because I simply feel that it's necessary to shed some light  on the erroneous assumption that by simply upping your intake of omega-3s or fish oil intake you could get away without decreasing your omega-6 intake, which in and out of itself will already increase the amount of anti-inflammatory omega-3 fatty acids (supplementation of DHA can still be advisable, specifically if you are a vegetarian).
  
  

  

  Figure 2: Effect of 4 weeks of high (red) vs. 4 weeks of low (green) linoleic acid (n-6) intake on short and long-chain omega-3 plasma phospholipid content in healthy men (Liou. 2007)

  In 2007, already Liu et al. conducted a very interesting experiment in the course of which they fed healthy men diets with identical amounts of omega-3 fatty acids (1% of the total energy intake), but two different amounts of linoleic acid (omega-6) and found that the high omega-6 intake (10.1% vs. 3.8% of the total energy intake) alone decreased the total amount of EPA among the plasma phospholipids (the major long-chain omega-3 fatty acid in fish oil), not just the ratio of omega-3 to omega-6, in the blood of their 29-45 year-old subjects by more than 25% (see figure 2). The paradoxical effect on DHA, on the other hand, would warrant further investigation, and underlines how reliant we are - if anything on the intake of pure DHA, which dropped in consequence to the test diet, which was devoid of fatty fish, while the original diet of the non-vegetarian subjects had fish in it.
  
  In this context, I would also like to point out that DHA is exactly where real fish is far superior to fish oil caps, because it has a way more favorable EPA:DHA ratio than fish oil caps. Salmon fillets for example have - depending on the fatty acid source in the diet 8.5g : 13.8g, 4.4g : 7.8g and 1.5g : 2.9g (all values per 100g) when the feed contains fish oil, fish and rapeseed and fish + rapeseed and rapeseed, only.
  
  And while the ratios are similar regardless of the chow, the data from the Seierstad et al. clearly shows that the fatty acid content of the diets can induce almost 5-fold differences in terms of the total DHA content and the omega-3 to omega 6 ratio (fish oil diet: 6.5, fish oil + rapeseed: 1.7, rapeseed: 0.6) of salmon fillets (Seierstad. 2003). 

• It does not take much: 500mg DHA not more effective than 250mg  (Nobili. 2012) -- At least if it comes to its beneficial effects against liver steatosis in children  (mean age 11 years; BMI 26.6kg/m² and 24.4kg/m², in the low and high dose groups respectively with with NAFLD, the amount of DHA does not appear to be so important. According to the results of their 2-year registered controlled trial, both 250mg and 500mg of Docosahexaenoic acid lead to identical and profound reductions in the odds ratio of developing more severe steatosis during the study period.
  
  

  

  Figure 3: Odds ratio (comparing DHA supplement vs. placebo) of more severe vs. less severe liver steatosis determined every 6 months during the 24-month study period (Nobili. 2012)

  If you take a closer look at the data in figure 3, you will even have to concede that the lower dosage did a better job - while the mean odds ratios were only marginally lower in the 250mg DHA group, the extremely high standard deviations in the 500mg DHA would suggest that the 250mg dose appears to be more reliable. In this regard it may be interesting that the increase in serum DHA did mirror the dosages. With a 0.65% and 1.15% increase in DHA those were about 2x higher in the 20 boys and girls in the high dose group compared to the 20 kids in the control group who received a 290 mg linoleic acid germ oil supplement "placebo" (by the way, a monosaturated fatty acid placebo would have been more of a placebo than 290mg of omega-6)
  
  In view of the fact that the changes in triglycerides, ALT, HOMA-IR and BMI (which was not even different from the placebo group) were likewise identical, it does not appear as if anything that goes beyond the amount you will find in 2x cheap fish oil caps, or 10g even of the cheapest salmon fillet (see last paragraph of previous item) would be necessary to ellicit the anti-steatosis effect of fish oil - since those kids weight on average 55kg, an adult may want to add in another fish oil cap to get up to 360mg DHA per day or simply eat his fatty fish once or twice a week.

• Selenium ameliorates aluminum toxicity (Viezeliene. 2012) -- With the whole upheaval about the potential negative side effects of the aluminum in vaccines, the formerly overlooked yet well-known neurotoxic (Exley. 1992; Gupta. 2005), hepatotoxic (Abubakar. 2003; Perez. 2005) and nephrotoxic metal (Geyikoglu. 2012) has all of a sudden returned to the center of public interest.
  
  Therefore I thought that you will be interested in the results of a study that's going to be published in the next issue of the Journal of Trace Elements in Medicine and Biology - irrespective of whether you believe, like Tomljenovic and Shaw that
  

  "the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community"(Tomljenovic. 2011)

  After all, vaccines are not the only potential source of aluminum in our environment, so that the ameliorative effects (all values remained normal in the aluminum exposed group, while there were 30%, 55% and 42% increases in GSH in the animals who received only the selenium injection) the co-administration of supplemental selenium had on the GSH reductions in liver, kidney and brain of Balb/c mice weighing 20–25g who were exposed (by i.p. injection)to AlCl3 (25 mg Al(3+)/kg body mass) for 16h could be important, regardless of whether you do or don't intend to get vaccinated.
  
  

  

  There is more about selenium at the SuppVersity, for example on its pro-fertility effects, and its anti-corrosive effects in the brain.

  That said, the dosage requirements necessary to maintain healthy GSH levels are probably much lower than the hillarious (for a healthy individual) in the study at hand 1,250µg/kg body weight of sodium selenite (Na2SeO3). Considering the elemental selenium content in Na2SeO3, the latter would equal to ~3,650µg - unquestionably WAY too much (remember this was a one-time dosage that was specifically co-administered w/ the aluminum). Even the 'no observed adverse effect' level for a 70kg man of intake which is ~1000µg/d (Whanger. 1999) appears unnecessarily high, so that the consumption of a handful of brazil nuts once or twice a week and/or other high selenium foods such as tuna, cod, oysters, shrimp, but also eggs, meats, poultry, mushroom and onions on a regular should suffice to get what you need, to fortify yourself against the constant assault of heavy metals.
  
  What would be interesting, though, is a study into the effects of adding selenium to the "safe" aluminum in vaccines. I mean, you cannot seriously tell me that we could not afford doing that and if it reduced any toxicity issues, why not?

That's about it for today, I did not post all too many new facebook news as of yet (I mean, come on, it's Saturday ;-), but if you are into medicinal horror-stories, you will certainly like the story about the flesh eating killer fungus. If you prefer microbes over fungi, you are probably better off with the latest insights into the associations of certain gutbacteria with the incidence of stroke. And if you are more into other aspects of the digestive tract you may be interested in the effects of gastric emptying time on postprandial gylcemia and insulin release.

If none of those news is to your liking, I suggest you either wait for me to post something else (could be happening within the next hours at www.facebook.com/SuppVersity), or simply enjoy the weekend and come back tomorrow when you are rested for another (hopefully) enlightening SuppVersity post.

References:

• Abubakar  MG,  Taylor  A,  Ferns  GA.  Aluminium  administration  is  associated  with enhanced  hepatic  oxidant  stress  that  may  be  offset  by  dietary  vitamin  E  in  the rat. Int J Exp Pathol 2003;84:49–54.
• Asvold BO, Bjøro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT Study in Norway. Clin Endocrinol (Oxf). 2012 Dec;77(6):911-7.
• Bowtell JL, Gelly K, Jackman ML, Patel A, Simeoni M, Rennie MJ. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J Appl Physiol. 1999 Jun;86(6):1770-7.
• Cassetti G, Pinelli M, Bindi M, Bianchi M, Castiglioni M. [Low T3 syndrome and left ventricular diastolic function]. G Ital Cardiol (Rome). 2009 Aug;10(8):553-7. 
• Exley  C,  Birchall  JD.  The  cellular  toxicity  of  aluminium.  J  Theor  Biol 1992;159:83–98.
• Geyikoglu  F,  Turkez  H,  Ozhan  Bakir  T,  Cicek  M.  The  genotoxic,  hepa- totoxic,  nephrotoxic,  haematotoxic  and  histopathological  effects  in  rats after aluminium chronic intoxication. Toxicol Ind Health 2012;15.
• Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009 Jan;89(1):106-13.
• Gupta  VB,  Anitha  S,  Hegde  ML,  Zecca  L,  Garruto  RM,  Ravid  R,  et  al.  Alu- minium  in  Alzheimer’s  disease:  are  we  still  at  a  crossroad?  Cell  Mol  Life  Sci 2005;62:143–58.
• Hashimoto K, Ishida E, Miura A, Ozawa A, Shibusawa N, Satoh T, Okada S, Yamada M, Mori M. Human Stearoyl-CoA Desaturase 1 (SCD-1) Gene Expression Is Negatively Regulated by Thyroid Hormone without Direct Binding of Thyroid Hormone Receptor to the Gene Promoter. Endocrinology. 2012 Dec 7.
• Hätönen KA, Virtamo J, Eriksson JG, Sinkko HK, Sundvall JE, Valsta LM. Protein and fat modify the glycaemic and insulinaemic responses to a mashed potato-based meal. Br J Nutr. 2011 Jul;106(2):248-53. 
• Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-13.
• Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007 Apr;137(4):945-52. 
• Mitchell ML, Hsu HW, Sahai I; Massachusetts Pediatric Endocrine Work Group. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol (Oxf). 2011 Dec;75(6):806-10.
• Perez  G,  Pregi  N,  Vittori  D,  Di  Risio  C,  Garbossa  G,  Nesse  A.  Aluminium  expo- sure  affects  transferrin-dependent  and  -independent  iron  uptake  by  K562  cells. Biochim  Biophys  Acta  2005;1745:124–30. 
• Schneuer FJ, Nassar N, Tasevski V, Morris JM, Roberts CL. Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. J Clin Endocrinol Metab. 2012 Sep;97(9):3115-22.
• Seierstad SL, Seljeflot I, Johansen O, Hansen R, Haugen M, Rosenlund G, Frøyland L, Arnesen H. Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis. Eur J Clin Invest. 2005 Jan;35(1):52-9.
• Waters KM, Miller CW, Ntambi JM. Localization of a negative thyroid hormone-response region in hepatic stearoyl-CoA desaturase gene 1. Biochem Biophys Res Commun. 1997 Apr 28;233(3):838-43. 
• Whanger P, Vendeland S, Park Y-C & Xia Y. Metabolism of sub-toxic levels of selenium in animals and humans. Annals of Clinical Laboratory Science. 1996;26, 99-113.

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".

Farmed vs. Wild-Caught: Pollutants and A Low Omega-3/6 Ratio - Is Wild Caught Fish Always the Better Choice? Plus: Krill, Fish Oil, or Whole Fish - What's Best for Your Health?

Wild caught or farmed? If you google it, it appears to be as if eating farmed  fish could be worse than eating no fish at all, but is this actually true?

Farmed fish is the ugly duckling in the "superfood" family. It is - at least that's what you'll read on the Internet - low in omega-3s, full of "bad" omega-6 fatty acids and laden with all sorts of pesticides. But wild caught fish is expensive and if we all ate it day in and day out not exactly eco-friendly, right?

In today's SuppVersity special parts of which you may have recently seen pop up for a few hours in interview form over at www.fighterdiet.com, before Pauline Nordin and I decided that due to its length and complexity it was rather an article than an interview and should thus be published as such, I am going to tackle the issue of "farmed vs. wild-caught" and "fish vs. fish oil" from all possible angles.

Do not underestimate fish as a protein source - fish is more than just omega-3!

Salmon Better Than Whey?

Cod protein for recovery

Krill = Super Protein?

High EAA protein for fat loss

Fast vs. slow protein

5x More Than FDA Allows

I would like to start my elaborations with the results of a recent paper by Nichols et al. (2014). A paper, in which the scientists investigate whether the existing differences of the fatty acid profiles from farm-raised vs. wild-caught cold-water fish would depend on what the fish were fed.

The general consensus on the Internet appears to be that wild-caught salmon is in all ways superior to its "industrially produced" counterpart from the large fish farms. In that, the opponents of farmed fish consumption usually highlight the (I quote) "exorbitant" amount of allegedly unhealthy omega-6 fatty acids in farmed fish.

Now it is certainly undebatable that the ratio of omega-6 to omega-3 fatty acids in wild-caught vs. farmed salmon differs significantly. The previously mentioned study by researchers from the Commonwealth Scientific Industrial Research Organization does yet also show that this effect is not a result of "farming", per se. Rather than that, the increase in omega-6 and decrease in omega-3 fatty acids in today's industrially produced cold-water fish is a result of the ongoing reduction of the fish(oil) content in the fish food.

Figure 1: Fatty acid profile of farmed and wild-caught baramundi in 1998, 2002 and 2010 (left) and the corresponding omega-3 to omega-6 ratios (right) – it's worth noticing that "back in the day" of high fish oil diets, the farmed barramundi had a more favorable omega-3 to omega-6 ratio than their wild-caught relatives (Nichols. 2014)

In 2001, for example, when farmed barramundi (Lates calcifer | another cold-water fish that is raised in large aqua-farms these days) were still fed a high percentage of dietary fish oil, the farmed fish actually had a more favorable omega-3 to omega-6 ratio than its wild-caught counterpart (see Figure 1).

Over the past 13 years, the fish farmers have yet replaced large amounts of the increasingly expensive fish oil in the feed by cheap poultry oils. The consequences are obvious: While this practice may reduce the levels of dioxins and dioxin‐like PCBs (Berntssen. 2005), the substitution of fish oil with vegetable oil in the feed lead to decreases in the total amount of PUFAs, most specifically omega-3s, though. Thus, the originally highly favorable omega-3/omega-6 ratios of 5:1 for farmed salmon and 3:1 for farmed barramundi has declined to a meager 1:1 (Nichols. 2014).

High omega-6 in today's farmed cold-water fish - a problem? For the average physical culturist who is following a diet that is comparatively low in potentially pro-inflammatory omega-6 fatty acids (they are only bad for you, when they are consumed in excess), tehe deterioration of the omega-3 to omega-6 fatty acid ratio in modern farmed vs. wild caught fish is relatively unproblematic. Unlike it is the case for the average Westerner, who is in dare need of high omega-3 and low omega-6 foods to balance his or her excessive omega-6 intake from vegetable oils and industrially processed foods, farmed salmon is thus still a good source of protein and fats for those of us who are following a whole foods diet with a balanced fatty acid profile.

So, if the relatively high omega-3 content is not a problem, because the effects of "high omega-6" farmed fish on your omega-3 to omega-6 ratio is still neutral (that's the case if the ratio is approx. 1) there is no reason to avoid farmed fish, right?

From "high omega-6" to high levels of organic and inorganic pollutants

Unfortunately the high omega-6 content is not the only problem farmed fish is supposed to have.  Next to the previously discussed issue, the occurrence of various pollutants in farmed fish is another of the topics that will be mentioned in almost every online- or gym-debate on the consumption of farmed fish. Rumors have it that farmed salmon was loaded with toxic chemicals. And guess what!? To a certain extend that is absolutely true.

Figure 2: Fish is by far not the only POP source in our diets. Each 0.5 serving of the above foods is associated with the given increase in µg of urinary phthalate and phenol biomarkers in the urine of 6-8 year old girls and may thus increase their breast cancer risk later in life (Mervish. 2001)

When we are taking a closer look at the latest scientific evidence on the real world effects of thes persistent organic pollutants (POPs), it turns out that a high fish consumption has no measurable impact on the concentration of this potentially cancerous endocrine disruptors (they mess with your hormones) in our blood and adipose tissue. In fact, the latest study by Hausken et al. clearly indicates that the POPs in the blood of their fish fed subjects and the corresponding control group have different food products as their main sources (Hausken. 2014).

It is thus no wonder that the researchers from the University of Bergen did not find any change in serum or adipose tissue POP levels, when they had their subjects, 42 outpatients with different metabolic disorders, increase their intake of farmed salmon or salmon oil and compared their subjects' serum and fat pollutant levels to a non-fish eating control group.

The results were unambiguous: The consumption of farmed fish did not affect the steady-state of organic pollutants in either the blood or fat tissue of the subjects.

High levels of persistent organic pollutant (POPs) - a problem? The ever-increasing amount of POPs in our diet and other consumer goods (deodorants, perfumes and cosmetics are another source of POP) is a problem and a potential threat to our health, but farmed fish is not the item on your plate or cupboard that will tip the scale.

Due to the ever-increasing pollution of the oceans, rivers and lakes, POPs and other pollutants are no "farmed fish" phenomenon, anyway. If you look at the results of a recent study from the Hong Kong Baptist University, for example, you will have to concede that "eating wild caught only" is not going to protect you from being exposed to chemicals like BPA (Wei. 2011).

Figure 3: Polycyclic aromatic hydrocarbon (PAH) content of farmed and wild-caught salmon samples (Easton. 2002).

Moreover, the amount of organic pollutants in farmed fish could be easily reduced if the producers were willing to invest more money into quality fish food. The results of a 2002 study by Easton et al. clearly indicate for example that the increased polycyclic aromatic hydrocarbon (PAH) content of farmed vs. wild caught salmon could be easily reduced if these organic pollutants were not already present in hilariously high quantities in the feed the fish are fed. Buying uncontaminated fish food would thus give the farmers a degree of control fishers whose wild caught chinook salmon can contain up to 4.8x  more PAH than farmed salmon (see Figure 3) will never have.

Fish oil can be POP free, but not everything that glitters is gold

Fish oil is a highly processed substance. If the processing is done right, it is possible to remove large parts of the previously discussed POPs, as well as inorganic pollutants like mercury from the fishy sludge. The fact that it can be pollutant-free, however, does not necessarily mean that your fish oil caps will actually be free of any harmful substances.


The fact that fish oil producers may not do their job properly is yet not the only reason I am a strong proponent of consuming whole vs. "capped fish" and a whole foods vs. processed "supplement diet.  Why? Well, fish is by far not the only so-called "superfoods" for which we have seen time and again that the isolation of certain ingredients, of which we think that they are what makes these foods so "super", is not going to yield the results we are looking for.

In fact, recent studies which highlight the benefits of fish proteins for man and women who strive to build and maintain a muscular physique (learn more in a previous SuppVersity article) clearly suggest that the often-cited high selenium content of fish is not the only "good thing" you'd miss if you ditch your salmon, tuna and other fatty fish for cheap and convenient fish oil caps.

Warning! "Whole fish" does not include fried fish as you will find it on a "fish mac" or fish & chips and/or fish sandwiches. An increased consumption of these "fish" meals has been shown not to influence the cardiovascular mortality risk of 3910 adults aged 65+ years in a 2003 study by Mozaffarian et al. Moreover, the previously discussed amount of environmental pollutants in the fish is another determinant of its beneficial health effects.

In an editorial comment in the Journal of Internal Medicine Jacobs, Ruzzin & Lee highlight that "[t]he evidence that environmental pollutants can affect the health benefits of fish is supported by previous experimental studies" (Jacobs. 2014). In rodent studies, only decontaminated farmed salmon oil ameliorated the negative effects of high fat feeding. A POP-laden salmon oil from Atlantic salmon, on the other hand, accelerated the development of insulin resistance-related disorders in the lab animals (Ibrahim. 2011). The question, whether we should eat fish and take fish oil supplements is thus intricately related to the question whether we can obtain POP-free fish and fish oil products.

Table 1: The amount of organochlorides in various types of fish oil supplements bought on the Canadian market can be significant - similar results have been found on other markets | ^aΣ of 1,2,3,4 tetrachlorobenzene, 1,2,3,5 tetrachlorobenzene, and pentachlorobenzene; ^bΣ of α-HCH, β-HCH, and γ-HCH; ^cΣ of oxychlordane, trans-chlordane, trans-nonachlor, and cis-nonachlor; ^dΣ of p,p′-DDT and p,p′-DDE.(Rawn. 2009).

And even if you're not interested in being muscular, a recent study by Brazionis et al. clearly suggests that getting your 1g of long-chain omega-3 fatty acids from fish vs. fish oil supplements "may have additional cardiovascular benefits beyond the omega-3 effect". Effects which lead to a significant reduction in blood pressure the scientists observed only in those subjects who consumed fresh salmon (two 150 g servings per week of John West fresh Atlantic salmon), but not in their peers in the fish oil arm of the study (Brazionis. 2012).

Is fish oil the safer alternative? If you buy your fish oil from a manufacturer who can prove that each and every batch is tested for its POP and heavy metal content, it may be safer, but in view of the synergistic effects of protein, fat, certain peptides and a plethora of micronutrients you will be missing if you scrap your two weekly servings of fatty fish and turn to fish oil caps instead, this does not mean that it will be healthier.

When we are talking about toxic substances in fish and fish oils, we obviously cannot dismiss the heavily debated issue of heavy metal contaminations.

Heavy metals are clearly no farmed-fish exclusive!

While the heavy metal issue is still a matter of open scientific debate, the epidemiological evidence in favor of the profound health effects of regular fish consumption appears to suggest that it is less of an issue for the general population than the hysteric news on the Internet may make you believe.

Figure 4: Mean (bottom axis) and max (top axis!) mercury content (mg/kg) in fish (FDA Monitoring Program. 1990-2010 from a 2012)

For fitness junkies and bodybuilders who are trying to satisfy their alleged protein "requirements" of 3-4g of protein per kg body weight by shoveling down one can of tuna after the other, however, the heavy metal content of the cheap fish cans may become a problem.

Or maybe I should say: I personally would not use canned tuna as my primary protein source, when aiming for a protein intake of 3-4g per kg of body weight.

And this goes regardless of the fact that I believe that the risks associated with consuming tuna containing 0.10-0.75ppm methyl mercury (Yess. 1993) may be overblown in some of the sensationalist articles on the Internet and other mainstream media.

Similarly, I am reluctant to rely on the purported protective effect of the high amounts of cysteine and selenium in seafood. A protection, by the way, of which scientists have recently shown that is cannot mitigate the loss of cardioprotective effects of high omega-3 intakes in individuals with high hair mercury levels (Virtanen. 2009 | learn more).

So mercury is less on an issue than people claim? Probably yes. I would subscribe to the FDA recommendation to limit your fish intake to 2-3x fish meals a week. More specifically, you should forget about the idea of tuna as a "healthy snack" you can eat as often as you want to and stay away from more than one fish meal if you are pregnant or trying to become pregnant. In this case buying either mercury controlled fish or fish oils may in fact be the better choice  – I mean: "Better save than sorry", right?

Speaking of fish oil, there is an increasing trend towards krill oil as the "hype" omega-3 supplement. A trend of which you, as SuppVersity readers know that it appears to be unwarranted, although krill oil has the advantage of providing a large amount of the omega-3 fatty acids in their phospholipid-bound form (learn more in a previous SuppVersity article).

Figure 5: Plasma, liver and white adipose tissue (WAT) levels of triglyceride (TL) and phospholipid varieties of DHA+EPA after 9 weeks on HFD diet with (w3TL or w3PL) or  w/out 30mg/kg chow DHA + EPA (Rossmeisl. 2012)

Compared to triglycerides, the phospholipid-bound version is easier to assimilate. Accordingly, it is not very surprising that Rossmeisl. et al. (2012) were able to show that phospholipid-bound long-chain omega-3 fatty acids increase the plasma and liver omega-3 content to a significantly greater degree than the same amount of triglyceride-bound omega-3 fatty acids. An effect that was – at least in rodent studies – associated with a significantly more pronounced reduction in fat cell size and insulin sensitivity (Rossmeisl. 2012).
A more recent study by Tillander et al. (2014) adds to the evidence that krill oil may have an edge over fish oil, as an anti-NAFLD agent, because it will epigenetically reduce the fatty acid synthesis in the liver (read more).
 
The very ability to reduce the synthesis of fatty acids in the liver makes krill oil particularly interesting for overweight and obese people.

The increased fatty acid oxidation in response to the ingestion of fish oil (vs. krill oil) the researchers observed in the same study, on the other hand, may be something that could be of interest for lean individuals who are trying to lose weight (learn more in previous SuppVersity article).

Fish or krill? It depends... The previously presented evidence does thus make one thing very clear: It is more than likely that it will depend on your goals and current health status which of these omega-3 sources you should prefer. Overall, there is yet still a paucity of independent research, which is why I would not be surprised if the previously made conclusions were refuted by future studies.

If not weight loss, but muscle gains and fat loss are your goal, though, neither fish nor krill oil will do - at least not in the absence of one of the previously mentioned synergists: Fish protein!

Fish protein, an overlooked anabolic?

What wanna-be bobybuilders need is protein. Fish protein, to be precise. In 2009, for example, Ramel et al. were among the first to observe that using fish, or more specifically cod protein as the major protein source in the diet of their overweight subjects would yield improved outcomes in terms of fat loss and lean mass retention (Ramel. 2009; see Figure 6).

Figure 6: Decreases in anthropometric measurements after the 8-week intervention with isocaloric energy reduced diets having in obese subjects consuming no, three or five servings of lean fish per week (Ramel. 2009).

It is thus quite obvious that there must be something special to fish proteins more common dietary protein sources do not provide.

This hypothesis is also supported by previous evidence from rodent studies. One of these studies that was conducted by Frédéric Tremblay et al. (2003) at the Laval University Hospital Research Center suggests that the benefits may be related to the potent anti-inflammatory effects of fish proteins, which will thus increase the muscular insulin sensitivity and favor fat over muscle loss and muscle over fat gain.

A more recent study by Vikøren et al. (2013) seems to confirm this hypothesis.

The overweight adults who participated in the corresponding experiment experienced significant improvements in glucose metabolism, increases in lean and decreases in fat mass, when the scientists added 3 g of fish protein per day to their diets for the first 4 weeks and 6 g/d for the last 4 weeks of the 8 week intervention.

Figure 7: Macronutrient composition of the diets at baseline, after 4 weeks and 8 weeks and changes in body composition compared to baseline (Vikøren. 2013 - learn more in a previous SuppVersity article)

What is particularly noteworthy about this study is the fact that these effects occurred in spite of the fact that "[p]hysical activity and energy and macronutrients intake did not change during the course of the study" (Vikøren. 2013).

More recent evidence from a rodent study by Kawabata et al. (2014) strengthens the "anti-inflammatory" hypothesis. In their experiments, the researchers compared the effects of casein and fish protein in a tightly controlled dietary intervention and found similar increases in muscle mass and improvements in glucose metabolism in their hairy subjects as Vikøren et al. did one year before in overweight adults (learn more in a recent SuppVersity article).

Why don't we use our consumer money to force producers to make a change? I hope my previous elaborations have made it clear that living off fish as your only protein and fat source in the diet is probably not the best idea. On the other hand, similar issues with antibiotics (ab)use, persistent organic pollutants (POP) and even mercury exist for other foods, as well – with the exception of antibiotics which are only used to produce animal products all these pollutants can also be found in veggies and fruits (so no "vegan advantage").

We would thus be good advised to use our most powerful weapon, i.e. consumer money, to steer the food industry away from doing everything to cut the production costs and buy fish from those farms that don't use cheap poultry instead of fish oils, intoxicate the water with antibiotics and buy the cheapest, yet POP-laden food from questionable sources in China to feed their fish.

Time to draw some conclusions: Based on the existing evidence there is no reason to shy away from either fish consumption, in general, or the consumption of farmed fish, in particular. The overwhelming majority of epidemiological evidence indicates that consuming two servings of fatty fish a week will have nothing but beneficial effects on your overall health and that in spite of the fact that the fish was not controlled for organic or inorganic pollutants in any of these studies.

Whether it makes sense to consume large quantities of fish on a daily basis is yet as questionable as the routine use of fish oil supplements. Most of us will be able to cover our fundamental omega-3 needs with the previously mentioned two servings of fish per week. Consuming more than that in supplemental form is – in my humble opinion – not necessary for healthy individuals, unless they need to balance their exuberant intake of omega-6 fatty acid from large quantities of vegetable oils and processed foods in their diets –both products of which I highly recommend that people limit their intake to a minimum.

Moreover, imbalanced diets that are dominated by a single food source have repeatedly been shown to increase one's risk of running into severe health problems in the long run. So why don't we combine fish with dairy products, grass fed beef, pork and vegetable protein sources to create a varied, tasty, health and physique promoting high protein diet we can follow for the rest of your lives, instead of looking for the one "superfood", of which I would hope that most of the people who read this interview will know by now that it doesn't exist, anyway.

References:

• Brazionis, Laima, et al. "The effects of fish or fish oil on the omega‐3 index." Nutrition & Dietetics 69.1 (2012): 5-12.
• Berntssen, Marc HG, ANNE‐KATRINE LUNDEBYE, and Bente E. Torstensen. "Reducing the levels of dioxins and dioxin‐like PCBs in farmed Atlantic salmon by substitution of fish oil with vegetable oil in the feed." Aquaculture Nutrition 11.3 (2005): 219-231.
• Easton, M. D. L., D. Luszniak, and E. Von der Geest. "Preliminary examination of contaminant loadings in farmed salmon, wild salmon and commercial salmon feed." Chemosphere 46.7 (2002): 1053-1074.
• Hausken, Trygve, et al. "High Consumption of Farmed Salmon Does Not Disrupt the Steady State of Persistent Organic Pollutants (POP) in Human Plasma and Adipose Tissue." Journal of Toxicology and Environmental Health, Part A 77.20 (2014): 1229-1250.
• Ibrahim, Mohammad Madani, et al. "Chronic consumption of farmed salmon containing persistent organic pollutants causes insulin resistance and obesity in mice." PloS one 6.9 (2011): e25170.
• Mervish, Nancy, et al. "Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004–7." Environmental Research 133 (2014): 12-19.
• Mozaffarian, Dariush, et al. "Cardiac benefits of fish consumption may depend on the type of fish meal consumed the cardiovascular health study." Circulation 107.10 (2003): 1372-1377.
• Nichols, Peter D., et al. "Readily available sources of long-chain omega-3 oils: is farmed Australian seafood a better source of the good oil than wild-caught seafood?." Nutrients 6.3 (2014): 1063-1079.
• Rawn, Dorothea FK, et al. "Persistent organic pollutants in fish oil supplements on the Canadian market: polychlorinated biphenyls and organochlorine insecticides." Journal of food science 74.1 (2009): T14-T19.
• Rossmeisl, Martin, et al. "Metabolic effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: possible role of endocannabinoids." PLoS One 7.6 (2012): e38834.
• Tillander, Veronika, et al. "Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice." Gene expression 24 (2014): 28.
• Tremblay, Frédéric, et al. "Dietary cod protein restores insulin-induced activation of phosphatidylinositol 3-kinase/Akt and GLUT4 translocation to the T-tubules in skeletal muscle of high-fat-fed obese rats." Diabetes 52.1 (2003): 29-37.
• Vikøren, Linn A., et al. "A randomised study on the effects of fish protein supplement on glucose tolerance, lipids and body composition in overweight adults." British Journal of Nutrition 109.04 (2013): 648-657.
• Virtanen, Jyrki K., et al. "Serum long-chain n-3 polyunsaturated fatty acids and risk of hospital diagnosis of atrial fibrillation in men." Circulation 120.23 (2009): 2315-2321.
• Wei, Xi, et al. "Assessment of risk to humans of bisphenol A in marine and freshwater fish from Pearl River Delta, China." Chemosphere 85.1 (2011): 122-128.
• Yess, N. J. "US Food and Drug Administration survey of methyl mercury in canned tuna." Journal of AOAC International 76.1 (1993): 36.

Curcumin, Genistein, Pomegrenate & Co. - A Dirty Dozen of Supplements & Foods to Keep Your Prostate Cancer Free

Which of the dirty dozen of supplements and foodstuffs in today's SuppVersity review can really help you to make sure, you're not the one out of those nine men who develops prostate cancer?

Supplements that are supposed to protect you from developing prostate cancer and/or agents that may help patients with existing prostate issues are - obviously - in high demand. And as W. Merkle points out in a recent article in the German science journal Urologe using them - even if they may not be as effective as some patients may believe - makes sense: from a psychological perspective, alone (Merkle. 2014).

Taking a pill with selenium, for example, has been shown to alleviate some of the side effects of chemotherapy. General protective effects against prostate cancer, on the other hand, have not been established. In fact, the most recent studies rather suggest that "supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status" (Kristal. 2014).

Supplements are nice, but without exercise you are missing 50% of the anti-cancer equation!

Tri- or Multi-Set Training for Body Recomp.?

Alternating Squat & Blood Pressure - Productive?

Pre-Exhaustion Exhausts Your Growth Potential

Full ROM ➯ Full Gains - Form Counts!

Battle the Rope to Get Ripped & Strong

Hula Hooping to Spot Reduce in the Midsection

Luckily, there are other supplements with more promising data. Supplements that will actually complement, a healthy diet and active lifestyle, the two pillars of all (not just prostate) cancer protection. Supplements like...

• Curcumin - As a SuppVersity reader you've probably already expected to see the curcumin on the list. Its potent anti-inflammatory effects and more specifically its ability to target multiple inflammatory pathways, which include NF-KappaB, COX2, STAT3 and high levels of CRP, Prostaglandins and TNF-alpha make it a particularly valuable anti-tumor agent of which Guo et al. observed in a recent study that it will induce cell cycle arrest and apoptosis of prostate cancer cells by regulation the expression of IkappaBalpha, c-Jun and androgen receptor (Guo. 2013)
• Genistein - Just like curcumin, genistein acts on NF-KappaB (Adjakly. 2013). In addition it will upregulate a protein called miR-574- 3p that will have cancer cells "kill themselves" (go into apopotosis; Chiyomaru. 2013). In addition scientists have found genistein to support the efficiacy of Cabazitaxel which is used for the treatment of hormone-refractory prostate cancer.
• Pomegranate - Pomegranate extracts or rather its ingredients, i.e. ellagic acid, caffeic acid, luteolin and punicic acic, have been shown to inhibit the proliferation and induce apoptosis in prostate cancer cells (NCI. 2013).

  

  Figure 1: If you look at the actual increase in apoptotic cancer cells in response to the pomegranate treatment, it is obvious that some patients (e.g. #53) benefited more than others (Pantuck et al. 2006)

  A clinical trial by Pantuck et al. (2006) was also able to show that the time it takes for the PSA levels, an albeit debatable marker of prostate cancer risk, to double decreased significantly, when the subjects, men with rising PSA after surgery or radiotherapy, were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Unfortunately, a more recent study by Stenner-Liewen et al. (2013) could not confirm these effects. 
• Brassica vegetables (cruciferous vegetables) - While general vegetable intake is already associated with a -39% reduced risk of developing extraprostatic prostate cancer (cancer, eating tons of cruciferous vegetable, it was the intake of broccoli and cauliflower that made the biggest impact in a 2007 study by Kirsh et al.
  
  

  

  Even if they don't protect you from prostate cancer broccoli & co will inhibit myostatin and could help you to grow more muscle... well, at least theoretically, you know about the difference between the petri dish and the real world, so don't expect monster gains | more.

  As it is usually the case the evidence is yet ambiguous. In a 2002 review of the evidence, Kristal, et al. found that of the six studies they could clearly interpret, only three reported statistically significant reduced risks (P < 0.05), while one reported a borderline significant reduced risk (P = 0.06). Against that background Verhoeven et al. are right, when they say: " Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general" (Verhoeven. 1996).
  
  More recently, Joseph et al. found that the existing differences in the epidemiological data may be due to genetic polymorphisms due to which only men with a certain genetic polymorphisms in glutathione S-transferases M1 and T1 will benefit from eating tons of cruciferous veggies (Joseph. 2004).
• Green tea - Green tea is good for everything, right? Well unless it's not loaded with toxic molecules (see previous SuppVersity article) this may in fact be right. Convincing evidence from human trials is albeit scarce. What we do have are rodent studies like the ones that were conducted with TRAMP mice, which model closely mirrors the pathogenesis of human prostate cancer.
  
  In these mice EGCG, one of the main catechins in green tea, decreased the proliferation of prostate cancer cells and reduced the PSA levels. Scientists believe that these effects are mainly mediated by the effects EGCG has on the growth promoting proteins ERK1/2. Unfortunately, the same rodent studies also suggest that it is probably too late for many of you to start drinking green tea, now, because said beneficial effects are only observed in young, not in old TRAMP mice (Donald. 2012).

• 

  Coffee is for the ladies, too! Studies show significantly reduced risks of breast cancer with 5+ cups of coffee. Tee and cacao help, as well | more

  Coffee - Obviously I am biased, when it comes to coffee. I still hope you believe me when I say that drinking 5+ cups of coffee per day has been associated with significantly reduced risk of prostate cancer in what is probably the most large-scale meta-analysis of the topic today.
  
  In their meta-analsis of 12 peer-reviewed case-control studies, Lu et al. calculated a 4% risk reduction for Europeans who consumed five or more cups of coffee and Americans who consumed 4 or more regular cups of coffee (equ. to approximately 400-500mg of caffeine). Moreover, the scientist found "a significant inverse association in all categories of prostate cancer except Gleason <7 grade" in both the "fixed-effects model" and the "random-effects model" (Lu. 2014).
  
  Wilson et al. also report an inverse association between coffee consumption and the incidence of highly malignant prostate cancer (Wilson. 2013). This means that drinking coffee is not only going to reduce your overall risk of developing prostate and other cancers (Geybels. 2013), it will also increase your chance that in the unfortunate case you still develop cancer, it's going to be a benign and treatable form of prostate cancer.
• Lignans (e.g. from flaxseed) - While many of you will probably know them as "bad anti-androgens", there is little doubt that lignans from flax and other foodstuff inhibit cancer growth. What is particularly interesting about these agents is that they don't work via the "regular" NF-kappaB pathway but inhibit the expression of the vascular endothelial growth favtor (VEGF; cf. Azrad. 2013).
• Lycopene - It's the bright red carotene and carotenoid pigment and phytochemical that gives tomatoes and other red fruits and vegetables, such as red carrots, watermelons, gac, and papayas, although not in strawberries, red bell peppers, or cherries their color.
  
  Based on the currently available evidence it appears to help not just with prostate, but also with pancreatic, intestinal and lung cancer (Giovannucci. 1999). In that, it makes a particularly effective adjunct to classic cancer therapy (Tang. 2011).

  

  Figure 2: Prostate cancer risk w/ high vs. low intakes of the given antioxidants according
  to XRCC1 genotype (Goodman. 2006)

  Unfortunately, the data is ambigious... as usual. Unlike for other agents, it does yet appear as if scientists have already identified a certain gene, i.e. XRCC1, which appears to determine whether you do or do not benefit from the consumption of increased amounts of tomato lycopene (Goodman. 2006).
  
  In view of the fact that certain genotypes actually increase their prostate cancer risk specifically if they are consuming both, a high amount of lycopene and vitamin E (alpha-tocopherol), the latest Cochrane Review on the protective effects of lycopene against prostate cancer considers the evidence for "preliminary" and "insufficient" (Ilic. 2011).
• Fish oil / omega-3 - In spite of the fact that the media jumped at the finding of the SELECT trial (learn more) that claimed that selenium would be bad, while a high fish consumption or rather a high amount of omega-3s in the blood would protect you against prostate cancer, a close re-analysis of the data you can read up on at the website of the Life Extension Foundation indicates that this was all media hype.
  
  With a de facto difference of only 0.18% the difference was... well, you'd say a joke, scientists would say "within the margin of statistical error" and thus by no means significant. If you take an even closer look at the data, it would even seem as if omega-3 fatty acids would increase the risk of prostate cancer.
• Resveratrol - If you look at the existing evidence you will be surprised to find studies that indicate that resveratrol increases (Klink. 2013) and studies that show that it inhibits prostate cancer growth (Iguchi. 2012; Kai. 2011).
  
  Again, it took a closer look at the data and another experiment to find out what really was going on: a dose-dependent effect with increased risk with low and decreased risk with high doses of resveratrol (Benitez. 2007). Bad news: With the current low biovailable oral resveratrol preparations you're likely to end up in the "increased risk" resveratrol exposure zone.
• Selenium - While I have mentioned it in the introduction already, it's certainly worth taking a closer look at what selenium is actually supposed to do.
  
  In their 2011 review of the literature, Rizky Abdulah et al. didn't just highlight the many different molecular pathways, by which selenium could protect you from developing cancer, they also point out that the type of selenium supplement used could be of critical importance with respect to the success of your efforts to avoid the development of cancer. In that,...

  

  In rodents selenium acts as corrosion inhibitor in the brain | learn more

  "[...] methylselenol is believed to be the critical metabolite in selenium chemoprevention. Since methylselenol is highly reactive, methylselenol precursors such as Semet and Se-mSC are important both in in vitro and in vivo experiments. Semet and Se-mSC conversion to methylselenol, however, requires enzymatic conversion by the enzyme β-lyase, which is 800 times less prevalent in human tissues than in mouse tissues.

  This may explain why the results of Semet and Se-mSC anticancer studies in humans were not as impressive as in vivo experiments. Although researchers have now turned to other Se compounds such as mSeA, which do not need enzymatic conversion to methylselenol, or selenite, which does not need to be converted to methylselenol for its anticancer properties, more substantial research on selenium compound metabolism in human tissues is necessary." (Abdulah. 2011)

  In other words, as of now, we don't know which form of selenium we actually have to use in human trials to generate similar impressive results as they have been observed in rodents.
  
  And as if that wasn't already "bad" enough, a meta-analysis of intervention studies by Hurst et al. (2012) indicates that there is a very narrow "band" of serum concentrations, where selenium is actually good for you! When your selenium level passes 170 ng/ml the tumor-protective effect disappears and - worst case scenario - your risk increases. So remember: More does certainly not help more!
• Silibin (from milk thistle) - You probably think of milk thistle as a "liver supplement". In fact, its main active constituent will yet also reduce the efficacy of osteoclast cytokines and reduce the concentration of RANKL-ligands. Thus it will regulate the NF-κB und AP1 levels in cells and inhibit the proliferation, invasion and migration of metastatic prostate cancer (Ting. 2011; Chen. 2012) 
• Vitamin D - Believe it or not: There are things vitamin D3 cannot do! One of this things is to protect you prostate cancer. That's the prerogative of active vitamin D aka calciferol. In rodent studies and studies on human cell lines calciferol and multiple analogs of active vitamin D have shown to be promising drugs for prostate cancer protection, though (Tokar. 2005).
  
  

  

  Underestimated Vitamin D Sources: Eggs, Chicken, Pork, Fish & Dairy Contain Ready-Made 25OHD | more

  Since simply popping tons of vitamin D3 is (luckily) without effect on the levels of calciferol (otherwise you would run the risk of being calcified from the currently prevalent abuse of vitamin D3 supplements), using vitamin D3 is less effective, but not useless.
  
  In 2010, for example, Woo et al. observed that the time it took for the PSA levels of prostate cancer patients to double was significantly reduced, when the subjects received 2,000 IU of vitamin D3 per day (Woo. 2005) - an effect of which previous in vitro studies suggest that it could be due to the local conversion of D3 to active vitamin D in prostate cancer cells (Tokar. 2005).
• Vitamin E - Needless to say that vitamin E has gotten a bad rep ever since scientists observed an increased risk when they gave the subjects of the SELECT trial vitamin E (learn more). Still, as long as you stay away from "classic" vitamin E and buy one of the still expensive tocotrienol supplements (or eat red palm oil), you can expect an anti-proliferative effect of the vitamins E (Conte. 2004; Srivastava. 2006)

It's never too late to make a change! In September 2005, researchers from the University of California-San Francisco pub- lished a study that shows that intensive lifestyle changes (i.e. changin the way you eat, the amount of exercise you get, etc.) may affect the progression of prostate cancer in a highly beneficial way (Ornish. 2005) - with PSA reductions of -4%, reduced glucose levels (-70%!) improved blood lipids and higher, not lower testosterone levels.

Bottom line: While all of the above supplements and food constituents will help, nothing beats a healthy lifestyle with a balanced whole foods diet, stress control and regular exercise.

Overweight (+20% risk for BMI >25.38, already), gaining 5-10% weight after your 20s (+30%; Putnam. 2000), being self-employed (+170%) and thus probably stressed, having a family history of prostate cancer (father +140%, brother +420%), being a "former drinker" (beer +20%, wine +20%) or a current liquor drinker (+40%) and consuming more than 96g of alcohol per week (+50%), on the other hand, will - for most of the variables unnecessarily - increase your prostate cancer risk (Andersson. 1996) | Comment on FB!

References:

• Abdulah, Rizky, et al. "Molecular targets of selenium in prostate cancer prevention (Review)." International journal of oncology 39.2 (2011): 301-309. 
• Andersson, Swen-Olof, et al. "Lifestyle factors and prostate cancer risk: a case-control study in Sweden." Cancer Epidemiology Biomarkers & Prevention 5.7 (1996): 509-513.
• Azrad, Maria, et al. "Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer." Journal of medicinal food 16.4 (2013): 357-360.
• Benitez, Dixan A., et al. "Mechanisms Involved in Resveratrol‐Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer—Derived Cell Lines." Journal of andrology 28.2 (2007): 282-293. 
• Chen, Rongxin, et al. "The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection." Annals of surgical oncology 19.3 (2012): 375-384.
• Chiyomaru, Takeshi, et al. "Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer." PloS one 8.3 (2013): e58929. 
• Conte, Carmela, et al. "γ‐Tocotrienol Metabolism and Antiproliferative Effect in Prostate Cancer Cells." Annals of the New York Academy of Sciences 1031.1 (2004): 391-394.
• Donald, J. L. "Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer." Molecular BioSystems 6.10 (2010): 1911-1916.
• Geybels, Milan S., et al. "Coffee and tea consumption in relation to prostate cancer prognosis." Cancer Causes & Control 24.11 (2013): 1947-1954. 
• Giovannucci, Edward. "Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature." Journal of the National Cancer Institute 91.4 (1999): 317-331.
• Guo H, Xu YM, Ye ZQ, Yu JH, Hu XY. "Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor." Pharmazie 68.6 (2013):431-4.
• Hurst, Rachel, et al. "Selenium and prostate cancer: systematic review and meta-analysis." The American journal of clinical nutrition 96.1 (2012): 111-122.
• Iguchi, Kazuhiro, et al. "Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells." Journal of andrology 33.6 (2012): 1208-1215. 
• Joseph, Michael A., et al. "Cruciferous vegetables, genetic polymorphisms in glutathione S-transferases M1 and T1, and prostate cancer risk." Nutrition and cancer 50.2 (2004): 206-213.
• Kai, Li, and Anait S. Levenson. "Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells." Anticancer research 31.10 (2011): 3323-3330.
• Kirsh, Victoria A., et al. "Prospective study of fruit and vegetable intake and risk of prostate cancer." Journal of the National Cancer Institute 99.15 (2007): 1200-1209.
• Klink, Joseph C., et al. "Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell‐line specific manner, through paradoxical effects on oncogenic pathways." The Prostate 73.7 (2013): 754-762.
• Kristal, Alan R., et al. "Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk." Journal of the National Cancer Institute 106.3 (2014): djt456.
• Lu, Yu, et al. "Coffee consumption and prostate cancer risk: an updated meta-analysis." Cancer Causes & Control 25.5 (2014): 591-604. 
• Merkle, W. "Prostatakarzinomprophylaxe durch Nahrungsergänzungsmittel." Der Urologe (2014): 1-7.
• NCI (2013) Pomegranate: prostate cancer, nutrition and dietary supplements (PDQ). NCI, Bethesda. http://www.cancer.gov
• Ornish, Dean, et al. "Intensive lifestyle changes may affect the progression of prostate cancer." The Journal of urology 174.3 (2005): 1065-1070.
• Pantuck, Allan J., et al. "Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer." Clinical Cancer Research 12.13 (2006): 4018-4026.
• Putnam, Shannon D., et al. "Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men." Annals of epidemiology 10.6 (2000): 361-369.
• Stenner-Liewen, Frank, et al. "Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer-Results of a Phase IIb Randomized Controlled Trial." Journal of Cancer 4.7 (2013): 597. 
• Srivastava, Janmejai K., and Sanjay Gupta. "Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells." Biochemical and biophysical research communications 346.2 (2006): 447-453.
• Tang, Yaxiong, et al. "Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels." Neoplasia 13.2 (2011): 108-119. 
• Ting, Harold, Gagan Deep, and Rajesh Agarwal. "Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer." The AAPS journal 15.3 (2013): 707-716. 
• Tokar, Erik J., and Mukta M. Webber. "Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells." Clinical & experimental metastasis 22.3 (2005): 265-273.
• Verhoeven, Dorette T., et al. "Epidemiological studies on brassica vegetables and cancer risk." Cancer Epidemiology Biomarkers & Prevention 5.9 (1996): 733-748.
• Wilson, Kathryn M., et al. "Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study." Cancer Causes & Control 24.8 (2013): 1575-1581.
• Woo, Tony Choon Seng, et al. "Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy." Nutrition and cancer 51.1 (2005): 32-36.