Are Elevated Iron and Uric Acid Levels Too Much of a Price to Pay for a Creatine-Induced 11% Performance Increase?

Video 1 (GSSI): Notre Dame's Michael Floyd goes all out on the Wingate test (click to watch)

I guess you could say that these are the "classic days", here at the SuppVersity, contrary to my previous post on choline, which is - judged by the few people who still use it today, an "old school supplement" (cf. "Choline: Stronger, Faster, Leaner & More Muscular, or Just Another Dumb-and-Barbell Story?") - yesterday's post on caffeine highlighted the efficacy of a potent ergogenic aid and metabolic activator, with the effects of which most of us are so familiar that we are alway tempted to turn to useless crap like raspberry ketones, when what we are already doing is not only tried and proven, but based on respectable scientific data even more effective than the latest "innovation" from the snake oil industry. And let's be honest, haven't we all been tempted by one or another "new creatine", as well?

+11% peak performance in one week, solely from 5x4g of creatine per day!

A a matter of fact, creatine monhydrate does in fact share the same fate of being proven, but "boring" staple supplement and although that alone should be incentive enough to address the unquestionably outstanding +11% in anaerobic peak performance, +5% in continuous anaerobic performance and a +6% increase in total workload in a classic wingate anaerobic performance test speak, Barros et al. observed in a group of trained male subjects in response to a 7-day creatine loading protocol (20g creatine monohydrate, in 5 doses spread across the day, not glucose / sugar added; cf. Barros. 2013) After all, my gut tells me that the contemporary changes in the concentration of iron in the blood of the subjects in the the creatine arm of the study could revoke the mainstream-media fearmongerish hoopla over the purported dangers of the #1 natural ergogenic.

Figure 1: Basal iron, FRAP, malondialdehyde (MDA) and uric acid levels before and after 7-day supplementation with 5x4g of creatine monohydrate per day (based on Barros. 2013)

I mean, there is no debating, the level of iron in the blood of the creatine supplemented undergraduate students (age, 23.1 ± 5.8 years; height, 175.4 ± 2.3 cm; weight, 81.1 ± 9.3 kg) all of whom had been avid trainees for at least 6 months did increase by no less than 94.3%, while the subjects in the placebo group experienced a -21% reduction of these highly reactive molecules (Just as an aside, the decline in serum iron in the placebo group and the significant difference in baseline levels between the random groups, alone, render any implications at least questionable; I mean, wouldn't you expect the serum parameters to stay the same, when you do nothing extraordinary, aside from popping some sugar pills?).

Figure 2: Changes in wingate anaerobic performance (left) and exercise induced changes iron, FRAP, malondialdehyde (MDA) levels during the wingate test at the end of the supplementation period (based on Barros. 2013)

In conjunction with the likewise highly significant increase in uric acid levels, conventional (blogosphere-)wisdom, which constantly ignores the antioxidative nature of uric acid, which acts as efficient antioxidant and chelating agent for iron ions (Karlsson. 1997), limits the oxidation of polyunsaturated fatty acid in the erythrocyte membrane and prevents hemolysis (= the rupture of red blood cells) in vitro (Einsele. 1987), would suggest that taking creatine takes a close second to fructose on the list of the villains of the bad, bad "neolithic" century.

How dangerous is the creatine induced increase in iron?

Image 1 (Paramount Pictures): I guess, it must have been creatine monohydrate, then, that turned Robert Downey Jr. into Ironman ;-)

Now, despite the as of late publicly propagated concerns about increased iron levels and their potential causative role in the etiology of insulin resistance and diabesity (obesity + diabetes), recent scientific evidence suggests that "high iron", such as all previous scapegoats people like to hold liable, just to make sure not to admit that it is the sickening combination of laziness, convenience and unsound dietary advice that is at the heart of the current obesity epidemic.

Huang et al., for example, did observe a direct effect of iron overload on diabetes risk - the latter was however a result of hereditary hemochromatosis (a genetic defect in iron metabolism) in their 2011 rodent trial (Huang. 2011). Results from two more recent studies by Silva et al. also indicate that the metabolic disturbances lead to differential expressions of the proteins involved in the metabolism of iron and thus substantiate the associative (and not causative) nature of the relation between high iron / ferritin and the metabolic syndrome (Silva. 2011; Silva. 2013).

Iron not causative? So why does phlebotomy help, then? If you read my post on the recently published data from the first controlled human trial that investigated the effects of phlebotomy on markers of blood glucose management, you will be aware that the measures they took, e.g. the HOMA-IR, are not really appropriate to assess the effects of this particular treatment (cf. "Phlebotomy: Can You Bleed Yourself Healthy and Lean?"). Furthermore, it is only logical that the removal of some of this "highly inflammable stuff" from an inflamed body will provide health benefits, even if the latter was totally benign for someone who has a lot less inflammation going on.

What is even more important, though, is that the difference between exercise-induced increases in serum iron and diet and diabesity-related increases in the storage form of iron, ferritin, in the liver. This is particularly true in view of the fact that our understanding of the former, i.e. the exercise induced release of iron into the blood stream is more than limited (Roberts. 1989; Smith. 1994). What we do see in the Barros study, however, is that the overall effect of creatine is rather anti- than pro-oxidative, since the increase in overall antioxidative capacity (as indicated by the changes in the iron-specific FRAP essay; cf. figure 1) did not just...

• negate the potential negative effects of increased basal iron levels (see lowered baseline MDA levels post supplementation in figure 1), it also 
• countered the exercise-induced lipid oxidation during the 2nd wingate test (as indicated by lower MDA levels; cf. figure 2). 

Eventually, the scientists say, the increase in antioxidant activity that is brought about by the ingestion of 20g/day creatine irrespective of whether you exercise or not could actually yield "general health benefits" (Barrios. 2013); and I would like to add that evidence for Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, recovery from ischemia and, guess what, diabetes already exists (Tarnopolsky. 2000;"Creatine Ameliorates Type II Diabetes")! Certainly not bad for one of those bodybuilding supplements, "anabolics" or "gateway drugs", as creatine is often mislabeled , when a 100% clueless "journalist" tries to get the attention of his editor-in-chief, wouldn't you agree?

Suggested readings (some also mentioned in the text):

• The Pharmacology of Creatine (Part 1 and Part 2) 
• Supercharging Creatine With Baking Soda (click here to read)
• 5g/day Creatine for Type II Diabetics? (click here to read)
• All posts tagged with "creatine" (click here to read)
• Phlebotomy: Can You Bleed Yourself Healthy and Lean? (click here to read)

References:

1. Barros MP, Ganini D, Lorenço-Lima L, Soares CO, Pereira B, Bechara EJ, Silveira LR, Curi R, Souza-Junior TP. Effects of acute creatine supplementation on iron homeostasis and uric acid-based antioxidant capacity of plasma after wingate test. J Int Soc Sports Nutr. 2013 Jun 12;9(1):25. 
2. Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED, Cooksey RC, McClain DA. Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes. 2011 Jan;60(1):80-7.
3. Orozco MN, Solomons NW, Schümann K, Friel JK. Response of urinary biomarkers of systemic oxidation to oral iron supplementation in healthy men. Food Nutr Bull. 2013 Mar;33(1):53-62. 
4. Roberts D, Smith DJ. Effects of high-intensity exercise on serum iron and α1-antitrypsin in trained and untrained men. Clin Sports Med 1989, 1:63–71.
5. Silva M, Bonomo Lde F, Oliveira Rde P, Geraldo de Lima W, Silva ME, Pedrosa ML. Effects of the interaction of diabetes and iron supplementation on hepatic and pancreatic tissues, oxidative stress markers, and liver peroxisome proliferator-activated receptor-α expression. J Clin Biochem Nutr. 2011 Sep;49(2):102-8.
6. Silva M, de Brito Magalhães CL, de Paula Oliveira R, Silva ME, Pedrosa ML. Differential expression of iron metabolism proteins in diabetic and diabetic iron-supplemented rat liver. J Biochem Mol Toxicol. 2013 Mar;26(3):123-9. 
7. Smith DJ, Roberts D. Effects of high volume and/or intense exercise on selected blood chemistry parameters. Clin Biochem 1994, 27:435–440.
8. Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):497-502.

Red Meat and Cancer? Not if You Protect Yourself With Coffee. A Cup of Coffee With / After Meals Will Do the Trick

Coffee-Chile-Cocoa Rubbed Sirloin, Creamed Kale (recipe) - The perfect way to eat your red meats?

I just realized that the last SuppvVersity article on coffee is about three months old. In view of the myriad of health benefits that have and (I guarantee) will still be associated with habitual coffee consumption (examples: heart disease - Lopez-Garcia. 2006; diabetes - van Dam. 2005; cancer - Wilson. 2011). This is obviously something that has to be changed. Luckily, there are scientists like Roman Sirota and his colleagues from the Hebrew University of Jerusalem who keep the interesting papers coming. For the Israeli scientists, the beneficial effects the consumption of coffee - roasted-ground coffee, to be precise - appears to have on the influx of maldonialdehyde (MDA) from the gut was at the center of their latest experiments.

Real coffee, real benefits - Filter coffee, but not instant will do the trick

While this is not directly related to the MDA issue, it is still intriguing that past studies on the role of coffee consumption in the etiology of gastric cancer are highly inconclusive. While studies conducted in the US and Europe have shown hardly relevant increases (US) and decreases (EU) in gastric cancer risk with high vs. low coffee intake, data from South America suggests that coffee consumption reduces the incidence of gastric cancer by 46% (Botelho. 2006). Without understanding the underlying effects the consumption of coffee has on both, the gastrointestinal tract and the stuff that comes into our system via that route, it is however difficult to come up with potential explanations for this discrepancy; and this is where the observations Sirota et al. made could actually come handy.

Figure 1: A coffee made from ground Turkish coffee or green coffee bean powder enriched (2%) ground coffee with (and most likely also after) a red meat meal reduces the AUC of the serum MDA levels (nmol/L*min) in the postprandial phase by ~30% (* indicates p < 0.05; data based on Sirota. 2013)

As you can see in figure 1, the co-ingestion of coffee with a standardized  red-meat cutlet meal significantly the absorption of MDA and subsequent changes in plasma MDA concentration in the ten volunteers who participated in this randomized cross-over trial (all volunteers participated in all conditions).

While green bean enriched coffee is slightly more potent, regular ground coffee does suffice

Green coffee beans suppements which contain up to 80% polyphenols of which∼50% are CGAs can be used as an alternative to coffee from ground roasted bean and may also help you burn body fat (read more)

With MDA being the most abundant active carbonyl generated in foods from lipid peroxidation in vitro, and a concentration of up to 300 mol/kg in red meat, food borne malondialdehyde appears to pla an important role not only locally, but also systemically. And this can have far reaching health effects, since the surge of plasma MDA levels following a red-meat meal has the potential to oxidize the low density lipoproteins (LDL; Kanner. 2013). With oxidize LD being one of the main initiators of atherogenesis and in view of the fact that the removal of circulating modified-LDL (=oxidized LDL) particles from the blood  has been shown to prevent the development of atherosclerosis without having to resort to statin therapy and irrespective of the total amount of LDL (Ishigaki. 2008), the importance Sirota et al.'s results can hardly be overestimated.

And while it is important to note that green coffee bean powders and extracts could be an alternative (see image on the right) for all of you who are not into drinking coffee, the instant and most probably even the standard "pad coffees" are no suitable alternative to the ground coffee beans used in this study, because their MDA inhibitory effect on muscle food lipid peroxidation is 2-5x lower than that of a cup of coffee from ground roasted beans.

Did you know that Coffee is also a testosterone booster? In this case it does yet appear as if the major player is caffeine, which probably does not play a role as far as the anti-MDA effects in the study at hand are concerned (learn more).

How does the protective effect work and is it red meat specific? The anti-oxidants blunt the pro-oxidative iron-redox cycle catalysis. Obviously this does happen in the gut first, but the beneficial effects don't stop at the wall of your intestines. The combination of lower MDA influx and increased circulating antioxidants will have systemic effects and could also help blunt the exercise induced increases in malondialdehyde (specifically in the presence of high amounts of highly oxidizable omega-3s, cf. "Increased Lipid Oxidation in Athletes With Omega-3 PUFAs"). What's more, the beneficial effects on lipid peroxidation appear for once to be independent of the caffeine content of coffee... the word "appear" does yet indicate that this hypothesis of mine and the efficacy of decaf. would still have to be experimental verified.

As Sirota et al. hypothesize, this is probably due to the extraction process that's used to produce instant, coffee. The latter extracts "only the hydrophilic, more soluble, and small polyphenols molecules" and leaves the more efficient hydrophobic polyphenols in the "waste" that's generated during this process. Similar but less pronounced differences will obviously be observed when you compare different brands of  roasted coffee or - as the producer of the enriched coffee brand used in the study did it - simply add a couple of mg of coffee bean extract.

So thumbs up for the post-meat-meal-coffee, right?

Table 1: Coffee doesn't only have the highest polyphenol content on a per serving base (compared to other "high potentials" as black tea, green tea, cacao and even berries and cherries), the polyphenols also make it into the lumen, where they work (among other things) their anti-MDA effects (Williamson. 2013).

As the researchers, whose study was supported by a grand from the Israeli National Science Foundation and who declare no conflict of interest point out, their

"[...] results seem to be of great importance for further investigations on the involvement of dietary polyphenols and other antioxidants in human health." (Sirota. 2013)

Moreover, their study appears to support their hypothesis that "coffee, the most popular beverage in the world, supplies the most significant portion of daily in-take of dietary antioxidants" (Sirota. 2013) - a contribution that's significant enough to "effectively control lipid peroxidation in the stomach medium and thus prevent post-prandial absorption and plasma MDA modification" (Sirota. 2013).

And the researchers even have a very concrete advice for you: Time your coffee intake so that you get it either the Italian way, right after, or as in their study right with a potential high MDA meal. Ok, I got to admit this is no exact quotation any longer, but basically it is what they wrote. Plus, this way it spares me to write an extra "bottom line" to which I just have to add that taking up drinking coffee (or tea) if you don't like it is not mandatory to survive meat consumption and that people who suffer from low iron levels should keep in mind that the coffee and tea (and other) phenols will inhibit the absorption of heme- and even more non-heme iron. 

References:

• Botelho F, Lunet N, Barros H. Coffee and gastric cancer: systematic review and meta-analysis. Cad Saude Publica. 2006 May;22(5):889-900. Epub 2006 Apr 28. Review. 
• Ishigaki Y, Katagiri H, Gao J, Yamada T, Imai J, Uno K, Hasegawa Y, Kaneko K, Ogihara T, Ishihara H, Sato Y, Takikawa K, Nishimichi N, Matsuda H, Sawamura T, Oka Y. Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation. 2008 Jul 1;118(1):75-83.
• Kanner J, Gorelik S, Roman S, Kohen R. Protection by polyphenols of postprandial human plasma and low-density lipoprotein modification: the stomach as a bioreactor. J Agric Food Chem. 2013 Sep 12;60(36):8790-6.
• Lopez-Garcia E, van Dam RM, Willett WC, Rimm EB, Manson JE, Stampfer MJ, Rexrode KM, Hu FB. Coffee consumption and coronary heart disease in men and women: a prospective cohort study. Circulation. 2006 May 2;113(17):2045-53. 
• Sirota R, Gorelik S, Harris R, Kohen R, Kanner J. Coffee polyphenols protect human plasma from postprandial carbonyl modifications.Mol. Nutr. Food Res. 2013; 00: 1–4.
• van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA. 2005 Jul 6;294(1):97-104. Review.
• Williamson G. Possible effects of dietary polyphenols on sugar absorption and digestion. Mol Nutr Food Res. 2013 Jan;57(1):48-57. doi: 10.1002/mnfr.201300511. Epub 2013 Nov 26.
• Wilson KM, Kasperzyk JL, Rider JR, Kenfield S, van Dam RM, Stampfer MJ, Giovannucci E, Mucci LA. Coffee consumption and prostate cancer risk and progression in the Health Professionals Follow-up Study. J Natl Cancer Inst. 2011 Jun 8;103(11):876-84.