Guanidinoacetic Acid (GAA) 'Superior' to Creatine in Terms of Bioenergetic & Health Effects on Brain, Muscle & More?

Not so fast! Just because it may have shuttled more creatine into the muscle GAA does not have to be able to build more strength or size.

It has been a while since the last creatine article was published. Luckily, the publication of the latest paper from Sergej M. Ostojic lab at the University of Novi Sad (Ostojic. 2016b) will change that... as soon as I've analyzed the study and written about it below that is ;-)

First things first, we are dealing with a randomized, double-blind, cross-over trial that was financed by a government grant - not non-existing (as of now) supplement companies who are pimping guanidinoacetic acid (GAA) as a "superior new form of creatine".

You can learn more about creatine at the SuppVersity

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Now, technically speaking, this claim would be bogus, anyways, GAA is, after all, an intermediate product formed enzymatically in the liver, pancreas, and kidney in the synthesis of creatine and not "a creatine" - "superior", or not.

The formation of increasing amounts of S-adenosylhomocysteine (SAH) ad subsequently homocysteine (HCY, not shown in the figure, which focuses on the synthesis of creatine) which is potentially bad for your heart- and brain will have to be controlled and means to blunt it will have to be found in future studies (da Silva. 2009).

In the study, of which I want to highlight that the number of subjects limits the significance of its results significantly (consider everything as preliminary evidence), five healthy young men (age 24.3 ± 3.1 years; body mass index 24.9 ± 1.9 kg/m²) volunteered to help the scientists find out, whether 4-week supplementation with 3g / day guanidinoacetic acid (GAA) would be superior to 3.4 g of creatine in facilitating creatine levels and thus have potential performance and health enhancing effects that go beyond those of the 'real thing' (creatine).

Figure 2: Percentage change of tissue creatine levels 0 vs. 4 weeks. GAA denotes guanidinoacetic acid. Values are presented as means, with error bars represent the standard error of the means (SEM). P between trials (Ostojic. 2016b).

As you can see in Figure 2, "GAA (3.0 g/day) resulted in the more powerful rise (up to 16.2%) in tissue creatine levels in vastus medialis muscle, middle cerebellar peduncle, and paracentral gray matter, as compared to creatine" (P < 0.05 | Ostojic 2016).

Another (add. cf. Fig 1) explanation for GAA's ill effect on homocysteine is that its conversion to creatine requires methyl donors that can then no longer be used to "recycle" cysteine. We'll have to see if supplementing met-don alone will solve the problem, though.

How does GAA work? GAA yields creatine mainly in the liver (also pancreas and kidney), w/ prev. studies (by the same group) confirming the creatine-boosting potential of dietary GAA in serum and skeletal muscle of healthy men and women (Ostojic et al. 2014; Ostojic et al. 2016a). As Ostojic et al. explain, "GAA is absorbed from the intestinal tract, enters the circulation and is methylated to creatine by guanidinoacetate N-methyltransferase (GAMT); substrates of this enzyme are GAA and S-adenosyl methionine, whereas its two products are creatine and S-adenosyl homocysteine. Usually considered as a less adequate source of cellular energy" (Ostojic. 2016b).

Next to the formation of homocysteine during the conversion process of GAA to creatine, the fact that this process requires additional methyl donors could be another reason why Ostojic et al. (2014) found that Hcy started to pile up in the blood of their GAA study (see Figure 3). Similar neg. effects on Hcy have been reported before; among others by Stead, et al.  (2001). And it seems only logical: If the methyl-donors are used for the GAA - creatine conversion they are no longer available to recycle homocysteine so that the latter is increasing progressively. This is bad news, since a high serum HCy concentration is an independent risk for cardiovascular disease and Alzheimer’s disease, dementia and cognitive impairment (Morris. 2003; Ganguly. 2015) - the causal nature of the epidemiologically observed link has yet been put into question, repeatedly, but until GAA receives the label "clinically proven safety" I cannot recommend using it as a replacement for creatine.

Ostojic et al. interpret (they didn't test and thus prove that their albeit logical interpretation is adequate) that these results signify that GAA would be "a preferred alternative to creatine for improved bioenergetics in energy-demanding tissue" (my emphasis in Ostojic. 2016). Needless to say that this will require

• 

  Figure 2: Fasting total plasma homocysteine concentration at baseline and at 1, 2, 4, and 6 weeks of supplementation (Week 1, Week 2, Week 4 and Week 6, respectively) in subjects receiving placebo or guanidinoacetic acid (GAA) for 6 weeks at 1.2, 2.4 or 4.8 g/day, respectively (Ostojic. 2014).

  experimental confirmation in studies testing the actual effects on cellular bioenergetics and health effects in energy-demanding tissues such as muscle and brain, 
• further investigations of the potential (health-)relevance of the subsequent increase in methylation reactions that occur during the formation of creatine from GAA in the human body (more specifically, the question "Is the sign. increase in homocysteine levels a health problem for GAA users?" will have to be answered - esp. in the long-term; after all, Ostojic's 2014 study indicated that these start to raise with time / Figure 3), and
• long(er) term studies and studies comparing different dosages of GAA and creatine; after all, the former is supposed to work, because it offers a greater variety of uptake channels - an advantage that may be easy to compensate by (a) administering more creatine (3.4g is not much) and/or for a longer time (4 weeks is short)
• independent confirmation of the experimental results from another lab to exclude a potential bias of the researchers who have been working on the issue for years, now.

Not a single one of these studies has yet been conducted. So that we are left, for the time being, with this short-term study with a very 'limited' (you could also say 'hardly sufficient') number of subjects.

If you haven't read it, yet I suggest you read up on my previous article about a study in Elite Footballers, where high doses of creatine actually resulted in inferior effects on body composition than lower doses. Quite an interesting result in view of the "more helps more"-mentality that's prevalent in the fitness community | Read the SV Classic from October 2015!

Bottom line: Why should GAA even be better than creatine? While Ostojic et al. still have a lot of work to do to actually prove that GAA is (a) safe and (b) "better" than creatine (namely in studies with relevant study outcomes, like performance or lean mass increases, for example) they do already have a hypothesis why it could be:

"This perhaps happens due to preferable uptake of GAA by target tissues via various mechanisms theoretically available for GAA transport, as compared to somewhat limited transport capacity of creatine, and/or complete (or near to complete) tissue methylation of GAA to creatine. While Cr is mainly transported via specific transporter (SLC6A8; also used for GAA transport), dietary GAA could be imported through additional delivery channels (SLC6A6, GAT2, passive diffusion) at least in the brain, and become readily available for tissue methylation to creatine by GAMT" (Ostojiv. 2016b).

In other words: GAA is incorporated into muscle and especially brain by more pathways than creatine and may thus be able to increase the creatine stores in said organs faster and to a greater extent than creatine and that's why it could be the 'better creatine' - one that lacks long-term safety data and convincing evidence that the advantage is practically relevant, though. I guess I don't have to tell you, then, that it is not (yet?) "SuppVersity suggested" | Comment!

References:

• da Silva, Robin P., et al. "Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo." American Journal of Physiology-Endocrinology and Metabolism 296.2 (2009): E256-E261.
• Ganguly, Paul, and Sreyoshi Fatima Alam. "Role of homocysteine in the development of cardiovascular disease." Nutrition journal 14.1 (2015): 1.
• Morris, Martha Savaria. "Homocysteine and Alzheimer's disease." The Lancet Neurology 2.7 (2003): 425-428.
• Ostojic, Sergej M., et al. "Dose–response effects of oral guanidinoacetic acid on serum creatine, homocysteine and B vitamins levels." European journal of nutrition 53.8 (2014): 1637-1643.
• Ostojic, Sergej M., Patrik Drid, and Jelena Ostojic. "Guanidinoacetic acid increases skeletal muscle creatine stores in healthy men." Nutrition 32.6 (2016a): 723-724.
• Ostojic, Sergej M., et al. "Guanidinoacetic acid vs. creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men." Applied Physiology, Nutrition, and Metabolism (2016).
• Stead, Lori M., et al. "Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate." American Journal of Physiology-Endocrinology And Metabolism 281.5 (2001): E1095-E1100.

Creatine Uptake, Bioavailability, and Efficacy - We've Gotten it all Wrong and Low Serum Creatine Levels are Better!?

If you put some faith into the marketing campaigns of supp producers, there's a creatine for everyone: one to get lean, one to get strong and one to get big and buffed... bullocks!

It has been a while since I've discussed the bioavailability of different forms of creatine. On various supplement sites, the notion that there was one form of creatine that was significantly more bioavailable and would thus allow you to 'load' muscle phosphocreatine (PCr) faster and more efficiently is obviously still a matter of constant debate... a debate of which the latest study by Ralf Jäger et al. (2016) indicates that it may argue based on a fundamentally flawed premise, i.e. that higher serum levels of creatine after the ingestion of a given product would signify an increased efficacy in terms of performance / strength / size gains.

How come? Well, the previously mentioned, as of yet unpublished data from a study by Ralf Jäger, Martin Purpura, and Roger C Harris did not just confirm the results of previous studies, which indicate that glucose (75g) and alpha lipoic acid (ALA | 200mg) will increase the bioavailability of creatine, i.e. "the proportion of a drug or other substance [in this case creatine] that enters the circulation when introduced into the body" (Merriam-Webster.com), it also indicates that the practically relevant predictor of creatine's efficacy is - assuming equal dosing and complete absorption - not a high, but rather a low level of creatine in the blood.

You can learn more about creatine at the SuppVersity

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What? Let me explain: Initially, it may be worth pointing out that we are talking about a small scale study the results of which have not yet been published in the peer-reviewed journal. In that study, Jäger et al. aimed to compare the effects of ingesting tricreatine citrate (5g, TCrC),

• in combination with 75g of glucose and 200mg of alpha-lipoic acid, or
• without the former bioavailability enhancers.

on only six subjects. These three men and three women (35.5+/-14.5 yrs, 172.5+/-12.2 cm, 75.3+/-9.0 kg), who were all healthy, normal-weight and non-vegetarian and thus not, with creatine being a deficiency nutrient in vegetarians, extraordinarily susceptible to creatine supplementation (Burke. 2003), participated in two testing sessions during which they received the previously explained two treatments (the powdered supplements were simply dissolved in 450 ml of water).

Adding carbohydrates or cinnamon to creatine may well increase its uptake to the muscle. What it does not do, however, is to enhance creatine's efficacy - at least not in a 2015 3-week creatine loading study Islam et al. conducted in 25 recreational gymrats.

What's the increased absorption worth? If we rely on a a recent study by Islam, et al. (2015) the answer is (unfortunately) nothing. In their 2015 study, the scientists from the Wilfrid Laurier University and the University of Lethbridge in Canada found no (=zero) significant differences in anaerobic power, strength, and endurance when creatine was administered solo, with the same 70 g carbohydrate (CHO) that were used in Jäger et al. (2016), or 500 mg cinnamon extract (CIN), of which the authors believed that its proven ability to improve insulin sensitivity and up-regulate glucose transport in skeletal muscle would likewise enhance the uptake of creatine in the muscle and thus make it more effective.

With their cross-over after the initial test and a 7 day break between the tests, the scientists would have been able to compare the effect of adding glucose and alpha lipoic acid to the tricreatine citrate (Creapure™ Citrate, AlzChem, Trostberg, Germany | 65% w/w creatine) on an individual level. Corresponding data, however, is not (yet?) available. Instead, we get the likewise interesting statistical averages (see Figure 1):

Figure 1: Mean plasma creatine concentration over 8 hours following ingestion of 5g tricreatine citrate (TCrC) and 5g tricreatine citrate + 75g glucose + 200mg alpha-lipoic acid (TCrC+Glu+ALA | Jäger. 2016).

And these data present a quite intriguing result. More specifically, they indicate that the increase in peak concentration and the area under the curve (indicative of the total amount of creatine that appeared in the blood of the subjects) were significantly lower in the TCrC+Glu+ALA group in comparison to TCrC (75.3%, p<0.05, and 82.2% respectively).

Less creatine in the blood with sugar + ALA? That's bad, right? No that's good!

Just as the likewise lower 0.5 and 1h plasma concentrations of creatine, in the TCrC+Glu+ALA group (in comparison to TCrC), these reductions do not indicate a reduced efficacy of the supplement. On the contrary! The significantly elevated mean 8h urinary creatine elimination in the control group (TCrC | 26.5 ± 13.9% of the dose administered  vs. 17.2 ± 13.0% for TCrC+Glu+Ala) rather indicates that the addition of glucose and ALA "enhanced rate of creatine uptake into the muscle" - as previous studies indicate probably due to the presence of raised insulin (by glucose) and / or an increased insulin sensitivity (by ALA / Koszalka. 1972; Steenge. 1998; Pittas. 2010).

Figure 2: The study on creatine + glucose and creatine + cinammon by Islam et al. (red box) is not the only one that shows that the increased deposition of creatine in the muscle doesn't give you athletic advantages. The exact same results have been observed in an 8-week study comparing 70 g of a dextrose placebo (PL), 5 g creatine/70 g of dextrose (CRD) or 3.5 g creatine/900 mg fenugreek extract (CRF) by Taylor et al. (2011)

Why's this study relevant? Well, the answer should be obvious. The few allegedly 'advanced creatine products' on the market that actually have scientific back-up of their efficacy often refer to studies showing increases in plasma creatine of which the study at hand shows that they are no valid predictor of the actual efficacy of the supplement. The latter obviously depends on muscle creatine uptake, not serum peak levels or AUC. Don't be a fool, though: This does not mean that lower serum levels after ingestion were automatically better. After all, those lower levels of creatine in the blood may well be a mere result of an impaired / incomplete absorption in the gut.

Confusing? Well, let's summarize: By measuring the creatine level in the blood and the excretion of creatine in urine, Jäger et al. were able to refute the (ostensibly) logical assumption that higher serum creatine levels would indicate an improved efficacy. What they did not prove conclusively, however, is that the creatine levels in the muscle were in fact significantly higher (no biopsies) and, most importantly, that this makes a performance difference. The latter has after all been refuted in previous studies, such as Islam et al. (2015 | see red box and Figure 2). The hunt for the "best form" of creatine will thus probably go on, albeit with different experimental means, i.e. either the measurement of serum and urinary creatine as it was done in the study at hand or (even better) the direct assessment of muscle creatine stores and the actual performance benefits | Comment!

References:

• Burke, Darren G., et al. "Effect of creatine and weight training on muscle creatine and performance in vegetarians." Medicine and science in sports and exercise 35.11 (2003): 1946-1955.
• Jäger, Ralf, Martin Purpura and Roger C Harris. "Reduction of Plasma Creatine Concentrations as an Indicator of Improved Bioavailability." Upublished data from privatt conversation (2016).
• Koszalka, Thomas R., and Carole L. Andrew. "Effect of insulin on the uptake of creatine-1-14C by skeletal muscle in normal and X-irradiated rats." Experimental Biology and Medicine 139.4 (1972): 1265-1271.
• Pittas, G., et al. "Optimization of insulin-mediated creatine retention during creatine feeding in humans." Journal of sports sciences 28.1 (2010): 67-74.
• Steenge, G. R., et al. "Stimulatory effect of insulin on creatine accumulation in human skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 275.6 (1998): E974-E979.
• Taylor, Lem, et al. "Effects of combined creatine plus fenugreek extract vs. creatine plus carbohydrate supplementation on resistance training adaptations." Journal of sports science & medicine 10.2 (2011): 254.

Want to Home-Brew Your Own 15x More Bioavailable Super-Curcumin? Buy Buttermilk and a Yogurt Starter Culture

No one says you cannot add other ingredients to the yogurt to make it more tasty if you add the curcumin before fermenting the buttermilk.

If you're a regular at the SuppVersity you will know that curcuminoids, the polyphenols found in turmeric roots (Curcuma longa), have health effects that are similar, in some cases even superior to several anti-inflammatory, anti-diabetic and lipid-lowering drugs. Yes, their consumption has even been linked to significant reductions in cancer risk. Unfortunately, there's a problem with these powerful polyphenols: they are hydrophopbic (Tønnesen. 2002) and prone to degradation in an aqueous environment at neutral and alkaline pH (Tønnesen. 1985; Wang. 1997) - two properties of which Gupta and others (2013) believe that they are responsible their poor oral bioavailability.

Unlike other supps and practices curcumin has not been shown to interfere with hormesis

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Low bioavailability or not, Shishan Fu and rightly highlight in the introduction of their latest paper, even the hardly absorbed "regular" curcuminoids have been reported to offer many health-promoting properties (Gupta and others 2013), it is thus only logical that there's an "interest in the development of functional foods containing these compounds is increasing" (Fu. 2016).

Figure 1: Even dispersing them in buttermilk will increase the bioavailability by decreasing the breakdown of curcuminoids during digestion - that's at least what a 2014 study by Fu et al. shows. 

Hitherto scientists have (more or less successfully) tried to increase the solubility and stability of curcuminoids by dispersing them in matrices such as lipid-based emulsions (Ahmed. 2012; Yu and Huang. 2012), modified starch (Yu and Huang 2010), hydroxypropyl methyl cellulose (Chuah. 2014), milk proteins (Yazdi and Corredig. 2012), and buttermilk (Fu. 2014). As Fu et al. point out, ...

"[...t]he bioavailability may also be increased when formulated in appropriate delivery systems. For example, lecithin–piperine formulations containing curcuminoids and curcuminoids encapsulated in cellulose have been reported to have enhanced bioavailability after oral administration in humans (Antony and others 2008; Vitaglione and others 2012)" (Fu. 2014).

Based on their own previous study with regular buttermilk and evidence that yogurt can significantly increase the stability and bioavailability of bioactives, like green tea polyphenols (Lamothe and others 2014), Fu et al. speculated that dispersing curcuminoids in buttermilk prior to yogurt manufacture would exert even more powerful effects than simply mixing them with buttermilk (see Figure 1). To test this hypothesis, the scientists did something anyone of you can do at home (see Figure 2 for information on how the control samples were prepared, too):

Figure 2: Preparation of yogurts (Fu. 2016).

"A buttermilk dispersion (14% total solids, w/w) was prepared by reconstituting 142.3 g of buttermilk powder in MilliQ-water which was made up to 1000 g. The powder was dispersed in the water at 45 °C with stirring using an overhead stirrer (Heidolph RZR 2051 control, Germany) at 1000 rpm for 30 min. The dispersion was then stored at 4 °C overnight for more complete hydration. The chosen fortification level of curcuminoids in yogurt was 300 mg/ 100 g yogurt (0.3% w/w)

An ABT-5 culture was prepared by mixing 0.2 g of culture granules in 10 mL of buttermilk dispersion (14% total solids, w/w) and stirring for 15 min in an ice bath. This culture solution was prepared freshly prior to fermentation. The ABT-5 culture was added at a level of 0.2 g/L of yogurt buttermilk. The buttermilk was subsampled (50 mL) into separate plastic containers and incubated at 43 °C until pH reached 4.6. These set yogurts were put into the ice water bath for 30 min, stirred at 200 rpm for 20 s using a mixer (Heidolph RZR 2050, Germany) and then stirred manually (approximately 20 times) to obtain a uniform product. The stirred yogurts were stored in a cool room (4 °C) overnight. All analysis was completed within 2 d of yogurt manufacture. The total solids of the yogurts were estimated using a moisture analyser (Sartorius AG, Germany)." (Fu. 2016).

To be able to tightly control the experiment, the curcumin enhanced yogurt and the other samples were exposed to in vitro digestion. During this procedure, the sample (5 g) was mixed with 15 mL of simulated gastric fluid (SGF) containing 2 g NaCl and 7 mL 37% w/v HCl per liter (pH 1.23) and 3.2 mg/mL pepsin, and incubated in a water bath with 100 rpm at 37 °C for 2 h (United States Pharmacopeia Convention 2009).

"After exposure to SGF, the mixture was adjusted to pH 6.5 using 1 M NaOH and mixed with 9.6 mL of simulated intestinal fluid (SIF) containing 3 mL of 2 M NaCl, 0.3 mL of 0.075 M CaCl2, and 6.3 mL of 36.5 mg/mL bile extract in 5 mM phosphate buffer. The pH was adjusted to 6.8 and then 5.4 mL of 10 mg/mL pancreatin in phosphate buffered saline was added. Samples were incubated at 37 °C, 100 rpm for 3 h and then placed in an ice bath to arrest the enzyme activity. At the end of the in vitro digestion period curcuminoids were extracted from the whole digested mixture with acetone and quantified using HPLC-DAD" (Fu. 2016). 

The in-vitro digestion, which is described in a previous paper by Fu et al. (2015), provided the scientists with an estimate of the amount of undegraded curcuminoids - it is yet not a 100% reliable method to determine the real world biological effects in humans, which would have to be tested in future studies. In view of the fact that the scientists calculations show that the resistance of the curcuminoids to degradation after sequential exposure to SGF and SIF improved more than just statistically significantly (see Figure 3), it is logical to assume that benefits would be observed in vivo, too.

Figure 3: Bioaccessibility of curcuminoids after sequential exposure of samples to SGF and SIF (Fu. 2016).

The difference pre-processing, i.e. the prior dissolution in ethanol (which wouldn't make you drunk, anyway, because the total ethanol content of the yogurt would be marginal), the dissolution of curcuminoids in buttermilk and its fermentation to "curcumin enhanced" buttermilk yogurt with a standard ATB yogurt starter culture, made in terms of the bioavailability is after all huge.

In fact, the bioavailability of the curcuminoids increased to an extent that easily surpasses the hyped "super / bio curcumins" that use a combination of curcumin and bioperin, which has been shown to exhibit a 6.93-fold higher bioavailability. In all fairness, we shouldn't forget, though, that, unlike the yogurt trick described here, Biocurcumax™ has already been studies in humans (Antony. 2008).

Curcumin has cancer protective effects, too | learn more

The total bioavailability is still low, but... As, Fu et al. point out in the conclusion of their soon-to-be-published paper, "[t]he most important and practical finding from the bioaccessibility data is that the incorporation of powdered curcuminoids into buttermilk prior to yogurt manufacture results in a 15-fold increase in bioaccessibility of curcuminoids compared to that of neat curcuminoids dispersed in aqueous buffer" (Fu. 2016).

The scientists are yet also right to point out that even with the enhanced bioaccessibility of curcuminoids the total bioavailability was still low (approximately 6%) when they were delivered in yogurt.

In view of the fact that the polyphenols which are transferred into the colon are degraded by gut microflora and the degradation products contribute to the bioactivity of these compounds in the body, the real-world relevance of this astonishing increase in bioavailability will have to be tested in in vivo, before we can have a final say on the practical significance of these findings | Comment!

References:

• Ahmed, Kashif, et al. "Nanoemulsion-and emulsion-based delivery systems for curcumin: encapsulation and release properties." Food Chemistry 132.2 (2012): 799-807.
• Antony, B., et al. "A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin." Indian journal of pharmaceutical sciences 70.4 (2008): 445.
• Chuah, Ai Mey, et al. "Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin." Food chemistry 156 (2014): 227-233.
• Fu, Shishan, et al. "Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models." Food chemistry 179 (2015): 52-59.
• Fu, Shishan, e al. "Enhanced Bioaccessibility of Curcuminoids in Buttermilk Yogurt in Comparison to Curcuminoids in Aqueous Dispersions." Journal of Food Science (2016): Ahead of print. doi: 10.1111/1750-3841.13235
• Yazdi, S. Rahimi, and M. Corredig. "Heating of milk alters the binding of curcumin to casein micelles. A fluorescence spectroscopy study." Food Chemistry 132.3 (2012): 1143-1149.
• Yu, Hailong, and Qingrong Huang. "Enhanced in vitro anti-cancer activity of curcumin encapsulated in hydrophobically modified starch." Food Chemistry 119.2 (2010): 669-674.
• Yu, Hailong, and Qingrong Huang. "Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions." Journal of agricultural and food chemistry 60.21 (2012): 5373-5379.

60%+ Reduced Absorption of EGCG if You Consume GTE W/ Food - Better Take Your Green Tea Caps On Empty

Green tea smoothies - If you don't want to waste more than 60% of green tea's precious EGCG content, you better don't blend it with too much other stuff

While the previously discussed effect of milk on the bioavailability of the polyphenols from green tea (the beverage) is probably negligible, a recent study from the University of Cranberra suggests that the inhibitory effect of food on the absorption of the major catechins in green tea may be significant enough to say that it's important to take them away from food.

To assess the effects of different food matrices on the bioavailability of capsulated green tea supplements, Naumovski et al. came up with a systemic absorption test healthy fasted humans.

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On three separate days, their four healthy, normal-weight participants (3 males and 1 female aged 18-64 years) had to come to the clinic fasted (10h of fasting minimum). At the laboratory, the participants ingested 500 mg of EGCG given either as

• two capsules (2 × 250 mg) with 100 mL of water only (without any breakfast), 
• two capsules (2 × 250 mg) provided with 50 g of Special K breakfast cereal (Kellogg’s, Pagewood, NSW, Australia), or
• in form of 200 mL of full cream milk or EGCG (500 mg) that had been incorporated in 200 g of strawberry sorbet 

All treatments were ingested within 5 min and no additional food was taken for a further 4 h. All participants were provided with a lunch and a drink three hours after ingesting the EGCG, which consisted of a sandwich (bread, ham, cheese, tomato, lettuce) and 200 mL of orange juice.

The reduction it antioxidant capacity you get if you just add milk to your tea is much lower (learn more)

Why is this study relevant for you? Obviously, more does not always help more, but if you ingest 500mg of EGCG, for example, to help you along with weight loss, it will make a difference if the amount that will actually arrive in the blood is diminished by 63% or 74%. That's the kind of difference that may even explain why some people are seeing an effect from green tea capsules, while others are not! It's also worth mentioning that this (albeit EGCG specific effect) of complex food matrices is significantly more pronounced than the effects of milk (esp. skimmed milk | see figure on the left) on the total antioxidant capacity of tea - an effect I discussed in detail in a previous article.

To determine the effect of the different food items on the absorption of EGCG, the scientists used blood samples that were taken before the ingestion of the capsules / sorbet, 30min, 1h, 2h, 3h, 5h, and 8h afterwards by the means of a previously installed intravenous catheter (BD, North Ryde, NSW, Australia).

Figure 1: The mean plasma EGCG concentration-time curves for the three different methods of oral delivery: capsules without breakfast (green), capsules with breakfast (purple) and strawberry sorbet (red). The values are means ± the standard error of the means for the four participants (n = 4 | Naumovski. 2015).

As the data in Figure 1 shows the amount of EGCG that actually made it into the blood of the study participants was significantly (and practically relevantly) reduced when the capsulse were ingested with food or the EGCG was incorporated into the sorbet.

SuppVersity Suggested: "Caffeine not Required for Performance Enhancing Effects of Green Tea in Recreational Athletes - 25% Increase in Fatty Acid Oxidation, 11% Increase in Maximal Endurance" | more

So what? With an AUC (area under the curve, is a measure for the total amount of EGCG that was released into the blood stream during the 8h study period) that was 2.7 and 3.9 times higher "on empty" compared to the "light breakfast" and "sorbet" trials and similar differences for the peak levels and the time it took for the EGCG levels in the blood to reach their maximum, there's little doubt that it does make a difference whether you take your green tea supplements with or without food.

In case you want to test whether my statement that GTE is still the most promising of the legally available fat burners (read more), you may thus want to make sure you're taking the EGCG on empty | Comment on Facebook!

References:

• Naumovski, Nenad, Barbara L. Blades, and Paul D. Roach. "Food Inhibits the Oral Bioavailability of the Major Green Tea Antioxidant Epigallocatechin Gallate in Humans." Antioxidants 4.2 (2015): 373-393.

Supplement Sensation? Oral Glutathione Supplements Dose-Dependently Double GSH in Randomized Controlled Human Studies. Health Implications Still to Be Determined

Blueberries and other foods w/ tons of polyphenols are GSH boosters (Moskaug. 2005) and make supplements obsolete. 

If you have been interested in dietary supplements for some time, I am pretty sure that you will have heard about oral glutathione ob(GSH) supplements in one of the "snake oil warnings" on various websites. The "master antioxidant" as it is called is after all believed by many to be not bioavailable - at least not orally. Studies in animal models, however, have already shown that oral GSH, administered either in the diet or by gavage, has the ability to increase plasma and tissue GSH levels ( Loven. 1986; Aw. 1991; Favilli. 1997; Kariya. 2007). It would thus be more appropriate to say that the efficacy of oral glutathione in humans has not yet been tested in peer-reviewed studies.

You can learn more about potential negative sides of too many / the wrong antioxidants:

NAC = GSH ￪, Anabolism ￬

Too Much "Vit C" For Gains?

Protein requ. of athletes

Block inflamma- tion, choke fire

C + E Get Avg. Joes Ripped

ROS Management Not Eradication

Now, the absence of human studies should definitely ring an alarm bell in the head of every healthily skeptic supplement user, what it should not do, though is mislead you to believe that GSH supplements don't work in human beings.

Now this is where John P. Richie Jr. and his colleagues from the Penn State Cancer Institute, the Department of Microbiology and Immunology at the Penn State University College of Medicine and the Orentreich Foundation for the Advancement of Science, come into play. As the scientist state, their "objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults." (Richie. 2014)

Warning - keep an eye on your wallets: Even if the supplements work, they are probably going to be expensive and in view of the fact that "the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period" (Richie. 2014), you will (a) have to take plenty to achieve maximal effects and (b) do that year-round. In view of the fact that we still don't have evidence of any downstream health benefits, I would thus be hesitant to recommend buying a GSH supplement at the moment - specifically if you are healthy, eat clean and work out!

To this end, they conducted a 6-month randomized, double-blinded,placebo-controlled trial in the course of which the subjects, 41 women and 13 men (6 dropouts not included) with a normal BMI and no known health issues, consumed either ...

• an oral GSH supplement dosed at 250mg/day,
• an oral GSH supplement dosed at 1,000mg/day, or
• an identically looking placebo.

The main study outcomes were obviously analyses of the GSH levels in (a) blood, (b) erythrocytes, (c) plasma, (d) lymphocytes and (e) exfoliated buccal mucosal cells (the effects on a battery of immune markers was tested only in a handful of subjects).

Figure 1: Effects of 6 months GSH supplementation on ratio of oxidized to reduced GSH and natural killer cell cytotoxicity in healthy men and women aged 28-72y (Richie. 2014)

As the data in Figure 1 already suggests, there was a dose-dependent increase in GSH levels. With the high dose (1,000mg/day) producing GSH increases of 30–35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells (P<0.05) and increases of 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P<0.05 - data not shown in Figure 1).

These improvements had beneficial downstream effects on the overall status of the subjects' antioxidant defense system. A fact you can conclude based on the decreased ratio of oxidized (used) to reduced (fresh) glutathione in whole blood the scientists observed in their subjects after 6 months. These benefits came hand in hand with an increase in natural killer cytotoxicity (+100%), another potentially highly desirable health benefit.

Inflammatory cytokines won't build muscle. Without them, however, your body won't notice that it's time to adapt and w/ too much glutathione just that could happen.

Bottom line: The fact that they obviously are bioavailable and have potent antioxidant and immune-strengthening effects make glutathione supplements particularly attractive for anyone who is suffering from chronic inflammation (obesity, diabetes, or both) and/or taking anti-inflammatory, but immune suppressive drugs (autoimmune diseases from simple allergies over asthma and rheumatism to multiple sclerosis).

Whether you, the not-so-average SuppVersity reader will feel, let alone see any benefits from using these supplements is in my humble opinion highly questionable. And in case you've already forgotten about the Janus-faced effects the GSH-booster N-acetyl-cysteine will have on training induced muscle injury, cytokine expression and anabolic signalling, I'd suggest you take another look at an almost 12-months old follow-up to the SuppVersity Science Round-Up.

References:

• Aw, Tak Yee, Grazyna Wierzbicka, and Dean P. Jones. "Oral glutathione increases tissue glutathione in vivo." Chemico-biological interactions 80.1 (1991): 89-97.
• Favilli, Fabio, et al. "Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters." British journal of nutrition 78.02 (1997): 293-300.
• Kariya, Chirag, et al. "A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration." American Journal of Physiology-Lung Cellular and Molecular Physiology 37.6 (2007): L1590.
• Loven, Dean, et al. "Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes." Diabetes 35.5 (1986): 503-507.
• Moskaug, Jan Ø., et al. "Polyphenols and glutathione synthesis regulation." The American journal of clinical nutrition 81.1 (2005): 277S-283S.
• Richie Jr, John P., et al. "Randomized controlled trial of oral glutathione supplementation on body stores of glutathione." European journal of nutrition (2014): 1-13.