Wednesday, August 31, 2016

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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Build 'Ur Own Buffered Creatine
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!
  • 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.