Monday, April 8, 2013

Antioxidants For Lazy Rodents: Alpha Lipoic Acid + CoQ10 + Vitamin E Work Mitochondrial Wonders On Untrained Female Mice... And ONLY On Untrained Female Mice!

ACE!? Are alpha lipoic acid, coQ10 and vitamin E good for them or not?
With all the bad press on anti-oxidants, you could actually get the impression that performance and longevity should be a function of the amount of oxidative stress you're exposed to.

Despite the fact that this hypothesis may have it's merit, the "True or False" item on the negative side effects of eccentric training should probably have reminded you that keeping a balance between the constant oxidative assault from our environment (in the broadest sense) on the one hand and our bodies' continuously evolving defense system is what we should actually be aiming for.

Whether or not we will benefit from an increase in exogenous anti-oxidants like vitamins, will therefore always depend on both the stressor and the state and performance of our anti-oxidant defense system. A recent paper that has just been published in the peer-reviewed online journal PLOS-ONE does actually appear to confirm this notion of "stress management". In other words:

Adaptation occurs, when you expose yourself to stressors which are taxing, but won't obliterate your defense system = the "i + 1" / hormesis principle

We know from previous human studies that vitamin C and vitamin E (1g Vit C, 400IU Vit E; about as much as you will find in any of the useless "high performance multis") can blunt the hormetic effects of exercise-induced oxidative stress on insulin sensitivity and the concomitant adaptive response of the endogenous antioxidant defense system (Ristow. 2009).
Figure 1: TBARS in the supplemented (no improve in insulin sensitivity) and non-supplemented trainees (Ristow. 2009)
A quick note on how to interpret study results: Whenever you take a look at one of the "pro-antioxidant studies", you got to make sure the scientists don't base their assessment that the use of the respective molecule was beneficial on the observation of a reduction in exercise induced stress.

If the (mito-)hormesis theory holds, the amelioration of the latter in the 2009 study by Ristow (see figure 1) is in fact to blame for the absence of increases in insulin sensitivity, adiponectin, etc.
The results of the Ristow study have caused quite an upset within the scientific community and the world of physical culture. Especially within the latter the results of the researchers from the University of Jena were often misinterpreted as "all anti-oxidants are bad for you" and then prematurely dismissed on the basis of studies in which the researchers were able to observe mostly marginal and in terms of the explanations in the red info box above, highly questionable "beneficial" effects of anti-oxidant supplements.

Not all "antioxidants" are created equal

Suggested read: In a 2012 letter to the proponents of the mitohormesis hypothesis pick the results of a paper by Higishada et al. that's often cited in support of vitamin C + E supplementation to pieces and conclude "The vast majority of experimental evidence clearly advises against this supplementation. Thus, we unreservedly confirm the conclusions derived from our previous research and disagree with Higashida et al. In our opinion, antioxidant supplements are, at the least, useless" (Gomez-Cabrera. 2012). The letter should be accessible for all of you, so feel free to read up on the evidence they provide to support this conclusion... keep in mind, though no honest scientist will claim he would tell you the one and only truth. What they will give you is their assessment of the facts and the conclusion they believe should be drawn based on these facts.
In fact, the actual number of exercise interventions in which scientists observed real-world benefits from vitamin C and vitamin E, in particular, is often overestimated. Therefore neither of these most prominent members of a very broad class of molecules that carries the label "antioxidant" can be considered a "proven ergogenic" and it is therefore not very surprising that Nikolaidis et al. conclude their 2012 review of the literature on the words:
"Based on the contradictory evidence regarding the effects of higher intakes of vitamin C and/or E on exercise performance and redox homeostasis, a permanent intake of non-physiological dosages of vitamin C and/or E cannot be recommended to healthy, exercising individuals." (Nikolaidis. 2012)
Now, despite the fact that the acronym may be the same (ACE usually stands for beta carotene, vitamin C and vitamin E), the "antioxidant" supplement in the study at hand has a different makeup. While it does contain vitamin E, it does not contain the additional "kamikaze vitamin" ascorbic acid, which cannot distinguish between "good" and "bad" ROS formation and will - much like a fire extinguisher - quench both "smoke signal" that's telling your boy "the mitochondrial engine is running at full speed, it may be time for an upgrade", as well as the not so beneficial "sparking" that occurs when the engines are overheating.

Does the mix make the difference?

CoQ10 on the other hand, is more or less specialized on protecting the mitochondria. It is not a "fire extinguisher", but rather a fire-proof coating that protects the mitochondria from "leaking" reactive oxygen specimen into the circulation. In conjunction with the cell-membrane protecting effects of vitamin E and the "vitamin recycler" alpha lipoic acid, we get a highly specialized antioxidant stack of which the results of the study at hand show that it is beneficial in those situations, where the baseline protection against an imposed stressor is insufficient.
Figure 2: Differential effect of anti-oxidant supplementation on trained (8 wks treadmill running) (n = 12/group) and untrained (n = 24/group) male and female rodents' endurance performance; data presented in meters (Abadi. 2013)
If you do now take a peak at the data in figure 2 you will realize that the latter was the case in the female rodents who were not exposed to the chronic exercise regimen. Correspondingly the provision of the ALA + CoQ10 + vitamin E stack did improve the exercise performance and mitochondrial respiratory chain protein capacity. The same data plot does yet also reveal that these effects were sex and training specific and generally absent in the trained rodents.
Figure 3: Questionable (female) and non-existant (male) "benefits" of antioxidant supplementation on the relative expression of the mitochondrial builder PGC-1a, the satellite cell recruiting "stress" kinase p-38 MAPK and the well known glucose sensitizing AMPK (Abadi. 2013)
One of the many things, Abadi et al. don't mention, though, is the fact that the "reduced the activation of the stress kinase p38-MAPK following acute exercise in untrained" (Abadi. 2013, cf. figure 3) could also decrease the "repair" and supercompensation process that will take place after the unaccustomed (remember the data in figure 3 is from untrained animals after the 2nd exercise test). After all, the "stress kinase" is at the same time "a molecular switch for satellite cell activation" (Jones. 2005) and thus heavily involved in the recruitement of satellite cells.

"Voilà it works.... ahm, ok only in one out of four groups, but it works!"

Similarly, Arkan Abadi and his colleagues unfortunately forgot to mention is that they did not measure "THE" training-induced adaptations in the sense of "all training induced adaptations", but only a couple of mitrochondrial protein expressions. Against that background we cannot exclude that the insulin sensitizing effects of exercise Ristow et al. have been missing in their human subjects was not blunted in Abadi's C57Bl/J6 mice, as well.

Remember the case is not yet settled: This is an analysis of a single study and the fact that this suggests that CoQ10, ALA and vitamin E are worthless for the majority of trainees does neither negate that the provision of only on of them, e.g. 200mg/day CoQ10 in athletes taking statins (Deichmann. 2012), or the provision of respective supplements during specifically stressful training periods can have ergogenic effects.
The absence of more comprehensive data on the actual metabolic effects of the supplement regimen, as well as the unexplained confounding effects of gender and training status, specifically the non-significant, yet paradoxically opposed effects the scientist observed in the male rodents certainly warrant the question, why the abstract focuses almost exclusively on the already moderate benefits they observed in the untrained females. After all, the scientists declare that the
"study was undertaken to investigate the effects of dietary supplementation with vitamin E, a-lipoic acid, and CoQ10 in combination on basal and training-induced mitochondrial adaptations in mice." (Abadi. 2013)
In other words, their interest was in the effectiveness in mice in general and not in untrained female mice. Against that background, the most significant finding of the study would actually have been that there are confounding factors rendering the combination of these three mitochondrial antioxidants useless.

Figure 4: Health and longevity as a function of mitochondrial reactive oxygen species (ROS) formation.
Both too much and too little ROS are detrimental, due to either insufficient stimulus for or overtaxing of hormetic processes (this graph is a mere illustration and is not based on any existing experimental data and was first published in a previous SuppVersity article from May 2011)
Bottom line: I bet you will soon see the results, or rather excerpts of the results of this study referenced on the bottles and shiny adverts of the supplement industry. "Most recent studies show that the combination of alpha lipoic acid, CoQ10 and vitamin E in RippYouOffSupplements (ROS) newest product increases ..." You know the whole spiel and are probably not fooled by pseudo-scientific nonsense like that anyway.

Take a look at the data and use your gray matter: Are you rather an untrained female mouse? Or would you rather describe yourself as a devoted physical culturist?  If choose the 2nd option, you don't have to rack your brain any longer about the what ifs and maybes pertaining to potential reductions in the exercise induced increase in insulin sensitivity, because the "scientific evidence" ROS presents in favor of the efficacy of their newest "blockbuster product" is not relevant for you, anyway.

Now that I am done ranting, I should maybe add that I sill like this study. Not just as an educative example of how easily scientifically valid data can be abused to provide proof for whatever you want, by simply skipping on parts of the results, but also because it adds sex as a new confounding factor you have to keep in mind, when you compare studies on the useful an uselessness of antioxidant supplements. And that's not just in an exercise, but also in any other scenario (e.g. longevity, metabolic syndrome, etc.) - after all, the gender-difference was present only in the non-exercised rodents.

  • Abadi A, Crane JD, Ogborn D, Hettinga B, Akhtar M, Stokl A, MacNeil L, Safdar A, Tarnopolsky, M. Supplementation with a-Lipoic Acid, CoQ10, and Vitamin E Augments Running Performance and Mitochondrial Function in Female Mice.
  • Deichmann RE, Lavie CJ, Dornelles AC. Impact of coenzyme Q-10 on parameters of cardiorespiratory fitness and muscle performance in older athletes taking statins. Phys Sportsmed. 2012 Nov;40(4):88-95.
  • Gomez-Cabrera MC, Ristow M, Viña J. Antioxidant supplements in exercise: worse than useless? Am J Physiol Endocrinol Metab. 2012 Feb 15;302(4):E476-7; author reply E478-9.
  • Higashida K, Kim SH, Higuchi M, Holloszy JO, Han DH. Normal adaptations to exercise despite protection against oxidative stress. Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E779-84.
  • Jones NC, Tyner KJ, Nibarger L, Stanley HM, Cornelison DD, Fedorov YV, Olwin BB. The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J Cell Biol. 2005 Apr 11;169(1):105-16.
  • Nikolaidis MG, Kerksick CM, Lamprecht M, McAnulty SR. Does vitamin C and E supplementation impair the favorable adaptations of regular exercise? Oxid Med Cell Longev. 2012;2012:707941.
  • Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8665-70.