Monday, February 16, 2015

The Latest on Glutathione Supplements - Yes, They Can Work; And Yes, They May Even be Beneficial for Athletes

Do you really need even more pills? The answer is "NO!" - even if GSH supplements actually seem to work.
If you'd asked me 2 years ago, I'd answered the question whether glutathione (GSH) supplements even work with a determined "I don't think so!" Meanwhile, there have been a handful of interesting papers which indicate that oral glutathione supplements could actually work.

The latest and one of the more interesting of these papers comes from the Graduate School of Life and Environmental Sciences at the Kyoto Prefectural University where Wataru Aoi et al. took the next step and tried to prove the significance of Kovacs-Nolan et al.'s (in press) and Park et al.'s (2014) finding that glutathione is intestinally absorbed and transported intact across the human intestinal epithelial wall in a rodent model and in humans.
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More specifically, the researchers hypothesized that glutathione supplementation may contribute to aerobic metabolism during exercise as a result of activated mitochondria via PGC-1α in skeletal muscle. The purpose of their latest experiment was thus to examine the effects of glutathione supplementation on muscle fatigue in exercise as a result of improved muscular aerobic metabolism.

After the scientists had randomly assigned a group of hairy subjects (=IRC mice) to one out of four groups: sedentary control, sedentary supplemented with glutathione (2.0%, 5 μL/g body weight), exercise control, and exercise supplemented with glutathione. The rodents who had been on the respective regimen for two weeks were subjected to a treadmill run at 25 m/min for 30 min. Immediately post-exercise, intermuscular pH was measured, and hind limb muscle and blood samples were collected to measure biochemical parameters. What the scientists found was:
  • Figure 1: The provision of glutathione was not without effect. More specifically it increased the mitochondrial builder PGC-1a and it's upstream protein AMPK (A,B), it reduced the decline in pH in response to exercise (C) and increased the mitochondrial DNA (D) levels (Aoi. 2015).
    Evidence of increased plasma fatty acid oxidation: Plasma NEFA after exercise was significantly lower with supplementation of glutathione compared with the control group (df = 31, F = 5.90, p < 0.01).
  • Evidence of the H+ buffering effects of glutathione: The interstitial pH levels in muscle were significantly reduced by exercise (df = 31, F = 4.36, p < 0.001; Figure 1C). However, the pH following exercise of the glutathione group was significantly higher than that of the control group (p < 0.05).
  • Evidence that glutatione supplements may improve mitochondrial health: PGC-1α was significantly higher with glutathione intake (df = 14, t = −1.88, p < 0.05). In addition, AMPK, an upstream protein of PGC-1α, was also significantly higher in the sedentary treated with glutathione group than in the sedentary control group (df = 13, t = −2.76, p < 0.05).
Now, rodent studies are nice, but human studies are the real deal, right? Well, luckily Aoi, et al. did an additional double-blind, cross-over study involving 8 healthy men (35.9 ± 2.0 y) who received either glutathione (1 g/d) or placebo for 2 weeks.
What is glutathione aka GSH & do I have to supplement? Glutathione (GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side-chain and the amine group of cysteine (which is attached by normal peptide linkage to a glycine).

Now, the really important question is yet if you do have to supplement GSH straight. Studies like Lands, et al. (1999) indicate that cysteine rich protein sources can have similar effects. In fact, Lands et al. found significant increases peak power and 30-s work capacity, as well as increased lymphocyte GSH in response to supplementing with Immunocal, a high cysteine whey protein isolate for 3 months. Similar results have been observed with non-patented whey protein formulas by Shute et al. (2004) & Zavorsky et al. (2007). 
After the 14 day supplementation week, the subjects exercised on a cycle ergometer at 40% maximal heart rate for 60 min. Psychological state and blood biochemical parameters were examined after exercise and yielded interesting results:
  • Evidence of decreased lactate production: There was a significant increase in blood lactate concentrations at 30 min after exercise compared with pre-exercise in the placebo trial (df = 41, F = 3.90, p < 0.05) but not in the glutathione trial.
  • Maintenance of stable muscular glutathione levels: The free form of glutathione in plasma was not changed by either exercise or glutathione intake. In contrast, protein-bound plasma glutathione was significantly reduced by exercise in the placebo trial (p < 0.05) although the reduction was moderated in the glutathione-supplemented group.
  • Figure 2: It looks as if two weeks of 1g/day of GSH had potentially performance relevant effects on untrained individuals (Aoi. 2015).
    Reduced heart rates and reduced perceived exertion & inreased vigor: There was a trend for lower heart rates during exercise at 40 and 60 min in the glutathione trial compared with the placebo trial (Z = −1.47, p = 0.071 and Z = −1.26, p = 0.104, respectively). There was also a trend for a lower RPE at 50 min (Z = −1.44, p = 0.075) and a significant decrease at 60 min (Z = −1.78, p < 0.05) in the glutathione trial compared with the placebo trial. Furthermore, the Profile of Mood State vigor–activity factor after exercise was significantly higher following exercise in the glutathione trial compared with the placebo trial (Z = −2.11, p < 0.05) (Table 1). In contrast, the fatigue–inertia factor was significantly lower in the glutathione trial compared with the placebo trial (Z = −1.82, p < 0.05), while marked difference was not found in the VAS scores between trials (Z = −0.98, p = 0.163)
Overall, it does therefore appear as if the previously doubted oral glutathione supplements could - if they are taken chronically and in high amounts - in fact be useful.
Figure 3: In the Richie Jr. study the GSH supplements turned out to be powerful natural killer cell "anabolics", too (Richie Jr. 2015).
Bottom line: Yes, I may have erred when I said that glutathione supplements are a waste of money two or more years ago and I have no problem admitting it. The study at hand, as well as the results Richie Jr. et al. (2015) present in their latest paper which shows that the chronic ingestion of 250 or 1,000 mg/day will lead to significant increases of GSH levels in blood increased after 1 and 3 months and 30–35 % and 17-19% increased GSH levels in erythrocytes, plasma and lymphocytes in response to the high and low dose of GSH and 260 % increased GSH levels in buccal cells in the high-dose group after 6 months, it stands out of question that oral glutathione supplements work. Specifically in view of the fact that Richie Jr. et al. also observed significant reductions in oxidative stress and up to two-fold increases in natural killer cytotoxicity increased in their recently published GSH study.

All this does not change that glutathione is still not a must have supplement for all of us, though. What the results do, however, is to demonstrate that GSH supplements are not the waste of money previous studies which suggested that they were not even absorbed had suggested. In view of the fact that the subjects wer untrained and considering the role of GSH as "master-antioxidant", is is yet questionable, whether athletes and not chronically inflamed individuals are the ones who are going to benefit most from 1g of glutathione per day does yet appear to be questionable specifically in view of the fact that whey contains significant amounts of cysteine and has been shown to have glutathione boosting effects, as well (Bounous. 2000; Shute. 2004; Zavorsky, et al. 2007) | Comment on Facebook!
References:
  • Aoi, Wataru, et al. "Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism." Journal of the International Society of Sports Nutrition 12.1 (2015): 7.
  • Bounous, Gustavo. "Whey protein concentrate (WPC) and glutathione modulation in cancer treatment." Anticancer Research 20.6 (2000): 4785-4792.
  • Kovacs-Nolan J, Rupa P, Matsui T, Tanaka M, Konishi T, et al. "In vitro and ex vivo uptake of GSH across the intestinal epithelium, and fate of oral GSH after in vivo supplementation." J Agric Food Chem. in press.
  • Lands, L. C., V. L. Grey, and A. A. Smountas. "Effect of supplementation with a cysteine donor on muscular performance." Journal of Applied Physiology 87.4 (1999): 1381-1385.
  • Park EY, Shimura N, Konishi T, Sauchi Y, Wada S, Aoi W, et al." Increase in the proteinbound form of glutathione in human blood after oral administration of glutathione." J Agric (2014):6183–9.
  • 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.
  • Shute, Max. "Effect of Whey Protein Isolate on Oxidative Stress, Exercise Performance, and Immunity." (2004).
  • Zavorsky, Gerald S., et al. "An open-label dose-response study of lymphocyte glutathione levels in healthy men and women receiving pressurized whey protein isolate supplements." International journal of food sciences and nutrition 58.6 (2007): 429-436.