What's the deal with Glutathione

Rafterman

Member
I had not heard of Glutathione until the Joe Rogan/Brian Dunning discussion on Joe's podcast a few weeks back. For those not familiar with the molecule, here's the quick wiki definition:

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.[2] It is a tripeptide with agamma peptide linkage between the carboxyl group of the glutamateside-chain and the amine group of cysteine (which is attached by normal peptide linkage to a glycine).

Brian took issue with Joe during the podcast because he felt that a former guest of Joe's pushed GSH as an anti-hangover "cure" and positioned it in such a way that it seemed to be a "get out of jail free card" for inebriated folks to keep on drinking. I'm not going to get into that discussion any further as much hilarity ensued after that. Suffice it say, it piqued my interest in GSH and whether or not it was legit or just one in a long list of "miracle woo drugs" that have flooded the market in recent years.

In looking around, GSH does seem to be an important molecule to the human body in a number of ways. Again, from wiki:

  • It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.[17]
  • Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated[18]
  • It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs.
It appears that the human body is perfectly capable of producing all of the GSH that it needs to carry out these functions. And while GSH supplementation shows promise in individuals fighting cancer and AIDS, the rub seems to be about whether or not there is any benefit to GSH supplementation in healthy people.

And I guess this is where my question comes in - is there legit science behind GSH supplementation for healthy individuals or is this simply another case of "Big Supplement" fleecing our pockets with half-baked claims that aren't backed up by research?

One of the difficulties I've found in looking into this is that a simple Google search bombards you with all kinds of claims about GSH's effectiveness, but it's all stuff that's very sales/marketing focused.
 
The other key role of glutathione is being the primary redox (reduction/oxidation) buffer in the cells, which affects virtually every cellular system in the body.
Of all the anti-oxidant type molecules it is in the highest concentration in the cells.

Healthy is a vague term, and we don't always know things are going wrong until its too late. Some studies have shown that the redox potential in the body starts dropping significantly after the age of 50, so I think a healthy person over that age would benefit, and there are plenty of people younger than that who could be at more optimal health for their age.

I've researched glutathione for years and have put together a very technical in-depth series of post, referencing many journal articles.
This will answer your question and more! The first part is at http://danielcampagnoli.com/redox-gsh-cysteine-1
Dan, I also cover how too much glutatione, and certain precursors, can be bad.
Enjoy!

Daniel
 
I appreciate the responses, but no offense to campers and sean, this is exactly the kind of stuff I'm talking about. All one has to do is Google GSH and one's bombarded with very marketing heavy materials about numerous benefits that, in my opinion, seem to fly in the face of accepted science. And campers, I checked out your YouTube page and you're clearly involved in the selling of GSH products. Red flags also go up when I see that you guys joined this site for the express purpose of replying to my thread.
 
It's always difficult to interpret results of metabolic studies in a way in which we can say for sure that taking a certain substance is responsible for an increase in longevity. There are many factors and variables that go into how healthy and how long one will live. I can honestly say that I haven't read a satisfying amount of material on this topic. It does, however, make sense that antioxidant supplements could help certain people in certain cases. At my current understanding, I'd say it seems like it could be a good idea depending on the situation. Here is a search result from NCBI on glutathione and longevity that might be little more helpful than a google search. I haven't read much from the links, but they are there if you would like to read. Hope they help.

http://www.ncbi.nlm.nih.gov/pubmed?term=(glutathione) AND longevity
 
I appreciate the responses, but no offense to campers and sean, this is exactly the kind of stuff I'm talking about. All one has to do is Google GSH and one's bombarded with very marketing heavy materials about numerous benefits that, in my opinion, seem to fly in the face of accepted science. And campers, I checked out your YouTube page and you're clearly involved in the selling of GSH products. Red flags also go up when I see that you guys joined this site for the express purpose of replying to my thread.

I provided about 15,000 words, which the culmination of researching the topic over a few years and weeks writing it up, which is primarily references from journal articles. I'm not sure how is that marketing heavy? And I took time out of my day to register and provide you with in-depth research from journal articles on the topic instead of the marketing materials you've only found so far.

Yeah I have one affiliate link for the product I take at the end of the 3 posts, and a couple of youtubes from a few years ago before I got hardcore into the research. That's what sparked my interest in it.

I highly recommend this article as a primer on the subject of redox and glutathione.

The redox stress hypothesis of aging.
Free Radic Biol Med. 2012 Feb
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267846/
Presently, the balance of evidence seems to favor the view that the role of structural damage is relatively minor compared to that emanating from the disruptions of the redox-based molecular switches. We have termed this phenomenon “redox stress”, as there are indications of a disturbance in the thiol redox state in the post-reproductive phase of life. Furthermore, transgenic studies have shown that augmentation of reducing power, provided by NADPH and GSH, is the most effective currently known experimental manipulation for the prolongation of lifespan.
Content from External Source
It appears that the human body is perfectly capable of producing all of the GSH that it needs to carry out these functions.
Very true, in most cases, and up until some point, which will be different for everyone. There's many factors effecting the levels and function of glutathione including:
  • Dietary intake
  • Epigenetic modifications,
  • Trans-sulfuration pathway
  • Enzyme activity
  • Common genetic problems
  • Cell surface transporters
That's all covered in the second post, all journal references - no marketing, in the series on my blog.

To get back to your original question of being healthy, an appropriate measure would be your redox state, which is measured in mV.

Here's a couple of journal articles on the topic:

Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826600/
Dean Jones at Emory University was the first to show that human plasma GSH/GSSG is controlled at a relatively constant redox state of −137 mV in 740 healthy adults through age 50 (Jones, 2006). However, an oxidative shift of about 7 mV/decade occurs over the next two decades, followed by a further decline to −110 mV in the 70 to 85-year-old group. ... Other diseases associated with an oxidized plasma glutathione redox state include type 2 diabetes at −110 mV (Samiec et al., 1998) and carotid artery thickening at values more oxidized than −130 mV (Ashfaq et al., 2006).
Content from External Source
Age-related changes of the redox state of glutathione in plasma
http://www.cmj.org/ch/reader/view_abstract.aspx?file_no=2005181560&flag=1
Before the age of 40 years, the Eh(GSH/GSSG) value in blood plasma was kept in a stable level, the Eh(GSH/GSSG) value of 20-29 age group[(-147.3±3.4) mV]was very close to that of 30-39 years age group [(-147.2±3.0) mV], without significant difference between these two groups (P>0.05). But the Eh(GSH/GSSG) value of the other three age groups [(-141.8±3.7) mV, (-139.3±4.9) mV, (-135.9±4.4) mV, respectively] were higher than those of the 20-29 and 30-39 years age groups (P<0.05), which showed that after the age of 40 years, the Eh(GSH/GSSG) value increased with the increase of age, the older the age, the higher the Eh(GSH/GSSG) value.
Content from External Source
Low blood glutathione levels in healthy aging adults.
http://www.ncbi.nlm.nih.gov/pubmed/1431500
These findings demonstrate an increased incidence of low glutathione levels in apparently healthy elderly subjects, who thus may be at risk because of a decreased capacity to maintain many metabolic and detoxification reactions mediated by glutathione.
Content from External Source
Age-related changes in the glutathione redox system.
http://www.ncbi.nlm.nih.gov/pubmed/11835271
GSH levels in groups 1 and 5 [41-69 years old] were significantly lower than the other groups (p<0.001).
Content from External Source
So for the average healthy person perhaps after the age of 40 is a time to consider it.

Maybe earlier for less healthy people. given the prevalence of obesity, diabetes, alcohol consumption etc, it would potentially be a decent chunk of the population.
Evaluation of Blood Plasma Redox Status in Smokers Versus Nonsmokers as a Potential Indicator of ARMD Susceptibility
http://abstracts.iovs.org/cgi/content/abstract/43/12/2821

I only had a coupleof those articles previously bookmarked, the rest are good additions to my research. Cheers for stimulating the research.

Regards,
Daniel
 
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What benefits are claimed for supplementing it?
And what evidence it there that it actually gives those benefits. It all seems rather theoretical. Like: the body needs water, so you should drink more water.

There's a more reasearch articles on PubMed that mention glutathione than you would ever want to read covering virtually all degenerative diseases and even genetic ones such as cystic fibrosis.
A couple of targeted search are
http://www.ncbi.nlm.nih.gov/pubmed/?term=supplemented+nac
http://www.ncbi.nlm.nih.gov/pubmed/?term=nac+reverses
NAC is N-Acetyl-Cysteine which has been the one of most commonly used precursors, but has its limitations.

That's a pretty broad question, there's a heap of info already talking about it at a high level. Happy to answer more specific questions.
 
Not evidence that it might. Evidence that it does. Like a study of actual changes in health from people taking it vs. people not taking it.
 
Here's a few from this year. Are any of these along the lines of what you're after?

N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress.
http://www.ncbi.nlm.nih.gov/pubmed/23993974
Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera

Effect of N-acetylcysteine on Cycling Performance following Intensified Training.
Med Sci Sports Exerc. 2014 Feb
CONCLUSION:
Oral NAC supplementation improved cycling performance via an improved redox balance and promoted adaptive processes in well-trained athletes undergoing strenuous physical training.


Combination of N-acetylcysteine, α-lipoic acid and α-tocopherol substantially prevents the brain synaptosomal alterations and memory and learning deficits of aged rats.
Exp Gerontol. 2014 Feb
http://www.ncbi.nlm.nih.gov/pubmed/24291247
These age-dependent changes in synaptosomal parameters are prevented markedly in the antioxidant supplemented group. When examined on T-maze, the aged animals are noticeably impaired in learning and memory functions, but the deficit is remarkably prevented in the antioxidant supplemented aged animals.


N-acetylcysteine supplementation decreases osteoclast differentiation and increases bone mass in mice fed a high-fat diet.
J Nutr. 2014 Mar
http://www.ncbi.nlm.nih.gov/pubmed/24381219
These results show that NAC supplementation increases the bone mass of obese mice induced by an HF diet through elevating glutathione status and decreasing bone resorption.
 
I have seen other human studies, not always easy to search through to find the ones you want. Most of the research is like the following two

Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIV-infected patients.
J Clin Endocrinol Metab. 2014 Jan;
"This work identifies 2 novel findings in older HIV-infected patients: 1) diminished synthesis due to decreased availability of cysteine and glycine contributes to GSH deficiency and can be rapidly corrected by dietary supplementation of these precursors and 2) correction of GSH deficiency is associated with improvement of mitochondrial fat and carbohydrate oxidation in both fasted and fed states and with improvements in insulin sensitivity, body composition, and muscle strength."


Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine.
Diabetes Care. 2011 Jan
CONCLUSIONS:
Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.
 
N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress.
Yeah I don't know what that means. What benefits does this result in? Just a vague improvement in wellbeing? Super-strength? Less wrinkles?
 
Yeah I don't know what that means. What benefits does this result in? Just a vague improvement in wellbeing? Super-strength? Less wrinkles?

Depends on the person. Some people take GSH supps and don't notice anything (not to say things aren't happening which can be measured with a blood test). I've met and heard from plenty of people who have had significant improvements in health. For the average person common benefits can be increased energy, better sleep, improved mental clarity, faster recovery. Looking at the data at a bio-chemistry level indicates there is a longevity/anti-aging effect.
 
Seems kind of expensive. Why wouldn't I just take ginseng which is cheaper and has similar claimed general benefits?

It also seems taking direct supplements is not necessarily very effective, but it can be boosted indirectly through cheaper supplements.


Raising GSH levels through direct supplementation of glutathione is difficult. Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract. In a study of acute oral administration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found "it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione."[26][27] However, it is possible to increase and maintain appropriate glutathione levels by increasing the daily consumption of cysteine-rich foods and/or supplements.[non-primary source needed][28]

Calcitriol (1,25-dihydroxyvitamin D3), the active metabolite of vitamin D3, after being synthesized from calcifediol in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.[29] Calcitriol was found to increase GSH levels in rat astrocyte primary cultures on average by 42%, increasing protein concentrations from 29 nmol/mg to 41 nmol/mg, 24 and 48 hours after administration; this effect was reduced to 11%, relative to the control, 96 hours after administration.[30] It takes about ten days for the body to process vitamin D3 into calcitriol.[31]

Other supplements, including S-adenosylmethionine (SAMe)[32][33][34] and whey protein[35][36][37][38][39][40] have also been shown to increase cellular glutathione content.

N-acetyl cysteine (NAC) is available both as a drug and as a generic supplement, and has positive effects on glutathione production. Alpha lipoic acid restores intracellular glutathione.[41][42] Melatonin stimulates a related enzyme, glutathione peroxidase.[non-primary source needed][43]
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$55 60 caps Glutathione.
Vitamin D3, $12 for 60 caps.
N-Acetyl Cystiene $40 120 caps.
Ginseng 4000 $22 50 caps
 
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You also have to consider the magnitude of these benefits. The general benefits are pretty vague and the end result of improvement of definable and measurable cellular functions, which is what I'm interested in. The other question is any amount of ginseng is going to make up for an intra-cellular deficiency in the amino acid cysteine, if you have one, and the implications of that.
 
Just checking, was that a statement or a question?
eg.
"The other question is, is any amount of ginseng going to make up..."?

Or,

"any amount of ginseng *is* going to make up..."?
 
Sorry, I had an extra 'is' in there, it was a questions. Is any amount going to make up?..

I should clarify when I say glutathione supplements, I don't mean one which just have the actual glutathione molecule which as you rightly pointed out have been shown to be ineffective. I'm referring to cysteine pro-drugs (such as N-Acetyl Cystiene or Ribose-Cystine), liposomal glutathione or S-Acetyl-Glutathione.

These provide the limiting building block which is cystine.

Some of the things you mentioned can increase cysteine supply by improving the flux through the trans-sulfuration pathway, which converts the one other sulphur containing amino acid, methionine, into cysteine.

The other way they increase glutathione is by increasing the enzymes required to synthesize it (via activation of the Nrf2 pathway) but at some point you need more of the building blocks. Particularly if you are losing cysteine/glutathione through detoxification. Glutathione conjugation (binding) is one of the primary detoxification pathways in liver and also every cell (important for protecting DNA). It binds to toxins (which requires another glutathione enzyme) so they can be excreted from the body, which means you're losing cysteine/glutathione for every detoxified molecule.

You'd need to look at some studies to determine the measurable benefits to work out what is more cost effective. Like the old saying, buy cheap, buy twice. Unfortunately not an easy task to find comparable studies. www.examine.com is a relatively new site which has quite good write ups on many different supplements referencing lots of journal articles.
 
There's a more reasearch articles on PubMed that mention glutathione than you would ever want to read covering virtually all degenerative diseases and even genetic ones such as cystic fibrosis.
A couple of targeted search are
http://www.ncbi.nlm.nih.gov/pubmed/?term=supplemented nac
http://www.ncbi.nlm.nih.gov/pubmed/?term=nac reverses
NAC is N-Acetyl-Cysteine which has been the one of most commonly used precursors, but has its limitations.

That's a pretty broad question, there's a heap of info already talking about it at a high level. Happy to answer more specific questions.
You need to cite some papers that actually discus the benefits of taking glutathione supplements. Neither of the papers you used as examples actually does this. Examining the effects of precursor chemicals is not the same thing as studying the effects taking gluthione as a supplement. Saying gluthione is mentioned in a large number of papers on Pubmed means nothing in terms of effectiveness as a supplement. Mice are mentioned in a lot of papers on Pubmed as well - that doesn't make the health supplements.

I have a lot of questions. For instance how is the supplemental gluthione administered? If it is administered orally what effect does a trip through the gastric system have on it? Are there any double blind studies that examine gluthione's effectiveness as a supplement and don't just mention it as part of the discussiob? Cant you refer us to them?

Edit:
I was writing this while you made your last post. I'll check the website you referred to.
 
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Using http://examine.com/ the only term I found specifically listed was N-Acetyl Cystiene. I read the abstracts for the papers and N-Acetyl Cystiene seems to have some fairly specific applications: Treatment of addiction and exposure to lead. I can't find anything in the studies that would support using it as a general health supplement. Even the web site points out there is no scientifically robust evidence for any of the claims.
 
As I understand it, Glutathione levels are regulated by the liver. Thus one may have a deficiency but surely any excess will be excreted? Also there are many many compounds that are antioxidants, like Vitamin C, what makes this unique?
 
For the average person common benefits can be increased energy, better sleep, improved mental clarity, faster recovery. Looking at the data at a bio-chemistry level indicates there is a longevity/anti-aging effect.

It's only things like this that I have a problem with. Again, I understand using a supplement to correct for a deficiency or other ailment, but it seems pointless for an average person to take it. Anecdotes of better energy, sleep, etc. don't provide anything useful. Another thing is that looking at biochemistry in-vitro could be significantly different than how the protein will function in-vivo. It's reasonable to say that correcting for a metabolic deficiency could lead to a longer life but it is tough to say with confidence that that is what is happening. Are there any clinical trials that have tested the efficacy of glutathione as a longevity enhancer?
 
Saying gluthione is mentioned in a large number of papers on Pubmed means nothing in terms of effectiveness as a supplement. Mice are mentioned in a lot of papers on Pubmed as well - that doesn't make the health supplements.
I didn't say anything about it's effectiveness, I only meant to point out there is plenty of research to comb through to come to your own conclusions. More than I can possibly look through that may have the answers to your questions.

Note on the examine.com page for NAC it said "This page on N-Acetylcysteine is currently marked as in-progress. We are still compiling research."

A quick search on PubMed shows positive human studies for lupus, obstructive pulmonary disease and Crohn's disease on page 1 of 109

"CONCLUSION:This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes."
"Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity."
"This study suggests that compounds able to maintain GSH/GSSG ratio to physiological values can be useful to restore normal MMP-2 levels reducing in CD patient intestine the dysfunction of epithelial barrier."


It's only things like this that I have a problem with. Again, I understand using a supplement to correct for a deficiency or other ailment, but it seems pointless for an average person to take it. Anecdotes of better energy, sleep, etc. don't provide anything useful. .. Another thing is that looking at biochemistry in-vitro could be significantly different than how the protein will function in-vivo
The person who asked that question just wanted a real simple answer, so I gave it to them ("Yeah I don't know what that means. What benefits does this result in?"), so give me a break :)

There are plenty of in-vivo studies. Also the core glutathione system is highly conserved, ie hasn't really changed from yeast to human. When you go a bit a higher, eg Situins, mTor then things do start changing a bit between higher level species, and makes studies manipulating these effects of these even more difficult to extrapolate to humans.

Now I think throwing around PubLinks is going to be bit of a dead end at this point, unless someone else would like to volunteer their time finding specific articles which prove/disprove the particular questions.

The perfect longevity human trial in healthy people doesn't exist, that I know of, I'll be the first to admit defeat there, and probably isn't going to for a very long time. We live too long! Which makes it very expensive, and then there's issue with the data because people aren't good at sticking to a rigid protocol and there's inaccuracies in self reporting. And research money isn't usually given for studies on healthy people. That's why mice/rats studies are particularly useful to test out theories as we slowly unravel the intricacies of it all. The scientific community is slowly building their understanding of the finer points so hopefully one day there can be a very well designed human study based on the lastest bio-chem knowledge. The really interesting studies I like at this point are when they genetically engineer a series of rats knocking out one protein/enzyme at time so they can determine the true cause/effect. While this human study everyone wants could give a simple answer, and I'd love to see one too, it doesn't necessarily provide the WHY and an understanding on where to go next.

For example, recently there was a big buzz how C60 buckyballs in evo oil ~doubled the lifespan of rats. Some people are taking it, but how it works is very much unknown. Even though it *doubles* rat lifespan, would you take it??

Now if you had the big bucks, tens of millions of dollars I'm guessing at lest for a long term study if not hundreds. And many willing participants (ideally identical twins separated into control and test groups) to follow a strict regime. Now if you want to start with healthy people, and from my previous posts on plasma redox state, the youngest you would want your participants is the age of 40. To follow then till a significant amount have passed would be another 40 years. What are you going to do in the meantime?

You could aim to be like the Stanford University professor Andrei Linde. He was in the news last week about new gravitational field data validating the (big bang) inflationary theory he developed from research and inference - 30 years ago.

I've tried to provide the current state of knowledge on the topic.

The perfect data we would ideally like isn't there yet, so moving forward the question is What are valid inferences we can agree on from the existing data?

"Inference (n): a conclusion reached on the basis of evidence and reasoning."

If A proves B and B proves C, what can we say about A and C?

Low GSH strongly correlates to increased susceptibility and progression of many chronic conditions. (Bulk PubMed articles on this)
Increasing GSH reverses the problematic bio-markers in many chronic conditions. (A handful already provided above for starters)
GSH precursors and other delivery technologies are able to raise glutathione levels and restore redox homoeostasis ie GSH/GSSG (A handful already provided above for starters)
for some basic starters.

Some other key questions to answer/consider:
If a supplement can reverse parameters of a chronic condition in the short term, how can that relate to reducing the persistent ongoing accumulation over years of damage ('aging') which leads to these chronic conditions (ie have an 'anti-ageing' effect).
What doses are optimal? Everything has a dose-response curve, which sometimes results in conflicting results in studies. Too much of most vitamins will have a negative effect. You can drink enough water to kill yourself.
What is "healthy". Give me a measurable definition. And not how you 'feel'. Which parameters are important? This is a topic in its own right, and to be able to answer this means we can do much more useful shorter term human studies. I've proposed plasma redox state as a useful one, esp in relation to GSH supps.

To make good inferences requires some substantial knowledge in the field, it is freaking complex. Again have a read through my blog posts which were a big labour of love at http://danielcampagnoli.com/redox-gsh-cysteine-1 to get some background information required to develop your own inferences. This discussion will be useful in completing the half-finished 3rd part where I go into supplementation options and answering the difficult questions!

As I understand it, Glutathione levels are regulated by the liver. Thus one may have a deficiency but surely any excess will be excreted? Also there are many many compounds that are antioxidants, like Vitamin C, what makes this unique?
Yes, glutathione levels are tightly homeostatically controlled. There are tight feedback mechanisms to maintain the optimal levels by reducing synthesis, and excess can be broken down an enzyme, GGT I think, or exported from the cell.

The liver has one of the highest concentration of GSH. Up to 50% of the anti-oxidant capacity is from GSH. It synthesises it and then releases it into the blood stream. GSH levels are also high in organs such as the kidneys and eyes, which are under more stress from UV and detoxification.

For what makes it unique, I'll have to refer you to this article (and the quote from it further below)
The redox stress hypothesis of aging.
Free Radic Biol Med. 2012 Feb
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267846/
"In summary, manipulating the expression of genes with antioxidant function that have little or no impact on redox state, such as SOD and catalase, confers minimal effects on longevity when tested in a robust genetic background. In contrast, modulating the expression of genes that directly impact cellular redox status, such as glutamate-cysteine ligase, G6PD and peroxiredoxins can significantly extend life span in long-lived backgrounds. Conversely, in one instance, underexpression of such gene products not only resulted in a rapid onset of redox stress, as measured by GSH/GSSG ratios, but also gave rise to an apparent rapid aging phenotype."

There has been a number of studies disproving the free radical theory of aging and indiscriminate high quantity anti-oxidant usage as it interferes with the hormetic stress response, ROS signalling etc

So I'm wrapping it up for me on this thread, I hope I have provided new information, references and food for thought to continue your own research and reach your own conclusions.

Are there any clinical trials that have tested the efficacy of glutathione as a longevity enhancer?
You didn't specify human studies in that sentence so I'll finish with this :)
"Furthermore, transgenic studies have shown that augmentation of reducing power, provided by NADPH and GSH, is the most effective currently known experimental manipulation for the prolongation of lifespan."
- The redox stress hypothesis of aging. Free Radic Biol Med. Feb, 2012


Regards,
Daniel
 
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If you admit the benefits are vague and you can't vouch for the effectiveness, then what are you saying? What is your claim?
Campers has referenced tens of thousands of words...many of which seem intended to overwhelm and obfuscate...
but the ones that keep coming back to mind are "I have one affiliate link for the product..."

Now, he seems like a genial enough guy, and--after all--he did "take time out of his day to register and provide us with in-depth research..."
but my question remains: if glutathione is genuinely as promising as Campers says, why is there no straightforward statement from
a credible source
that says as much? Why the need for such a gigantic, impenetrable pile o' vagueries?
 
Those who are taking it should keep records and be having DNA tests every year, or testing of whatever area it is the benefits would show in. 5 years should be sufficient to note improvement.

I don't think there's any intent to obfuscate, but it seems that it's an area that hasn't really been studied enough yet, or that it is so much a part of complex systems and interactions that a concrete cause and effect is very hard to find.
 
Those who are taking it should keep records and be having DNA tests every year, or testing of whatever area it is the benefits would show in. 5 years should be sufficient to note improvement.
I've just been taking it for 3.5 years...seems pretty good so far
(though I have had mild paranoia that there's always a white guy right behind me)

Screen Shot 2014-03-22 at 5.47.05 PM.png
 
I didn't say anything about it's effectiveness, I only meant to point out there is plenty of research to comb through to come to your own conclusions. More than I can possibly look through that may have the answers to your questions.

Note on the examine.com page for NAC it said "This page on N-Acetylcysteine is currently marked as in-progress. We are still compiling research."

A quick search on PubMed shows positive human studies for lupus, obstructive pulmonary disease and Crohn's disease on page 1 of 109

"CONCLUSION:This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes."
"Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity."
"This study suggests that compounds able to maintain GSH/GSSG ratio to physiological values can be useful to restore normal MMP-2 levels reducing in CD patient intestine the dysfunction of epithelial barrier."

If you are not advocating for the effectiveness of NAC what are you trying to do? Yes the examine.com website does say that they are still compiling research but you chose to use it as a reference in your arguments so you have to own all the contents of the page. The applications are targeted and right now they don't consider the evidence for any application to be scientifically robust.

I looked through the first three pages of the Pubmed search you did "N-Acetylcysteine patients" and the studies either refer to specific applications or discuss how the chemical behaves in the body. So I tried my own search using the terms "N-Acetylcysteine diet supplement". This produced a much smaller body of research (three pages) http://www.ncbi.nlm.nih.gov/pubmed/?term=N-Acetylcysteine diet supplement. These studies either include it as look at the effects of antioxidants in general or discuss targeted applications. None of these support the taking NAC as a dietary supplement by healthy individuals and there was nothing to support this statement:
For the average person common benefits can be increased energy, better sleep, improved mental clarity, faster recovery. Looking at the data at a bio-chemistry level indicates there is a longevity/anti-aging effect.
If you are going to make this claim then you need to be ready to produce the specific studied proving it rather than point to a large number of targeted unrelated studies and citing the transitive property as proof. Similarly this statement:
Depends on the person. Some people take GSH supps and don't notice anything (not to say things aren't happening which can be measured with a blood test). I've met and heard from plenty of people who have had significant improvements in health.
You accept the claims of people that reinforce your opinion without question. If you are going to dismiss people when they tell you it produces no benefits by claiming the results can be measured with blood test then you need to be able to produce some blood test as evidence. If you can't you have to accept their claims that the supplement has no effect as well and consider that the people telling you the news you want hear may be benefiting from the placebo effect.

If you are not willing or are unable to do that then you may very well be guilty of spreading woo.
 
Campers has referenced tens of thousands of words...many of which seem intended to overwhelm and obfuscate...
but the ones that keep coming back to mind are "I have one affiliate link for the product..."
You're still hung up on that? Yawn. In terms on monetary ROI, doing all that writing and research was a fat waste of time. I would have been far better off writing a direct-response marketing piece (the marketing heavy ones you wouldn't like), run paid ads and split test the ad copy, headlines etc to optimize conversions. The day job pays more than enough, this is more of an intellectual pursuit, and for my own health. And if it overwhelms you then you'll need to learn more on the subject. I've had a number of complements on the research I've put together there.

If you admit the benefits are vague and you can't vouch for the effectiveness, then what are you saying? What is your claim?
I mean things like improved energy. better sleep, slowing aging aren't very measurable ways of describing its benefits. They are emergent secondary results which are more subjective. If I say the benefits include maintaining cellular redox homoeostasis then peoples eyes glaze over. Sure I'll vouch for it's effectiveness, I noticed a difference and could provide plenty of what you would call anecdotal data ie testimonials, from family and friends to high-profile people you would know of.

So I tried my own search using the terms "N-Acetylcysteine diet supplement"
Excellent!!! good to hear someone has done their own search on PubMed. You don't need me anymore. I don't actually advocate NAC.

If you are going to dismiss people when they tell you it produces no benefits by claiming the results can be measured with blood test then you need to be able to produce some blood test as evidence. If you can't you have to accept their claims that the supplement has no effect as well and consider that the people telling you the news you want hear may be benefiting from the placebo effect.
I'm not dismissing them, different people notice different things, its harder to quantify. The benefits are why I have people loving the product. As for the blood tests here's one http://danielcampagnoli/files/GXLAbstract.pdf


I don't think there's any intent to obfuscate, but it seems that it's an area that hasn't really been studied enough yet, or that it is so much a part of complex systems and interactions that a concrete cause and effect is very hard to find.
Thank you Pete.


but my question remains: if glutathione is genuinely as promising as Campers says, why is there no straightforward statement from a credible source that says as much?
Would this guy be a credible enough source?

Dr. Nagasawa received his B.S. degree in chemistry from Western Reserve University (now, Case-Western Reserve) in Cleveland, Ohio, and a Ph.D. degree in organic chemistry from the University of Minnesota. Subsequently, he spent two years as a Post-doctoral Fellow in biochemistry at the University of Minnesota before joining the research staff of the V.A. Medical Center in Minneapolis as a Senior Chemist. He was appointed Assistant Professor of Medicinal Chemistry at the University of Minnesota in 1959. He was named Principal Scientist of the VAMC in 1961 and was promoted in 1976 to Senior Research Career Scientist, a nationwide VA title reserved for the VA's top scientists. He was promoted to Associate Professor in 1963 and to Professor of Medicinal Chemistry in 1973.

He also held joint professorships in the Department of Pharmacology and the university-wide Division of Toxicology, and served as Visiting Professor at Washington State University in 1990. He also served for 32 years as a Senior Editor for the prestigious international Journal of Medicinal Chemistry from 1972 to 2004, and one year as Acting Editor-in-Chief. In addition, he served on the Editorial Board of the journal, Bioconjugate Chemistry for eight years, and as an ad hoc grant reviewer for the NCI and NIAAA, National Institutes of Health. He has published over 165 papers in peer-reviewed journals. In June of 2010, Dr. Nagasawa and his team attended the National Institutes of Health-Homeland Security 4th Annual Countermeasures Against Chemical Threats Network Symposium to present their work on the cyanide antidote.
 
Low GSH strongly correlates to increased susceptibility and progression of many chronic conditions. (Bulk PubMed articles on this)
Increasing GSH reverses the problematic bio-markers in many chronic conditions. (A handful already provided above for starters)
GSH precursors and other delivery technologies are able to raise glutathione levels and restore redox homoeostasis ie GSH/GSSG (A handful already provided above for starters)
for some basic starters.

I understand and can agree with that. As I said in my previous post, it makes sense that restoring normal levels of these proteins could correct for debilitating deficiencies and ailments.

If a supplement can reverse parameters of a chronic condition in the short term, how can that relate to reducing the persistent ongoing accumulation over years of damage ('aging') which leads to these chronic conditions (ie have an 'anti-ageing' effect).
What doses are optimal? Everything has a dose-response curve, which sometimes results in conflicting results in studies. Too much of most vitamins will have a negative effect. You can drink enough water to kill yourself.
What is "healthy". Give me a measurable definition. And not how you 'feel'. Which parameters are important? This is a topic in its own right, and to be able to answer this means we can do much more useful shorter term human studies. I've proposed plasma redox state as a useful one, esp in relation to GSH supps.

All important questions that I would ask as well. "Healthy," at least in this case, would just mean not in an obvious place to benefit from the supplement. No diagnosed or measurable diseases or deficiencies.


You didn't specify human studies in that sentence so I'll finish with this
"Furthermore, transgenic studies have shown that augmentation of reducing power, provided by NADPH and GSH, is the most effective currently known experimental manipulation for the prolongation of lifespan."
- The redox stress hypothesis of aging. Free Radic Biol Med. Feb, 2012

Clinical trial by definition means human studies. Transgenic studies can be extremely powerful in demonstrating the molecular mechanism of a particular disease via a single gene. They always, however, need to be supplemented (hah, see what I did there?) with data from humans in order to be solidified as useful in humans. For example, if proteins are shown to aggregate in yeast when a particular gene is mutated/knocked out and the same aggregates are found in the tissue of diseased human subjects who have the same mutant gene, then that provides pretty strong evidence of a causal link. But in this case, there are no such model organism to human links and there are many factors that work together to influence longevity. Metabolism, resistance to stress, gene dysregulation, and genetic stability all influence the length of our lives. Humans are more complex than the model organisms we use in labs, so it is hard to say how common and effective an increased longevity associated with intake of supplements will be. This is because the system is so complex and the field is relatively young.

It makes sense and we can infer that supplements could, in the right conditions, help increase the longevity of an individual's life. This, however, is where I draw the line and say that I, personally, would not recommend it as a general health tip to the public because we don't know the whole story yet. The advice I would give is to talk to a doctor and see if there is any reason (disease or deficiency) that would suggest any room to benefit from the supplement.
 
I noticed a difference and could provide plenty of what you would call anecdotal data

Wouldn't you also call testimonials from friends and family anecdotal data? I'm sure they are good people, but testimonials in general are prone to biases that make them very dubious sources of evidence. For instance, I know plenty of friends, family and high-profile people that will swear under oath that Glenmorangie gives them energy and makes them sleep better. You could have saved yourself a lot of time and words by just researching the scientific value of anecdotes.

gm1.jpg

What appears to be happening here is that on the one hand you're claiming your product has demonstrable effects, and on the other hand you're claiming the effects are hard to demonstrate, all the while making up excuses for why science can't validate your vague claims.
 
Thanks for your replies Dan Wilson.

What appears to be happening here is that on the one hand you're claiming your product has demonstrable effects, and on the other hand you're claiming the effects are hard to demonstrate, all the while making up excuses for why science can't validate your vague claims.
My point was
- the only thing glutathione supps claim, or should claim, is to raise GSH levels.
- here's some science on the current state of knowledge of GSH, redox, supp options etc
- the subjective benefit (demonstrable effect) of raising glutathione levels will vary person to person, and very possibly will be nothing, more so the more healthier you are (already have optimal glutathione).
- if you don't get any demonstrable effect then don't bother spending any more money on it
That's all.
Anyone can always do the study that really counts if they care to. Sample size N=1. Yourself.

Why not? Isn't that the form the body converts into glutathione most efficiently, whereas the pure substance itself has poor uptake?
I take a different cysteine pro-drug
 
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Anyone can always do the study that really counts if they care to. Sample size N=1. Yourself.

This is absolutely wrong. Relying on one's own anecdotes is just as unreliable as relying on somebody else's. We're all prone to the same biases. Science based medicine is the mechanism that removes these biases and bases it's conclusions on facts.

if you don't get any demonstrable effect then don't bother spending any more money on it
That's all.

I've got a better idea, first show me it works, then maybe I'll spend money on it. If my physician tells me it's safe and beneficial to do so.
 
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This is absolutely wrong. Relying on one's own anecdotes is just as unreliable as relying on somebody else's. We're all prone to the same biases. Science based medicine is the mechanism that removes these biases and bases it's conclusions on facts.
With blood tests of course. Is that what you mean by "works"?

Well that's going to be quite subjective too, depends which physician you go to. Mine barely knew what glutathione is. "something to do with the liver?" was his response.
 
If there is no evidence that taking it is a net benefit, the "try it and see if you like it" is just silly.

Taking it as a general health supplement seems nothing more than modern snake oil. And nothing more than the vast array of existing supplements that people can buy on the internet. And really nothing more than folk remedies, like "drink eight glasses of water a day"
 
With blood tests of course. Is that what you mean by "works"?

By "works" I mean: show me it does whatever you claim it's supposed to do. Show me it gives longer life, better sleep, general well being or whatever.

Well that's going to be quite subjective too, depends which physician you go to. Mine barely knew what glutathione is. "something to do with the liver?" was his response.

Ya, that's funny. He may not have known what glutathione is or does, but he is be better able to evaluate glutathione than you, your friends, family and high-profile people.
 
You're still hung up on that? Yawn. In terms on monetary ROI, doing all that writing and research was a fat waste of time. I would have been far better off writing a direct-response marketing piece (the marketing heavy ones you wouldn't like), run paid ads and split test the ad copy, headlines etc to optimize conversions. The day job pays more than enough, this is more of an intellectual pursuit, and for my own health. And if it overwhelms you then you'll need to learn more on the subject. I've had a number of complements on the research I've put together there.


I mean things like improved energy. better sleep, slowing aging aren't very measurable ways of describing its benefits. They are emergent secondary results which are more subjective. If I say the benefits include maintaining cellular redox homoeostasis then peoples eyes glaze over. Sure I'll vouch for it's effectiveness, I noticed a difference and could provide plenty of what you would call anecdotal data ie testimonials, from family and friends to high-profile people you would know of.


Excellent!!! good to hear someone has done their own search on PubMed. You don't need me anymore. I don't actually advocate NAC.


I'm not dismissing them, different people notice different things, its harder to quantify. The benefits are why I have people loving the product. As for the blood tests here's one http://danielcampagnoli/files/GXLAbstract.pdf



Thank you Pete.



Would this guy be a credible enough source?

Dr. Nagasawa received his B.S. degree in chemistry from Western Reserve University (now, Case-Western Reserve) in Cleveland, Ohio, and a Ph.D. degree in organic chemistry from the University of Minnesota. Subsequently, he spent two years as a Post-doctoral Fellow in biochemistry at the University of Minnesota before joining the research staff of the V.A. Medical Center in Minneapolis as a Senior Chemist. He was appointed Assistant Professor of Medicinal Chemistry at the University of Minnesota in 1959. He was named Principal Scientist of the VAMC in 1961 and was promoted in 1976 to Senior Research Career Scientist, a nationwide VA title reserved for the VA's top scientists. He was promoted to Associate Professor in 1963 and to Professor of Medicinal Chemistry in 1973.

He also held joint professorships in the Department of Pharmacology and the university-wide Division of Toxicology, and served as Visiting Professor at Washington State University in 1990. He also served for 32 years as a Senior Editor for the prestigious international Journal of Medicinal Chemistry from 1972 to 2004, and one year as Acting Editor-in-Chief. In addition, he served on the Editorial Board of the journal, Bioconjugate Chemistry for eight years, and as an ad hoc grant reviewer for the NCI and NIAAA, National Institutes of Health. He has published over 165 papers in peer-reviewed journals. In June of 2010, Dr. Nagasawa and his team attended the National Institutes of Health-Homeland Security 4th Annual Countermeasures Against Chemical Threats Network Symposium to present their work on the cyanide antidote.
Seriously? You typed "Yawn" to address the issue of possible financial conflict of interest? Should I type "OMG! You so totally did not go there!" in response?

I'm presuming you are referring to Dr. Herbert Nagasawa (as it's his credentials you seem to have lifted verbatim from a website set up to sell Glutathione)...
honestly it's hard to find much on this legendary doctor--there is no Wikipedia page on him--since the overwhelming majority of search results are...again, attempts
to sell glutathione.

Let's re-focus on the point of the thread: "Is there legit science behind GSH supplementation for healthy individuals?"

I asked (in post #27) "if glutathione is genuinely as promising as Campers says, why is there no straightforward statement from a credible source that says as much?"

I guess I should have been more specific: I was not looking for an individual, as we all know that individuals sometimes endorse things for less-than-stellar reasons:
perhaps they're older and have lost their edge...perhaps the lure of money bends one's opinions or standards. Such dubious endorsements
(celebrity and otherwise) are a dime a dozen.
So I was hoping for an institution, (hospital, respected research facility, Mayo Clinic, AMA, WebMD, etc.) I have done some looking, and do not see any such institutions
recommending supplementation for healthy individuals. Okay, given that we have an individual, a retired professor, who is getting paid to endorse this stuff, where is the

"straightforward statement" from this financially compensated source, that healthy people will benefit from glutathione supplements?

I think it would be wonderful if average humans enjoy superior health merely by adding glutathione to their medicine cabinet.
Trying to find credible, unbiased evidence to that end, at this point, seems unfruitful.
 
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