The Controversy of Antioxidants

[Wishful]

because on paper, as they say, it looks really promising

Yup, that's the real issue. Lots of things "look good on paper", but fail in real life. Aircraft manufacturers don't invest billions in a production line based on a nice drawing. They run simulations, test scale models, etc, first. For biology, computer simulations are less useful, since there's still so much we don't know about what needs to be in the simulation. Likewise, in vitro tests may not apply to the real body, since the test tube lacks the regulatory mechanisms that work in blood vessels, and other such factors.

Large-scale human trials are better for basing "Should I take this?" decisions on. I don't care whether there wasn't any theory to explain why durian-flavoured jellybeans cured ME; if they cured ME in 789/1000 patients, I'd definitely order some for myself. Trials aren't perfect, but they're better than overly simplistic theories.

Antioxidants as anti-ageing treatments "looked good on paper" too. The large scale trials showed that they weren't, and that they reduced lifespan slightly. That doesn't prove than all claims for benefits from antioxidant supplements are false, but it certainly makes me a bit cautious about believing other claims that are based only "on paper" too.

 

[YippeeKi YOW !!]

That doesn't prove than all claims for benefits from antioxidant supplements are false, but it certainly makes me a bit cautious about believing other claims that are based only "on paper" too.

Right there with you .....

Sometimes I really miss the distant days when it never occurred to me that:

• A well-known, 'respected' company selling a supplement or medication that's supposed to be beneficial would actually put their profits above my health, or even, in extreme cases, my life, or....
• That Drs weren't genuine healers with only my health and well-being at heart .... I know, I know ..... there's a tiny handful that still are, and I treasure every one of them even if I may never manage to find one, but I'm talking about what most of us are given to deal with, or....
• That politicians could nod and smile and nod and smile, and take away the funding for shelters for the poor and hot school meals for impoverished children who would otherwise never have one ....

The world was a sweeter, happier place for me.

And infinitely more dangerous .... Pollyanna Prancing Thru the Bear's Lair ....

Oscar Wilde famously said, and I'm infamously misquoting here: "Scratch any cynic and you'll find the dying heart of a romantic underneath...."

 

[JES]

Have you ever tried to titrate to bowel tolerance?

I was attempting liposomal and regular vitamin C a couple of years ago when I found a paper showing high doses (mainly IV) could reduce EBV titers in blood. The experiment failed because of the mentioned increase in inflammatory symptoms and a secondary problem, kidney pain developing from what I assume is oxalate issues. My tolerance of medications and supplements have gone down since, so it would be a bit tricky to even attempt 500 mg of Vitamin C it now. I can affirm what your link mentioned, when I was sick with an acute cold I could easily tolerate a higher dose.

 

[gbells]

From ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/ )

In other words, they don't know whether glutathione supplementation actually does anything useful for most people. As with antioxidants, simplistic theories don't necessarily apply to human health. I think this needs a properly run large scale study on measurable health indicators.

Wishful,

One glutathione study you cited was for 2014 for oral glutathione. It is well known that this form isn't absorbable and isn't what I was referring to. Only reduced (L-glutathione) and acetyl-glutathione are absorble and were suggested. As previously mentioned, cells lose their ability to synthesize glutathione with age. Cells have bidirectional glutathione transporters but I am not sure whether the plasma concentrations during oral dosing are high enough to activate them to uptake it into the cell. There are two strategies to increase glutathione, supplement precursors (NAC, L-cysteine, SAM-E or supplement the absorbable forms and meditation (raises glutathione 20%). The precursors don't make up for lowered glutathione syntheis so they won't do anything for adults. I'm going to assume that cellular uptake from the transporters is minimal however Bellatori states that the cells make a lot of glutathione to be excreted into plasma as a buffer against environmental oxidation damage.(1)

Increased plasma oral glutathione would make up for the slowing production and allow the smaller amounts of natural glutathione to be conserved in the cell. Glutathione has a half-life of six hours (12 hours to be used up). I have tested glutathione using my appetite and found that it does need to be dosed twice daily which is consistent with the half life and suggests that it is staying in the plasma. So I think that it is a useful buffer to reduce the amount of intracellular glutathione needed so that the aging production deficit can be compensated for.

References

1. Ballatori N, Krance SM, Marchan R, Hammond CL. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med. 2009;30(1-2):13-28. doi:10.1016/j.mam.2008.08.004

2. -Bidirectional Mechanism of Plasma Membrane Transport of Reduced Glutathione in Intact Rat Hepatocytes and Membrane Vesicles. Carmen Garcia-Ruiz. THE JOURNAL OF BIOLOGICAL CHEMISTRY 0 1992 by The American Society for Biochemistry and Molecular Biology, Inc. Val. 267, No. 31, Issue of November 5, pp. 22256-22264,1992

 

[Wishful]

@gbells , have you encountered any properly done trials that show measurable improvements in health from taking supplemental glutathione? Studies about transporters and cellular levels might be interesting, but given the complexity of the body, they don't say much about actual health effects from taking supplements. Some people might notice a benefit, but possibly not due to any of the theoretical mechanisms known.

At this point, I'm not even tempted to try glutathione based on vague theories for why it might be beneficial. Antioxidants usually make my ME worse, so I don't really want to spend money for things I expect to make me feel worse.

As far as dietary supplements are concerned, I expect that nutrients I'm sensitive to the level of should show up as fluctuations in my symptom severity when I alter my diet. I spent more than a year eating mainly cornstarch, and didn't notice any changes in my ME from that, even though I was probably getting close to deficiencies in some nutrients. Switching back to a more varied diet didn't make a difference either, so from that I conclude that my ME just isn't very sensitive to nutrient levels.

 

[gbells]

@gbells , have you encountered any properly done trials that show measurable improvements in health from taking supplemental glutathione?

Do you understand what it does? It is the master antioxidant of the blood plasma. Deplete it and you're on the fast track for wrinkles and cancer. I don't need a study to know that replacing something my body used to make is a good idea.

 

[gbells]

I made a mistake. I listed my dosing for nicotinamide ribose (BID now at 10 mg) instead of the adenyl glutathione. My appetite for adenyl glutathione is only one pill every 3 days which is very low.

 

[gbells]

(sic acetyl glutathione)

 

[Pyrrhus]

This is a great thread, @Wishful , Thanks for starting it.

the level of antioxidants in the body are carefully regulated;

That's a key point. For example, for a cell to be able to divide, it must go through a pro-oxidant stage where the body's natural antioxidants are temporarily suppressed. Once the cell division is complete, the body's natural antioxidants are re-activated.

A quick googling showed plenty of papers about the controversy, with the common conclusion being "We don't know how much is good for you."

Just don't assume that "more is better".

High doses of supplemental antioxidants are generally anti-inflammatory. Whether "anti-inflammatory" is what you actually want depends upon the specific health status of the individual. Remember that inflammation is usually a good thing, as it means the immune system is doing its job. (But even when inflammation is a good thing, it still can make you feel like crap.)

Something labelled as an antioxidant might help you by altering your gut microbiome, or it might alter reaction rates of some protein or whatever.

Very few supplements that are labeled as "antioxidants" are really pure antioxidants. Mostly they have a range of different effects, and one of those effects could be interpreted as "antioxidant". Then the marketing folks promote it as an antioxidant because they know that "antioxidants" sell.

Vitamin C is strange, it actually increases my inflammatory symptoms quickly at dosages above 500 mg

I have experienced this too. I suspect that the extra vitamin C is being scavenged/hoarded by macrophages involved in inflammation, and this somehow increases the activity of the macrophages. People who aren't currently experiencing macrophage-mediated inflammation may be able to tolerate high doses of vitamin C, but I can't.

Oral administration is controversial; while most research shows that oral glutathione does not increase RBC glutathione, there are a few studies that show efficacy.

The main problem with oral glutathione is that your stomach acids rapidly degrade glutathione into its three constituent amino acids. Inside your cells, these three amino acids can be reformed as glutathione. Or the three amino acids could be diverted for other purposes.

IV glutathione has a short half-life

A short half-life is not a bad thing if it means that the glutathione is being rapidly taken up into cells. But there is another possibility to explain the short half-life: glutathione is rapidly degraded by enzymes in the liver that scavenge glutathione.

Cells have bidirectional glutathione transporters

Thanks for those interesting papers. I personally find the topic of glutathione transporters fascinating.

The precursors don't make up for lowered glutathione syntheis so they won't do anything for adults.

Not quite. The lowered glutathione synthesis seen in aging is actually due to a deficiency of precursors. It's kind of a chicken-egg problem actually. The oxidative damage seen in aging gradually depletes glutathione, which concurrently depletes the precursors faster than they can be replenished by the diet. So taking precursors such as cysteine can indeed boost glutathione synthesis in older adults.

Here are some papers you might find interesting:
https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.11338
https://www.sciencedirect.com/science/article/abs/pii/S0306987700911940
https://www.infona.pl/resource/bwmeta1.element.elsevier-6833adf5-072f-3fc1-86ef-41e373a56fb5

 

[gbells]

Not quite. The lowered glutathione synthesis seen in aging is actually due to a deficiency of precursors. It's kind of a chicken-egg problem actually. The oxidative damage seen in aging gradually depletes glutathione, which concurrently depletes the precursors faster than they can be replenished by the diet. So taking precursors such as cysteine can indeed boost glutathione synthesis in older adults.

Americans generally eat 3x the protein they need so there is already a lot of precursors (cysteine, methionine) available. The big problem is that the cells can't produce enough of their own, even with supplemented precursors) so the best strategy is to use absorbable glutathione supplementation. However, you don't want to overdo it because as Pyrrhus states too many antioxidants are not a good thing.

The amino acid cysteine has been termed a ‘semi-essential’ amino acid as humans can synthesize cysteine from the sulphur-containing amino acid methionine only to a limited and generally not sufficient extent. If cysteine and methionine are taken together, an adult person in Western countries consumes, on the average, proteins equivalent to 2–4 g cysteine per day (Breitkreutz et al. 2000a). A series of recent clinical studies has shown that cysteine supplementation on top of the normal protein diet has several positive effects, implying that the ‘normal’ dietary intake of cysteine may be suboptimal although the average intake of calories in Western countries is generally considered superoptimal.

-Dröge W. Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2355-2372. doi:10.1098/rstb.2005.1770

 

[pamojja]

Very few supplements that are labeled as "antioxidants" are really pure antioxidants. Mostly they have a range of different effects, and one of those effects could be interpreted as "antioxidant". Then the marketing folks promote it as an antioxidant because they know that "antioxidants" sell.

That is the main problem with generalizing categories from just a single function: they don't do justice to each and every substance at all, which also has antioxidant properties. But other function not considered even much more essential. Like for example the basic functions of vitamins C copied from a textbook:

• Collagen synthesis. Vitamin C is an essential coenzyme in collagen synthesis. Cofactor in the hydroxylation of lysine and proline, stimulation of gene-expression in fibroblasts; development, maturation and repair of connective tissue such as skin, bone, tendons ligaments, scar tissue, blood vessels and cartilage (anti-scurvy effect = ascorbic). Lack of ascorbic acid results in poorly formed connective tissue in the skin, joints, muscles, and bones.
• Hormone production. Glucocorticoids synthesis in adrenal cortex (stress-response), and Vitamin D-hormone (calcitriol synthesis). Production of epinephrine and norepinephrine, (the hormones released by the adrenal gland in response to stress) are dependent on adequate vitamin C status.
• Neurotransmitter metabolism. Ascorbic acid is essential for the production of norepinephrine and serotonin, two important neurotransmitters in the brain. Conversion of tryptophan in 5-hydrotryptophan (=precursor of serotonin), hydroxylation of dopamine into noradrenalin, synthesis of L-dopa.
• Amidation of neuro-endocrinic hormones. Gastrin, CRH (corticotropin-releasing- hormone and TRH (tyreotropin-releasing-hormone).
• Bile acid synthesis and cholesterol breakdown and excretion. The first key step in the degradation of cholesterol (also tyrosine; bile-acid-synthesis, cholesterol-7-hydroxylasis, HMG-CoA-recductasis) depends on vitamin C. Cholesterol levels in the liver and blood increase if vitamin C status is impaired.
• Carnitine synthesis. Ascorbic acid - together with cofactors niacin, vitamin B6, lysine and methione - is essential for the formation of carnitine, an amino acid required for breakdown of fats for energy. Lack of ascorbic acid lowers levels of carnitine and reduces energy production, producing fatigue and muscle weakness.
• Tyrosine metabolism. Synthesis and catabolism.
• Iron absorbtion and metabolism. Vitamin C sharply increases non-heme iron absorption from diet or supplements. Raising iron transference from transferritin (transport protein) to ferritin (storage protein)-
• Folic acid activation. To tetrahydrofolate (THF).
• Antioxidant function. Vitamin C is the body’s primary water-soluble antioxidant. It is present in the blood, body fluids, and inside all cells and helps protect against oxidative damage by free radicals of lipids (lipid-peroxidation), proteins, nucleic acid and cell membranes. (anti-inflammatory and anti-degenerative effects, e.g. in cancers, diabetes, arthritis, cataracts and cardiovascular diseases..). Vitamin C is also important in the conversion (reduction) of iron and copper to the form in which they function as cofactors in many enzyme systems, such as reduced copper in superoxide dismutase (another antioxidant).
• Antioxidant regeneration. Central building-block in the redox-chain of vitamin C, vitamin E, coenzym Q10 and lipoic acid and/or glutathione, Regeneration of glutathion-disulfide into glutathione.
• Vitamin E sparing effect. Regeneration of tocopherol radicals (vitamin E radical) into the reduced, anti-oxidative active alpha-tocopherol (vitamin E).
• Protection of folate and vitamin E from oxidation. Ascorbic acid protects folate and vitamin E from oxidation and helps maintain these vitamins in their active forms.
• Endothelial cell protection. Raising of NO-bioavailability. (anti thrombotic and blood-lowering effect)
• Detoxification and excretion of drugs and chemicals. Ascorbic acid helps maintain the enzyme systems in the liver that detoxify and excrete drugs and toxic environmental chemicals (such as pesticides and heavy metals). Detoxification of xenobiotika (synthesis/anti-oxidative protection of CYP 450) in the liver, excretion of toxins.
• Antiviral and antibacterial effect. Vitamin C is important for healthy immune function. It is essential for optimum activity of white blood cells and production of the chemical mediators that direct the immune response. Lack of vitamin C sharply increases vulnerability to infection (Immunocompetence). Stimulation of the cellular (antibodies) and hormonal immune system (interferon), protection of phagocytic membranes from oxidative self-destruction (prolonged function-time of immune cells), activation of complementary systems and of chemotaxis.
• Anti-glycation. Inhibition of protein glycosylation and AGE-formation. (e.g. HbA1C).
• Anti-allergic. Vitamin C plays a role in controlling body and blood histamine levels (histamine degradation and mast cell stabilization), and blood histamine levels increase when vitamin C status is poor. High levels of histamine can aggravate allergies, asthma, stomach ulcers, and certain psychiatric disorders.
• Anti-carcinogenic. Inhibition of the formation of carcinogenic nitrosamines from nitrites and secondary amins (especially of the digestive system), protection of DNA from oxidative damage.

Where most functions can't simply be replicated by any other 'antioxidants'. For example the very high doses of vitamin C in Linus Pauling's recomendations against CVD are mainly for collagen repair at the endothelium. The place of artheriosclerotic plaque build-up. Or if taken as preventive, to avoid damage to the endothelium.

Americans generally eat 3x the protein they need so there is already a lot of precursors (cysteine, methionine) available.

Again, don't rely on generalizations. About 50% according to food-intake questionaires are even deficient in vitamin A intake. Personally calculated for 3 years my average cystein intake at 0.8 g/d. About 0.3 g would be the meager RDI. Therapeutically up to 6 g/d have been used.

We are all different, and therefore might need more or less.

 

[gbells]

Again, don't rely on generalizations. About 50% according to food-intake questionaires are even deficient in vitamin A intake. Personally calculated for 3 years my average cystein intake at 0.8 g/d. About 0.3 g would be the meager RDI. Therapeutically up to 6 g/d have been used.

We are all different, and therefore might need more or less.

Regardless, according to Droge no matter how much cysteine you eat we are rate limited and can't produce enough glutathione to meet our needs from it as adults which results in our aging. It's the same problem that some vegans have trying to produce EPA from flax oil (ALA). Most have switched to hemp oil to get around it which has the EPA. Similarly we should use acetyl glutathione or reduced glutathione not cysteine to meet our glutathione needs. Actually, there should even be a new RDA for it for adults.

 

[pamojja]

Regardless, according to Droge no matter how much cysteine you eat we are rate limited and can't produce enough glutathione to meet our needs from it as adults which results in our aging.

I don't believe in generalizations. If cysteine is deficient due to special need, that alone will already limit the rate of its endogenous production. Also spending about 1/3 of my income on affordable supplementation - which already effected remissions in chronic diseases (PAD, COPD, T2D, ME) - I abhor any single supplements at stellar prices (which I could only afford if I abandoned what already helped).

Glutathione recycling is just as important than the substance itself. See this article:

https://drknews.com/glutathione-recycling-for-autoimmune-disease/

... Boosting glutathione levels though a liposomal cream or intravenously—as glutathione taken orally is ineffective—is a key strategy in combating the damage of stress. However these levels can be quickly depleted if the body cannot recycle glutathione to keep the supply on hand to meet the many stressors.

... Glutathione recycling is a separate function from just boosting glutathione levels through a liposomal cream, intravenously, a nebulizer, a suppository, or other means. These forms of glutathione delivery will help one’s antioxidant status but they do not raise levels of glutathione inside the cells. ..

... Supporting glutathione recycling

So how do we support glutathione recycling? The first thing is to reduce the stressors depleting this vital system. The bulk of my thyroid book is devoted to this: balancing blood sugar, addressing food intolerances, restoring gut health, and managing adrenal function are foundational.

Other considerations are neurotransmitter imbalances and hormonal imbalances, which may require specialized guidance from a qualified health care practitioner. And of course making any lifestyle changes you can, such as getting enough sleep, paring down an overactive schedule, making exercise a priority each day, creating time to do things you love, and so on.

Once you have addressed these factors (which for many people can actually take care of the problem) and autoimmune dysfunction persists, then boosting glutathione recycling may be necessary. Below I cover the basic botanicals and nutritional compounds researchers have found support glutathione recycling pathways.

• N-acetyl-cysteine (NAC): NAC is a key compound to glutathione activity. It is rapidly metabolized into intracellular glutathione.
• Alpha-lipoic acid (ALA): ALA directly recycles and extends the metabolic life spans of vitamin C, glutathione, and coenzyme Q10, and it indirectly renews vitamin E, all of which are necessary for glutathione recycling.
• L-glutamine: Research has shown that l-glutamine is important for the generation of glutathione. It is transported into the cell, converted to glutamate, and readily available to intracellular glutathione synthesis.
• Selenium: Selenium is a trace element nutrient that serves as the essential cofactor for the enzyme glutathione peroxidase, which converts GSH to GSSG so glutathione can “take the hit” by free radicals to spare cells.
• Cordyceps: Cordyceps has been shown to activate both glutathione and peroxidase synthesis in the body. It has also been shown to protect cells by engaging the glutathione enzyme cycle.
• Gotu kola (Centella Asiatica): Research has clearly demonstrated that oral intake of gotu kola rapidly and dramatically increases the activity and amount of glutathione peroxidase and the quantity of glutathione.
• Milk thistle (Silybum marianum): Milk thistle has been shown to significantly increase glutathione, increase superoxide dismutase (another powerful antioxidant) activity, and positively influence the ratios of reduced and oxidized glutathione.

Taken together these botanicals and compounds activate the glutathione peroxidase and reductase enzymes that promote a healthy glutathione recycling system.

As usual vitamin C left out, also recycling glutathione.

 

[Pyrrhus]

Personally calculated for 3 years my average cystein intake at 0.8 g/d. About 0.3 g would be the meager RDI.

In the US, the official combined RDA for cysteine and methionine together is 1330mg for a 70kg adult. This assumes that cysteine and methionine are easily interconvertible. However, people with vitamin B6 deficiency or impaired methylation can not easily interconvert the two amino acids. And people with low glutathione will need more cysteine than healthy people. So there are many reasons for an increased need for cysteine.

Regardless, according to Droge no matter how much cysteine you eat we are rate limited and can't produce enough glutathione to meet our needs from it as adults which results in our aging.

You may want to go back and re-read Droege one more time. He actually says the opposite: that the oxidative stress of aging causes a degradation of glutathione, and standard recommendations for cysteine intake are probably insufficient for older people, who need more cysteine to make more glutathione.

 

[gbells]

In the US, the official combined RDA for cysteine and methionine together is 1330mg for a 70kg adult. This assumes that cysteine and methionine are easily interconvertible. However, people with vitamin B6 deficiency or impaired methylation can not easily interconvert the two amino acids. And people with low glutathione will need more cysteine than healthy people. So there are many reasons for an increased need for cysteine.



You may want to go back and re-read Droege one more time. He actually says the opposite: that the oxidative stress of aging causes a degradation of glutathione, and standard recommendations for cysteine intake are probably insufficient for older people, who need more cysteine to make more glutathione.

The article doesn't support that. If you want to only replenish 10% of the need then go buy cysteine. I'll pay a little more and do it all.

 

[mitoMAN]

Quickly question:
When studies say that oral Glutathione is not absorbed. This does NOT include reduced L-Glutathione or Acetyl Glutathione?

or is IV Glutathione the way to go?

 

[gbells]

Quickly question:
When studies say that oral Glutathione is not absorbed. This does NOT include reduced L-Glutathione or Acetyl Glutathione?

or is IV Glutathione the way to go?

No, they are referring to glutathione (early studies). IV was used to get around this but is now unnecessary because acetyl and reduced (L-glutathione) are orally absorbable. Oral is preferable because of lower cost, no doctor's visit fees, no needles and more frequent dosing.

 

[PatJ]

Other antioxidants like ALA, NAC and pycnogenol initially reduce inflammatory symptoms, but after a day or two make flu-like symptoms and hypoglycemia worse.

All three of those supplements are known for reducing blood sugar. CoQ10 and resveratrol lower blood sugar too by increasing insulin sensitivity. Even apple cider vinegar is very good at reducing post-meal and fasting blood sugars. All of them can lead to less energy for someone who already has problems with hypoglycemia.

For quite awhile I've been trying to figure out why have much less mental and physical energy when taking certain supplements. First I wondered about healing effects where the body becomes more tired while repairing itself. Then I noticed many of the supplements are known for reducing BP, and I already have a low to very low BP at times so I wondered about lower BP increasing fatigue. But then I started checking which supplements lower blood sugar in various ways which often works by increasing insulin sensitivity. So far the ones that make me feel worse are all known to reduce blood sugar. Since I already have problems with hypoglycemia these supplements worsen it enough that I can't take them, even if they have beneficial effects in other areas.

 

[YippeeKi YOW !!]

the basic functions of vitamins C copied from a textbook:

Glutathione recycling is just as important than the substance itself. See this article:

Excellent posts, @pamojja ..... have bookmarked them for future reference and re-reading ....

Thanks for these !!!

 

[dannybex]

I had nothing more to loose, with a PAD-diagnosis 11 years ago - a 60% walking-disabilities from a 80% stenosis at my abominal aorta - and conventional medicine considering it a mercylessly progressing disease. With only invasive interventions and no hope on recovery.

Therefore I tried it the old way with high-dose antioxidants by Linus Pauling's therapy. Though his hypothesis is a bid more sophisticated, than being based on antioxidant-actions only. And really includes lifestyle-adaptations and comprehensive supplementation with all essential nutrients.

Not only did I experience remission from the walking-disability, but as benefial side-effects also remission from NAFLD, a cystitis circumscripta of the bladder, psoriasis and retinal migraine flare-ups, a CKD stage 1, and ME/CFS symptoms. Beside further minor ailments improving. All conditions conventional medicine has little to offer. Than trying to slow progression.

So my thesis wasn't even antioxidant, nor anything more sophisticated, but 'nothing more to loose', and I gained everything back again. This thesis or that thesis - in the end is really irrelevant - experience of remissions do count. And I found out by trial and error how much is good for me:

A lot. Like 24 g of vitamin C per taken throughout the day for the last 11 years.

24 grams is definitely a LOT. Enough to become a prooxidant, which is how it often works w/difficult cancer cases, and may be how it helped you. Anyway, that's great to hear it helped you with so many things, many of which I have. But I also have bowel issues even at (relatively) very low doses, so am trying to sort that out.