Does oversupplementing with antioxidants cause reductive stress?

GSH can, but what about other antioxidants?

The most common cause of reductive stress is excess NADH/NADPH, which is different from, say, extra amounts of melatonin/ascorbic acid/C60/conjugated double bonds. Dayan Goodenowe discusses some implications of excess NADH/NADPH in his “breaking autism” webinars

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One data point on antioxidants…

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BUT WHAT KIND? Vitamin C/E yes, ALA yes, but glutathionine-based antioxidants have been shown to be neutral-to-beneficial, as with melatonin.

IT DEPENDS ON THE KIND

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Yes - some seem helpful, not sure if the mechanism is the antioxidant property…

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Vitamin C is harmful? I thought excess is excreted. @TongMD said vitamin C is a pro-oxidant.

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https://x.com/MitoPsychoBio/status/1887521593569513723?s=19

I’ve held this same opinion for a long time now. I don’t know how I feel about antioxidants all getting lumped into one. Do we even know for sure that’s it’s the antioxidant effect that shows harm when you take too much Vitamin A, E, etc? Or is it simply the individual vitamins themselves? I just want to know how we landed on blaming antioxidants as a whole for this.

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Vitamin C is harmful? I thought excess is excreted. @TongMD said vitamin C is a pro-oxidant.

Anecdotal, but my neighbor is the most active 92 year old I’ve ever seen. Comes and goes all day long, has a girlfriend, and talking to him you’d think he was in his mid 70’s.

I asked him what he supplements, he said vitamin C and calcium. Good genes really are a trump card.

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High dose C (1g) does blunt benefits of exercise if you take it around workouts though.

Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial - PMC)%20and%20biochemical/molecular%20analyses%20of%20blood%20and%20muscle.

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Would it not be the vitamin E in cause? Vitamin C’s absorption rate really slows down after 500mg and vitamin C itself is quite a weak antioxidant compared to vitamin E :thinking:

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Good question actually. I’m not sure if they tested each one separately. The ones I’m looking at seem to say vitamin C and E together, so you might have a point.

Yes, vitamin C + E, reduces the effects from exercise, but vitamin C also increases functions in the body, for instance, the levels of glutathione. The question should be, is supplementation with vitamin C a net positive or a net negative? To only focus on the effect on adaptation to exercise is a bit narrow and does not give me the full picture.

And the effects of vitamin C alone, on exercise is not consitent.

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Too much vitamin c can potentially deplete copper, however

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This is a good example of that: when we focus too narrowly on one mechanism, we risk blinding ourselves to other aspects of the physiology. The latest headlines drive our thinking and actions.

Human studies on interventions and how they affect multiple human biomarkers (Like was done with GLYNAC) or studies on primates (like was done with Taurine) are more relevant than mouse studies. One has to love the complexity and the detective work it brings to us.

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Well, this was timely…

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The IMPORTANT antioxidants are taurine/zeaxanthin/astaxanthin/melatonin… Not the vitamins…

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What is it with these kinds of statements? At least back them up. “Important”… in what way? I know, I know, it’s a waste of time trying to get answers. Always same MO - hit and run, make some claim with no backing, then disappear. Best way forward: ignore.

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In proliferating and differentiating neuroblastoma (Neuro 2a/N2a) cells, sulforaphane-mediated Nrf2 activation resulted in increased transcription/translation of antioxidants and glutathione (GSH) production along with significantly declined ROS in a dose-dependent manner leading to a reductive-redox state (i.e. RS). Interestingly, this resulted in endoplasmic reticulum (ER) stress leading to subsequent protein aggregation/proteotoxicity in neuroblastoma cells. Under RS, we also observed elevated Tau/α-synuclein and their co-localization with other protein aggregates in these cells. Surprisingly, we noticed that acute RS impaired neurogenesis as evidenced from reduced neurite outgrowth/length. Furthermore, maintaining the cells in a sustained RS condition (for five consecutive generations) dramatically reduced their differentiation and prevented the formation of axons (p < 0.05). This impairment in RS mediated neurogenesis occurs through the alteration of Tau dynamics i.e. RS activates the pathogenic GSK3β/Tau cascade thereby promoting the phosphorylation of Tau leading to proteotoxicity. Of note, intermittent withdrawal of sulforaphane from these cells suppressed the proteotoxic insult and re-activated the differentiation process. Overall, this results suggest that either acute or chronic RS could hamper neurogenesis through GSK3β/TAU signaling and proteotoxicity. Therefore, investigations identifying novel redox mechanisms impacting proteostasis are crucial to preserve neuronal health.

Loss of proteostasis bad…

We postulate that augmentation of reductive-redox signaling, leading to impaired glutathionylation of oxidized proteins, may cause adverse changes in neuronal function as observed in the current study

Glutathionylation is really interesting. The thiol on cysteine residues can be reversibly oxidized under mild conditions to sulfenic acid (-SOH). This sulfenic acid can be further oxidized to sulfinic acid (-SO2H) and sulfonic acid (-SO3H), and these processes are irreversible. To prevent this, the cell can use glutathione as a “protecting group” to “cap” the sulfenic acid and prevent these irreversible oxidative modifications.

Under reductive stress though, you never get to the sulfenic acid, which means you also don’t get to the glutathionylated form and any signaling functions it may serve.

With supplementing something like NAC, I wonder if it makes more sense to dissolve your daily dose in the total amount of water you’re going to drink that day, and then just sip it throughout the day.

Supremely speculative, but maybe that way you could mildly and smoothly increase GSH synthesis/antioxidant capacity throughout the day, while avoiding reductive spikes and impaired protein folding that may be caused by a bolus.

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Our Cochrane review from 2008 demonstrated that antioxidant supplements seem to increase mortality. This review is now updated.

The potential damage from vitamin A disappeared when only the low risks of bias trials were considered. The increased risk of mortality was associated with beta-carotene and possibly vitamin E and vitamin A, but was not associated with the use of vitamin C or selenium. The current evidence does not support the use of antioxidant supplements in the general population or in patients with various diseases.

As always, that was a study on supplements. There was no study of carrot or carrot juice intake (beta carotene). Same with cod liver oil (vit A).

Vit E, was the study on tocopherols? What about tocotrienols?

Below is the pdf of the abstract.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007176.pub2/epdf/abstract

Authors’ conclusions

We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.

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