Does oxidative stress play a role in Covid and its severity?

[jim mcnamara]

TL;DR Summary

Baylor researchers found that levels of glutathione were statistically lower in Covid patients than controls. Glutathione reduces oxidative stress, low levels were typically seen in 60+ year old healthy patients prior to the pandemic.

If you already kind of understand anti-oxidant effects on inflammation jump past the "background" paragraphs

Background anti-oxidant:
Mitochondria produce energy in the cell, primarily from Krebs cycle (citric acid cycle is another name). Reactive Oxygen Species (ROS) like H₂O₂ Hydrogen peroxide, are by-products. Glutathione (GSH) is produced in the cytosol of all mammalian cells,
and can also be produced by the liver. Rate limiting of GSH synthesis is beyond the scope of this post, if you want details see:
https://pubmed.ncbi.nlm.nih.gov/18601945/
There are other ROS mop-up molecules but GSH is the bellwether:
GSH mops up the ROS nasties before they damage the cell. This ability declines rapidly in patients over age 60 due to lower GSH levels.

Background oxidative stress due to inflammation:
When ROS molecules hang around because of insufficient levels of mop-up molecules - GSH is major player - cell damage occurs. Damaged cells cause a localized immune system reaction to the problem. The reddened area around an insect bite is localized inflammation.

When the scope of the problem is much larger because of a low systemic level of GSH, entire organ systems can be inflamed. At the highest level this is exemplified by a cytokine storm. Covid damages lung tissue this way.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308649/

Background metabolic disease -
Metabolic disease is a family of pathologies related to oxidative stress: Type II diabetes, atherosclerosis, BMI>=30, waist >39 inches, elevated C-reactive protein (CRP), elevated blood pressure, and a list of other rarer system problems. Heart patients have many of the issues mentioned, for example. I don't believe large segments of Western populations have all of these problems all at once. I hope.

Putting it together:
The Baylor team tested GSH level in Covid patients and found that it was low, indicating oxidative stress. The surprising part was that even young people had low GSH during Covid. They had been doing GSH level testing for several years before Covid. Which made possible the comparison against a control. It was already known that older populations (>60yo) have lower GSH levels than younger ones. Aside: it is possible to use stored sera to test for GSH levels. Correct me if this is wrong.

The implication, of course, is that patients with Covid comorbidities and/or >60 years old, appear to manifest already lower than normal antioxidant serum levels. Before Covid came in and made things a lot worse. More research will continue, but it requires a pre-covid pandemic GSH blood sample. And one during illness or recovery. Not too many places do that kind of test routinely. Or have the necessary stored sera. AFAIK. The UK probably has a better chance of doing larger population testing.

This appears to be very explanatory in terms of why we see the worst problems from Covid where we do:
old people,
comorbidities (pre-existing problems)

 

[sysprog]

It looks like oral supplementation of GSH doesn't work: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162377/

 

[jim mcnamara]

Trying to fix the problem of autoxidation of GSH in organ transplantation:
https://journals.lww.com/transplant...idation_and_stabilization_of_reduced.464.aspx

Which is a lot like what happens to reduced GSH in the gut.

But:
https://pubmed.ncbi.nlm.nih.gov/33783984/ is a clinical trial that shows (in older patients) increased GSH on supplementation with glyNAC. Offhand I do not know of a source "pill" with glycine and NAC in them. If you try to find one on the internet the ad demons on the internet flood you with cruddy non-germane ads.

FWIW glyNAC is a supplement regimen that does increase rates of GSH synthesis. There are other glyNAC references. Some are from the same Baylor group from back in 2018. This is also why GSH studies also closely monitor patient diets. Poor diet affects GSH synthesis.

glyNAC is not one thing, it is a combination of N-acetylcysteine (NAC) and glycine. NAC is used to treat Tylenol poisoning and as a supplement, glycine is an amino acid also used as a supplement. The doses mentioned in some papers seem reasonable: 500mg of the stuff 2 times per day. I assume it is a stoichiometric mix, i.e 2 molecular weights of each component plus filler/binder in a pill. Do not know for sure.

As a side note GSH exists in phytosome form in pills - which gets past gut degradation problems by directly moving small fatty acid spheres with reduced GSH (chemically reduced as in opposite to oxidized) payload unhindered through the intestinal membrane barriers- right into the blood.
Phytosomes:
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/phytosome

PS: mRNA Covid vaccines are also fatty acid nanoparticles (another name for phytosomes or micelles ) with RNA as the payload.

 

[Laroxe]

A lot of the work on reactive oxygen species rather fell apart when it was discovered that our immune system uses many of these to induce apoptosis, this includes the destruction of abnormal (cancerous cells) and infected cells. Perhaps the most famous study found that supplements of Vitamins A and E actually increased mortality from Lung cancers.
https://www.cancer.gov/news-events/cancer-currents-blog/2015/antioxidants-metastasis

The control of the many varieties of reactive oxygen molecules is very complex and can potentially involve a wide range of intrinsic chemicals and nutritionally sourced antioxidants. The problem seems to be in getting the appropriate antioxidants to the right place at the right time, usually simple supplementation doesn't seem to have the expected effect. This may also reflect the large number of potential stages in the control of the reactive oxygen species and the range of antioxidants that may be involved.

Antioxidants were for some time thought of as the holy grail of anti-ageing research and a potential treatment for many age related health problems. Unfortunately, it seems that we continue to have a very limited understanding of what is a complex physiological system.

It may be that some of this work does represent a real advance in understanding and using these chemicals, there has been a lot of work that has suggested real potential for improving health, but ...