It is very clear that Oxidative Stress is a factor in the deterioration of cellular health.
Looking at the creation of ROS. I would see the first limiting factor being the production of Pyruvate through Glycolysis. I have not seen what limits this detailed, but I would assume it is the partial pressure of Oxygen near the mitochondria which can be varied through higher external partial pressures and the availability of glucose.
Then this feeds into the creation of Acetyl CoA. The limits on this are the availability of NAD+ and Pyruvate. Then it goes into either the Krebs Cycle or gets converted into Melatonin (which can reduce the ROS either directly or indirectly).
One would assume, that an increase in blood glucose or an increase in partial pressure of Oxygen both individually as well as jointly would have the ability to kick off more Glycolysis. However, the limiting factor on processing Pyruvate remains NAD+ so we get some Oxidative damage if NAD+ is not available.
This would give a logical mechanism whereby Cortisol in increasing Glucose levels can lead to more cellular damage as increasing Glucose levels does not in itself increase NAD.
There is also an interesting conundrum whereby Melatonin is known to inhibit HIF creation whereas a reduction in the partial pressure of Oxygen increases HIF production (varioxia). Hence you have a conflict between using HIF for creating new stem cells and ensuring adequate levels of Melatonin in mitochondria to prevent Oxidative Stress and reduce inflammation etc.
I think also that increasing glycolysis does increase ATP production even if it becomes much more dirty ATP production with more Oxidative Stress. There is a view that a bit of Oxidative Stress is OK. Arguably that would be until you run low on Melatonin to handle it
Hence if Glucose levels go up one would expect the heart rate to go up (if other variables remain constant) and similarly it would make neurons more active and keep people awake.
Given my own personal obsession with studying the impact of interventions on sleep I upgraded my fitbit to include Oxygen Saturation. That does not necessarily vary the partial pressure of Oxygen going into the Mitochondria which is more dependent on the partial pressure of Oxygen in the atmosphere. Yesterday I implanted a Continuous Glucose Monitor to give me information on glucose levels throughout the day (DexCom G6) and that seems to be quite good. This will enable me to test my thesis on the impact of glucose/cortisol on sleep/neuronal activity.
However, I have decided in the light of the above to cycle varioxia with a view towards using varioxia to deplete mitochondrial DNA and kick off HIF on a limited number of days whilst otherwise trying to keep a reasonably well topped up supply of Melatonin in the mitochondria. I am of the view that the addition of exogenous Melatonin to mitochondria operates to reduce inflammation on a reasonably short timescale (10s of minutes, maybe low numbers of hours). This comes from experiments using Melatonin to resolve perio issues.
Does anyone know exactly how the variation in Reactive Oxygen Species acts as a messaging system (other than the depletion of Melatonin).
Edited by johnhemming, 26 January 2022 - 07:09 AM.
