Oxygen, hypoxia and hyperoxia

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#36

Intermittent hypoxia seems to have opposite effect compared to chronic hypoxia:

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#37

You’ll like this one @John_Hemming: Chronic intermittent hypoxia elicits distinct transcriptomic responses among neurons and oligodendrocytes within the brainstem of mice 2024

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#38

AIUI The pathway is stimulated by a change in partial pressure of oxygen. Whether that is geometrical/logarithmic or arithmetical i dont know. But you can have a delta of say 0.32 bars at a normobaric air pressure by going from 32% to zero, 42% to 10% or 53% to 21%. 21% say to 10% only gives a delta of 0.11 bars. Going to zero has i would think a guarantee of brain damage. I am not sure where the thresholds are with 10%, but in a practical sense going from hyperoxic to normoxic takes less effort and runs no risk of cerebral hypoxia. I think the lower partial pressure needs to be maintained for enough time for HIF 1 alpha to be active.

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#39

What do you think of Wim Hof Method? You can achieve a 100% concentration measured with an oxygenometer using this technique but my guess is that this is less than what you achieved with your oxygen concentrator, right? Because in your case oxygen can dissolve into the serum but in my case it will only be transported by hemoglobin (maybe even safer but with less effect?)

#40

I dont understand what you are saying. Some o2 is carried by Hb and some dissolved in water. Hence the partial pressure at the cell membrane is affected strongly by that in the lungs. However, even with a 95% concentrator the lung % may not exceed 60%

#41

Do we have any evidence that what matters is the change in O2 rather than the time spent in hypoxia?

If that were the case, we would find many papers showing the benefits of intermittent hyperoxic therapy. But I couldn’t find a single one. On the other hand, there are many papers on the benefits of intermittent hypoxic therapy or combined hypoxia–hyperoxia.

Also, this paper suggests that it’s just that at 30%, the body thinks it is in hypoxia: Oxygen Variations—Insights into Hypoxia, Hyperoxia and Hyperbaric Hyperoxia—Is the Dose the Clue? 2023

Fratantonio et al. [14] described the activation time trend of oxygen-sensitive transcription factors in human peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects after one hour of exposure to mild (MH), high (HH), and very high (VHH) hyperoxia, corresponding to 30%, 100%, and 140% O2, respectively. They confirmed that MH is perceived as a hypoxic stress, characterized by the activation of HIF-1 α and nuclear factor (erythroid-derived 2)-like 2 (NRF2), but not of the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB). Conversely, HH is associated with a progressive increase in oxidative stress leading to NRF2 and NF-kB activation, accompanied by the synthesis of glutathione (GSH). After VHH, HIF-1 α activation is totally absent and oxidative stress response, accompanied by NF-kB activation, is prevalent. Intracellular GSH and Matrix metallopeptidase 9 (MMP-9) plasma levels parallel the transcription factors’ activation patterns and remain elevated throughout the observation time (24 h). This confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1 α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post-exposure.

If I’m correct hen what matters is the time in hypoxia, not the degree of change: HIF1α/SLC7A11 signaling attenuates 6-hydroxydopamine-induced ferroptosis in animal and cell models of Parkinson’s disease 2025

Hypoxia-inducible factor-1α (HIF1α) is a transcription factor consisting of α and β subunits. In the presence of normal oxygen levels (normoxic state), HIF1α undergoes hydroxylation by prolinehydroxylase (PHD), leading to its degradation by the Von Hippel-Lindau (VHL) complex. However, in hypoxic conditions, this degradation process is inhibited, allowing HIF1α to accumulate and form a complex with HIF1β. Subsequently, HIF1α translocates from the cytoplasma to the nucleus,where it regulates the transcription of downstream genes by binding to the hypoxia response elements (HREs).9 Yang et al showed that HIF1α, but not HIF2α, played crucial roles in ferroptosis resistance of cancer cells under hypoxia via upregulation of the glutamate transporter SLC1A1.

(Also interesting from this paper: “Our findings shown a significant decrease in HIF1α expression in both animal and cell models of PD induced by 6-OHDA. Moreover, upregulation of HIF1α promoted ferroptosis, while downregulation of HIF1α inhibited this process. These findings indicate that HIF1α has diverse roles in diseases associated with ferroptosis.”)

I also trust the “Lindiness” of hypoxia: going in altitude for a retreat has been considered healthy for a long time. See also: Acute and cumulative effects of hypoxia exposure in people with Parkinson’s disease: A scoping review and evidence map 2024

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#42

I haven’t read up on this recently, but when I read up on it in 2022 it was the change in partial pressure of O2. This is what is used in HBOT where really high partial pressures are used.

What we don’t really know is what the minimum change in partial pressure is and the periods that are required at the higher and lower partial pressures.

HBOT does not use any hypoxia.

I have not, however, read up on any more recent papers.

My blog post is I think unique in trying to analyse the distinction between HIF, NRF2 and NF kappa B activations.

Re reading your post where it says: " They confirmed that MH is perceived as a hypoxic stress,"

What they should have written is that the switch back to normal oxygen stimulates HIF1alpha. Strictly the name HIF should be changed to remove Hypoxia and replace it with a name implying a reduction in partial pressures.

That is what the normobaric oxygen paradox is.

This has been cited quite recently

#43

I will try to be simple: if I hyperventilate my oxygenometer will say 100%. What does this mean? I thought it meant that my red blood cells cannot carry more oxygen.

If I take an oxygenometer into an HBOT will it show 300%? Or get stucked in 100%?

#44

This is what they wrote: “This confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1 α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post-exposure.” (They cite the “normobaric oxygen paradox”)

But why would 30% to 21% activate HIF-1 α but not 100% to 21%? So it’s not only the Δ(ppO2) that matters.

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#45

More on this: Pulsed Hyperoxia Acts on Plasmatic Advanced Glycation End Products and Advanced Oxidation Protein Products and Modulates Mitochondrial Biogenesis in Human Peripheral Blood Mononuclear Cells: A Pilot Study on the “Normobaric Oxygen Paradox” 2024

We have previously characterized the time trend of oxygen-sensitive transcription factors in human PBMCs, in which the return to normoxia after 30% oxygen is sensed as a hypoxic trigger, characterized by hypoxia-induced factor (HIF-1) activation. On the contrary, 100% and 140% oxygen induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post exposure.
Our results show that AGEs and AOPPs increase in a different manner according to oxygen dose. Mitochondrial levels of peroxiredoxin (PRX3) supported the cellular response to oxidative stress and increased at 24 h after mild hyperoxia, MH (30% O2), and high hyperoxia, HH (100% O2), while during very high hyperoxia, VHH (140% O2), the activation was significantly high only at 3 h after oxygen exposure. Mitochondrial biogenesis was activated through nuclear translocation of PGC-1α in all the experimental conditions. However, the consequent release of nuclear Mitochondrial Transcription Factor A (TFAM) was observed only after MH exposure. Conversely, HH and VHH are associated with a progressive loss of NOP response in the ability to induce TFAM expression despite a nuclear translocation of PGC-1α also occurring in these conditions. This study confirms that pulsed high oxygen treatment elicits specific cellular responses, according to its partial pressure and time of administration, and further emphasizes the importance of targeting the use of oxygen to activate specific effects on the whole organism.
Our results show that this “linearity” on reduced risk is not only present on the toxicity side, but also on the elicited response. In fact, it seems that in the first 24 h following a session, lower oxygen concentrations act more positively than higher levels of hyperoxia on mitochondrial biogenesis factors.

So I wouldn’t go above 30% O2. But should we also go to 15%?

#46

Its also the exposure to high oxygen. That is a time and quantity issue and I do some detailed analysis in my blog post.

Basically you need to avoid long exposures at higher partial pressures of oxygen otherwise you kick off NF kappa B. Interestingly also very low oxygen levels also kick off NF kappa B and that is part of the function of the stem cell niches.

#47

They had an exposure of an hour. HBOT uses 20 mins.

#48

Looking at my post I find

https://www.sciencedirect.com/science/article/abs/pii/S0952818012004175

This is 100% oxygen for 30 mins which increases reticulocytes (an indicator of HIF).

#49

Yes, that is SPO2 it is a different thing to the percentage of oxygen in the air. The “partial pressure” of oxygen is the key issue. That is that proportion of air pressure caused by oxygen and it affects how much oxygen is dissolved in water. In the end this drives the partial pressure of oxygen next to the mitochondrial membrane. This is lower than that in blood serum, but it directly affects how the mitochondria behave. It is also driven by the serum partial pressure.

#50

Interesting here: ClinicalTrials.gov

The Nobel Prize in Physiology was recently awarded to scientists who established the basis for our understanding of how varying oxygen levels affect cellular metabolism, which paved the way for promising new strategies to fight diseases. Breathing low levels of oxygen, or hypoxia, stimulates glucose uptake in skeletal muscle via 5’ adenosine monophosphate-activated protein kinase (AMPK), the same signaling pathway as muscle contraction, which acts independently from the actions of insulin. Thus, patients with type 2 diabetes were exposed to either normoxia or 60 min of continuous hypoxia (fraction of inspired oxygen of ~0.15, arterial oxygen saturation of 92%) immediately before performing a 4-hour intravenous glucose tolerance test. Hypoxia lowered blood glucose levels and did not affect insulin concentrations, therefore, it was suggested that the improved glycemic control was caused by the activation of the AMPK pathway in combination with an improved insulin sensitivity. Similarly, a single exposure to intermittent hypoxia, consisting of 6 min at a fraction of inspired oxygen of 0.13 alternated with 6 min of normoxia for 1 hour, improved glycemic control in patients with type 2 diabetes. Specifically, there was a greater decrease in glucose levels measured immediately after intermittent hypoxia, and the increase in glucose levels following a meal was attenuated following intermittent hypoxia when compared to a placebo condition. A decrease in glucose levels was also observed following a single session of intermittent hypoxia, consisting of brief desaturation and resaturation cycles to maintain an arterial oxygen saturation of 80% for approximately 70 min, in overweight and obese individuals with normal baseline glucose levels.

#51

https://www.sciencedirect.com/science/article/pii/S0021925820698672

The toxicity of high levels of oxygen is caused by increased ROS. At a point the cells defences are overwhelmed and NRF2 and NF kappa B start being initiated.

It is important to avoid this. Hence if you start with high levels of oxygen then the period should be short. It has to be long enough to stablise.

I use 8 minutes.

#52

According to Dr Dallam, adaptation to lower oxygen partial pressure for RBC boosting (live high; train low) only comes from being in lower O2 “almost all of the time”. Sleeping in a low O2 tent wouldn’t being enough.

I was asking him if I could get benefit from shallow breathing …. keeping my spo2 at 90% for 10 minutes would be helpful for signaling RBC increase. He said no. He said it might help with co2 tolerance which is good enough.

I do it 1x/week. I hope also to get additional epigenetic signaling.

Dr Nelson said to use nasal breathing during exercise and breath holds to stress the body on lower O2 and higher CO2. I do 5 sets of 30 second exhale holds plus 10 seconds breathing (5x 40 seconds = 200 seconds or almost 3.5 minutes) every morning. Subjectivity I get an energy/ alertness boost from it. I think my spleen releases extra RBC so it’s also useful for accelerating my cardio warmup, I think.

Any thought?

#53

There is an interesting question if there is a difference between people who live at a high altitude and never visit sea level or other lower altitudes and those that shift between altitudes.

I don’t know the answer.

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#54

I put all the other ongoing trials here: Hypoxia–Hyperoxia trials - Google Sheets

Most use 10% O2, 1.5 min hypoxia, 1 min normoxia, 15 cycles, once daily, 3 days per week.

@John_Hemming did you notice the same impact on glycemic control with your protocol? Discussion about Oxygen, Hypoxia and Hyperoxia 2024 03 30 AntiAging Reading Group - #50 by adssx

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#55

One of my difficulties is separating out individual interventions and their effects. Hence although I can say in the round that I am doing reasonably well on glycemic control (HbA1c below 5 lowest was 4.18) I cannot say precisely why.

From a process perspective I think a middling to short period at a higher oxygen level followed by an extended period at a lower oxygen level would get the best results.

I think the cells need a period of time to get HIF functioning properly and if you take the oxygen back up too quickly then that will undermine the activation of HIF.

I have no evidence base to justify this, however.

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