#23

NF Kappa B is generally a sign of over inflammation, but during differentiation I think the situation may be different.

The problem with hypoxia is that we don’t really know what is best in terms of direct exposure to changes in partial pressure of oxygen. There is a lot of research in subsets such as the hypoxia caused by exercise.

I don’t have a good answer on VEGF.

#24

surprised no one has mentioned this system

EWOT with hypoxic training

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#25

Fascinating stuff this. Criminally understudied for healthspan and lifespan in humans outside of elite sports.

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#26

@murraci I agree. But based on a few tidbits I have become convinced that I can augment the benefits of exercise by artificially stretching my adaptive homeostasis capabilities, focusing on extremes in:
(1) hi/low co2/o2 (shallow breathing to hold SpO2 at 90%, exhale breath holds, nasal breathing during exercise, wim hoff breathing)
(2) hot/cold (sauna vs cold exposure)
(3) fat/carb metabolism (fasting, fasted exercise for fat burning)
(4) hi/lo sensory environment (sensory deprivation at night: light, stress, food, etc. plus extra stimulus during day: sunlight, morning exercise)
(5) of course HIIT exercise and low intensity endurance and strength and range of motion and balance, etc

Thoughts?

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#27

That’s a great list. I would agree with most of your thoughts here. I strongly believe the secret to longevity is constantly midly stressing your body to get it to adapt and become stronger. There are many ways to stress it.

So yeah stuff like exposing the body to low and high oxygen environments, cold and heat, hunger (or cheat with rapa) and feasting, exercise (endurance, HIIT, stretching and resistance) and rest, etc. Also agree best to exercise in the morning if you can. It’s all about constantly giving your body a different look so-to-speak.

I wouldn’t reduce hypoxia to simply enhancing the benefits of exercise though. It of course does but it also produces desirable adaptations on its own even without exercise. I’m splashing out on converting our bedroom to a hypoxic chamber as I’ve become convinced it’s a really powerful intervention. We plan to sleep at altitude moving forward. It’s very expensive so not everyone will do it but it’s the only real way one can get exposure for a sufficient hours a day to really see the full spectrum of benefits one can get from hypoxia.

Of course the shallow breathing does really work too as Millet stated in that clip. I can also see myself adding that to my program.

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#28

I’m more and more interested in intermittent hypoxia therapy.

This paper by Matt Kaeberlein showed that it doubles lifespan in worms: Intermittent hypoxia therapy engages multiple longevity pathways to double lifespan in C.elegans 2022

The protective effects ischemic preconditioning (IPC) in mammalian systems requires the activity of G-protein coupled receptors, and inhibition of Gi/o with pertussis toxin can abrogate this protection(31). While IPC has been studied for decades, and the use of various IHT regimes to improve athletic performance equally well established(32), the clinical use of hypoxia in western medicine has been relatively limited(33). However, recent work shows that exposure to continuous hypoxia can rescue mitochondrial dysfunction in a mouse model of the mitochondrial disease Leigh syndrome, while an IHT regime failed to show a similar results(34, 35). Mitochondria are the primary consumers of molecular oxygen in the cell and mitochondrial dysfunction is one of the key hallmarks of aging(36). The role of oxygen in the aging process, primarily as a putative source of damaging ROS has been hypothesized for decades, however low oxygen therapies have shown limited results in increasing longevity(37). Our results suggest that organismal responses to low oxygen are complex, and that sensory or reproductive signals triggered by acute hypoxia exposure, rather than decreased total lifetime oxygen levels, can trigger endogenous protective pathways to dramatically increase lifespan in wildtype animals. Further studies are warranted to determine whether the effects of IHT on longevity are conserved in mammals with the potential to promote healthspan and lifespan in humans.

Hypoxia is currently being studied in an RCT for Parkinson’s disease: Parkinson's disease - #371 by adssx

There’s the protocol: Randomized controlled trial of intermittent hypoxia in Parkinson’s disease: study rationale and protocol 2024

They showed safety in a phase 1 trial. The researcher told me: “Our the main manuscript from our first study is currently in revision, and we are writing up the manuscript for the second study as all lab results have just come in.”

If successful, it might explain some mysteries of Parkinson’s disease: why are exercise, smoking, and altitude protective? :thinking:

I’ll give a try to intermittent hypoxia, trying to reproduce the protocol in the PD study:

45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks
A commercially available hypoxic generator (b-Cat ALT-120, B-cat High Altitude, Tiel, the Netherlands) is used, which is similar to devices regularly used in hypoxic training studies
the device automatically titrates the correct fraction of inspired oxygen (FIO2) of 0.16 in a closed feedback loop with an FIO2 sensor

I also found this machine but can’t find its price: https://www.cell-oxy.com/

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Parkinson's disease
#29

I did this summary of variations in partial pressure of Oxygen in 2022

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#30

I’m surprised, there are many ongoing trials of intermittent hypoxia therapy: ClinicalTrials.gov

For instance:

And a dozen trials of IHT for spinal cord injuries?!

One trial in Israel is comparing Intermittent Hypoxic Training (IHT) Versus Hyperbaric Oxygen Therapy (HBOT) for Aerobic Performance.

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#31

HIF is a pathway stimulated by exercise.

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#32

What I don’t understand from your article: why would one prefer hyperoxic followed by normal rather than just doing hypoxic?

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#33

Both hyperoxic and hypoxic can cause harm depending upon the level of oxygen and the time of exposure. If you wish to create a change in oxygen levels it is easier and (imo) safer to take them up and then back. You could go from say 42% oxygen to 10% oxygen. I have not studied the time levels of exposure to low oxygen and potential harm in that much detail. I take a simple approach which is to not have a hypoxic period.

In the end the cells first need a period during which to adjust to a higher level of oxygen (or potentially normoxia) and then a period at at lower level during which HIF is stimulated.

The research is not, however, that clear on what timings these are.

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#34

Brain cells are very sensitive to a lack of oxygen. Some brain cells start dying less than 5 minutes after their oxygen supply disappears. As a result, brain hypoxia can rapidly cause severe brain damage or death.

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#35

Is this a typo? Should it be 21% instead of 10%? If you go to 10% that’s hypoxic.

I think that’s about critical hypoxia (<6% O₂). Is there brain cell death at mild hypoxia (~16-19% O₂)? That’s found at ~1,500–2,000 meters altitude. Most of the trials I linked above use moderate hypoxia (~10-15% O₂), equivalent to ~4,000–5,000 meters altitude.

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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

#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