#21

Good podcast on hypoxia and more

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#22

@John_Hemming, thanks for the podcast! Very interesting. I have some further questions if you dont mind:

  • overexpression of NRF2 seems to be good for health. Does this means the bad guy is NF Kappa b?
  • Dont we have any metric to guide us using hyperoxia exercises? Right now itā€™s all hoping the intervention is working?
  • The ā€œgrowth factorā€ part in VEGF makes me not want to activate it as this means aging, at least when its related to IGF, GH, mTor. Are those different paths vs Vegf?
#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 donā€™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 donā€™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

Thatā€™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. Itā€™s all about constantly giving your body a different look so-to-speak.

I wouldnā€™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. Iā€™m splashing out on converting our bedroom to a hypoxic chamber as Iā€™ve become convinced itā€™s a really powerful intervention. We plan to sleep at altitude moving forward. Itā€™s very expensive so not everyone will do it but itā€™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

Iā€™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 Parkinsonā€™s disease: Parkinson's disease - #371 by adssx

Thereā€™s the protocol: Randomized controlled trial of intermittent hypoxia in Parkinsonā€™s disease: study rationale and protocol 2024

They showed safety in a phase 1 trial. The researcher told me: ā€œOur 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.ā€

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

Iā€™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 canā€™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

Iā€™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 donā€™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% thatā€™s hypoxic.

I think thatā€™s about critical hypoxia (<6% Oā‚‚). Is there brain cell death at mild hypoxia (~16-19% Oā‚‚)? Thatā€™s found at ~1,500ā€“2,000 meters altitude. Most of the trials I linked above use moderate hypoxia (~10-15% Oā‚‚), equivalent to ~4,000ā€“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

Youā€™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%