Oxygen, hypoxia and hyperoxia

[John_Hemming]

I have done a post looking a bit more at Oxygen levels.

Aging, Development, and Living at High Altitudes (Oxygen Levels)

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See also this paper: Healthy Aging at Moderate Altitudes: Hypoxia and Hormesis 2024

Consequently, it could be speculated that living at higher altitude, and therefore in hypoxic conditions, accelerates aging. This assumption is indeed supported by evidence from populations residing at very high altitudes (>3,500 m). In contrast, accumulating evidence suggests that living at moderate altitudes (1,500–2,500 m) is protective rather than injurious, at least for some body systems.
In this review, we critically evaluate the hypothesis that the physiological responses to mild hypoxic stress associated to life at moderate altitudes provide protection from many hypoxia-related diseases through hormesis. Hormesis means that a low dose of a stressor (here hypoxia) elicits beneficial outcomes, while a higher dose can be toxic and might explain at least in part the dose-dependent contrasting effects of hypoxia on the aging processes. The lack of well-designed longitudinal studies focusing on the role of the altitude of residence, and difficulties in accounting for potentially confounding factors such as migration, ethnicity/genetics, and socioeconomic and geoclimatic conditions, currently hampers translation of related research into uncontroversial paradigms.

This one is also very good: The Hypoxia Response Pathway: A Potential Intervention Target in Parkinson’s Disease? 2023

We had a call with @John_Hemming. We agree that:

1. Chronic hypERoxia is bad.
2. Extreme hypoxia (below 10%?) is bad, whether chronic or acute.
3. Mild chronic hypoxia (17–20%) seems safe and probably beneficial.
4. For HIF: delta matters + time at the high and low levels. 1 min might not be enough. The above paper suggests 3 to 5 minutes.
5. Non-HIF benefits of hypoxia: we don’t know enough…

[John_Hemming]

I think, however, that non-HIF benefits of hypoxia arise from a reduction in ETC ROS from Complexes 1 and 3 and the consequent reduction in mtDNA damage. I don’t think Antoine agrees with me on this point.

[adssx]

Ah I don’t disagree on that, I just have very limited knowledge so I can’t comment.

[Joseph_Lavelle]

@adssx

For HIF: delta matters + time at the high and low levels. 1 min might not be enough. The above paper suggests 3 to 5 minutes.

@adssx @John_Hemming In terms of spo2, is there a target to creating a signal? I can move my spo2 via breathing. I don’t have a O2 machine.

[adssx]

I think no one knows. From the PD paper above:

There is debate on whether hypoxia should be dosed based on the FiO2 or based on the resultant oxygen saturation. If activation of downstream mechanisms is ultimately determined by the resultant hypoxemia, dosage based on the resultant oxygen saturation might be superior for optimal individualized downstream effects. In our first systematic hypoxic conditioning trial in PD however, we applied a fixed FiO2 to determine intervention uniformity and study replicability, and to investigate whether interindividual variability in target engagement or symptomatic outcomes can be explained by differences in physiological responses or target engagement.

10% FiO2 might lead to something like 50–70 SpO₂ according to ChatGPT! While 17% <> 85–92%.

[Joseph_Lavelle]

Thanks. I cannot hold spo2 below 90% for very long. I’m happy to stay at the “safe and probably beneficial level” anyway.

[John_Hemming]

I don’t think SPO2 has much effect it is the variation in oxygen dissolved in the water in blood serum that impacts the partial pressure of oxygen at the mitochondrial membrane.

[Joseph_Lavelle]

Well that would explain why short periods (<1 minute) of low O2 or SpO2 wouldn’t have much effect. But why wouldn’t oxygen on red blood cells be related to oxygen dissolved in blood plasma? Where does the oxygen dissolved in blood plasma come from? O2 delivered by red blood cells I’d assume.

[John_Hemming]

Oxygen starts in the lungs. Some goes into blood cells, some is dissolved in the water in the blood. Interestingly at a high enough pressure enough oxygen will dissolve in the water in the blood to enable oxygenation of cells without any red blood cells. This has been done experimentally with a pig which survived at high pressure without any red blood cells.

The oxygen in the red blood cells comes out into the water of the blood. Therefore the partial pressure of the oxygen at the cell wall is driven by the partial pressure of oxygen in the water of the blood at the cells. This is affected by the partial pressure of inspired air. It goes down at a gradient as you get the blood away from the lungs.

Normally venous blood has a pO2 of 40 (mmHg - millimetres of mercury) whilst in the alveoli the pO2 is 104. During strenuous exercise pO2 of interstitial fluid can drop to 15.

Haemoglobin acts primarily as a buffer. Normal air pressure at normal 02 percentage (21%) results in a pO2 of about 160.

As the partial pressure of inspired air increases so does the partial pressure in the tissues. With 3 Atmospheres of pressure and 100% Oxygen the difference between arterial and venous pO2 hits 350mm.

Source: Handbook of HBOT, FIsher, Jain, Braun and Lehri.

[John_Hemming]

The oxygen cascade

[Joseph_Lavelle]

From ChatGPT

“ The relationship between PaO₂ and SpO₂ is described by the oxygen-hemoglobin dissociation curve, which is sigmoid-shaped.

Key points:

•	PaO₂ of 60 mmHg ≈ SpO₂ of 90%: This is the critical point where oxygen saturation drops steeply with small decreases in PaO₂.
•	Above 90% SpO₂, small changes in PaO₂ don’t significantly affect SpO₂.
•	Below 90% SpO₂, PaO₂ drops rapidly, indicating hypoxemia.”

It seems that 90% is the key level. Below 90% SpO2 causes significantly (dangerously) low O2. How long the hypoxia takes to show up in mitochondria is a question, but I wouldn’t expect it take very long. Holding my spo2 at 90% is very hard for 3 minutes. So far I am failing to keep it below 93 for more than several seconds.

[John_Hemming]

Deep learning reveals diverging effects of altitude on aging - GeroScience

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Really good! Let’s all move to the Alps!

Notably, we observed significantly lower risk exposure rates and a reduced disease burden as well as increased life expectancy by lower mortality rates in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells (PBMCs) in blood smears with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.

[John_Hemming]

I think we can separate out the various effects of altitude

1. Lower mtDNA mutations
2. Problems with breathing from a shortage of oxygen
3. Higher UV damage.

There probably is an optimal pO2.

[Joseph_Lavelle]

This podcast has lots of useful information on this topic

#29 - Altitude training and hypoxic conditioning with Dr Grégoire Millet

Athletic performance and longevity should be parallel goals unless pushing the envelope too far.

Since I no longer live at altitude nor do I have access to devices to increase or lower my o2 intake I have to resort to HIIT exercise and breathing (and not-breathing) drills.

The rabbit hole goes deep on the respiratory system and delivering O2 to cells but here I am just looking for ways to provide a “low O2” stress to signal the cells to run programs that have health and longevity benefits. Not hormesis as in damage but just a stress to tell the cells that this is an ongoing risk to be prepared for (retaining an adaptive homeostasis ability). Maybe HIIT is enough but I’m using breath holds and sustained shallow breathing to provide more stimulation.

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Grégoire Millet recently published (worth a read @John_Hemming): Mechanisms underlying the health benefits of intermittent hypoxia conditioning 2023

Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies.
In elderly adults (≥65 years), moderate sleep apnoea (apnoeic index 20–40/h) was associated with a significant survival advantage, in comparison with age-, sex and ethnicity-matched national mortality data (Lavie & Lavie, 2009), exemplifying the importance of the hypoxic dose.

These protocols typically consist of repeated 4–8 min exposures to hypoxia, i.e. fractions of inspired oxygen (FIO 2 = 10–15%, alternating with 2–5 min exposures to normoxia (IHE: FIO 2 = 21%) or hyperoxia (IHHE: FIO 2 = 30–35%), totalling 35–40 min/session applied 3–5 times per week for 3–8 weeks. IHHE has also been termed intermittent hypoxia hyperoxic conditioning (IHHC)

Much remains to be optimized to fully harness the potential of hypoxia conditioning. It is essential that the different basic and clinical research fields harmonize their understanding and communication of hypoxia conditioning research, differences in adaptation to continuous hypoxia vs. IH be better described, and individually optimal hypoxic doses systematically established. It will be especially important to establish organ/function-specific hypoxic dose thresholds that allow the eliciting of specific benefits, without triggering maladaptation in other organs. For example, a severe IH protocol (90 s cycles of 10% and 21% oxygen for 8 h/day for several weeks; Wu et al., 2015) reduced pain responses in rats, but similar IH protocols elicit maladaptive sympathoexcitation and cardiovascular remodelling in rodents.

In addition, several practical questions related to hypoxia conditioning remain, including: how long do respective benefits persist after concluding hypoxia conditioning? Once the improvements wane, can abbreviated hypoxia conditioning programmes restore them? Do medications or dietary supplements, e.g. β-adrenoceptor antagonists or antioxidants, interfere with hypoxia conditioning outcomes, as shown for cardio(Mallet et al., 2006) and cerebroprotection (Jung et al., 2008) in animals? Lastly, which conditioning protocols are most effective for different applications in prevention, rehabilitation and performance enhancement (including comparisons of IHE and IHHE)?

He also wrote last year: Hypoxia Sensing and Responses in Parkinson’s Disease 2024

We describe cases suggesting that hypoxia may trigger Parkinsonian symptoms but also emphasize that the endogenous systems that protect from hypoxia can be harnessed to protect from PD.
These effects of inspiratory hypoxia likely overlap with and may, to some degree, reproduce or amplify so-called “functional hypoxia” caused by increased oxygen demand, for example, in skeletal muscle during exercise or in the brain due to motor-cognitive training [102,103,104]. Therefore, “functional hypoxia” may also play a role in the well-documented benefits of exercise [35] and motor–cognitive training in PD.
However, even though clinical trials are on the way and will provide important new information on individual responses to hypoxia in people with PD, we probably should not expect to be able to appreciate the full potential of hypoxia conditioning in PD too soon. The determination of the hypoxic doses required to induce an optimal effect while also minimizing hypoxia-associated risks will be a major future challenge, especially since many parameters have to be optimized, including the intensity, duration, and frequency of the hypoxic stimulus, but also the type of hypoxia (normobaric versus hypobaric), the role of CO2 levels (isocapnic versus poikilocapnic hyperventilation in hypoxia reduces CO2 levels), and various environmental (e.g., temperature) and behavioral (e.g., activity level) factors likely play a decisive role. Increased CO2 levels, by themselves or in combination with hypoxia (e.g., by adding CO2 to the breathing gas), for example, promote ventilatory plasticity and increased cerebral blood flow. While the evidence is mounting that responses to oxygen level changes are crucial in neurological diseases, and especially PD, understanding the role of the factor oxygen requires systematic investigation.

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Looks like this Grégoire Millet is a prolific writer (@John_Hemming another good paper): Hyperoxia-enhanced intermittent hypoxia conditioning: mechanisms and potential benefits 2024

Figure 1:: Molecular signaling elicited by IHC and IHHC activates adaptive gene expression to confer health benefits.Note: Moderate hypoxia activates the powerful transcription factors hypoxiainducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) and their respective gene programs. Decreased cytosolic oxygen (O2) concentrations stabilize HIF, allowing its translocation to the nucleus where it activates transcription of genes encoding an array of proteins, e.g., glycolytic enzymes, angiogenic factors and erythropoietin, that adapt the organism to hypoxic conditions. Also, hypoxiareoxygenation cycles cause the formation of reactive O2 species (ROS). Upon reoxygenation, endoplasmic reticular nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase becomes the principal ROS generator. ROS liberate Nrf2 from its cytosolic binding complex, allowing its nuclear translocation and activation of a host of genes encoding antioxidant and anti-inflammatory enzymes and factors. Collectively, the products of the HIF and Nrf2 gene programs enhance metabolic control of serum glucose and lipids, increase physical exercise capacity, strengthen cellular ischemic resistance, improve memory function of cognitively impaired individuals, and increase cardiopulmonary function in patients with chronic cardiovascular and pulmonary diseases. Whether IHHC protocols induce such beneficial effects more efficiently than IHC requires confirmation.

Reactive O2 species (ROS) generated during the abrupt hypoxia-to-normoxia transition have emerged as major factors that induce adaptations to IHC. Moderate increases in ROS trigger redox signaling cascades that mobilize the nuclear factor erythroid 2-related factor 2 gene program to effect adaptations that increase cellular, tissue and organism resilience. On the other hand, higher ROS levels impose oxidative stress that damages biomolecules and cells.

Formation of ROS during hypoxia-normoxia transitions is rather modest, limiting the induction of protective antioxidant defenses. Compared with normoxia, reoxygenation with moderate hyperoxia (intermittent hypoxia-hyperoxia conditioning, IHHC) may affect greater ROS production, including by nicotinamide adenine dinucleotide phosphate hydrogen oxidase in endoplasmic reticular membranes (Figure 1), thereby eliciting more robust induction of antioxidant genes. In patients with metabolic syndrome, IHHC proved to be a safe and readily tolerated intervention supporting the therapy and secondary prevention of components of metabolic syndrome and bolstering the patient’s anti-inflammatory status. As those studies did not directly compare IHHC with IHC, it remains unclear whether IHHC really confers benefits superior to IHC, and, if so, whether IHHC’s superiority may be due to more intense ROS formation and induction of antioxidant gene expression. Since ROS formation parallels increased O2 concentrations, the therapeutic range of hyperoxia intensity likely has an upper limit, beyond which the cytotoxicity of excess ROS would outweigh the benefits. Our aim here is to summarize and evaluate the limited empirical evidence on this topic and propose future research to define potential safety and efficacy differences between IHC and IHHC.
The collective evidence indicates that, although studies in rodents support the hypothesis that IHHC may induce beneficial adaptations more efficiently than IHC, a similar IHHC superiority in humans is not yet established.
Typically, 30–35% O2 is applied during the hyperoxic periods, but this moderate hyperoxia may be too weak a stressor to trigger meaningful responses to the hyperoxia. On the other hand, more intense hyperoxia may elicit excessive, potentially harmful ROS formation. The possibility that hyperoxia might interfere with aspects of hypoxia responses, e.g., by reversing hypoxia-inducible factor activation, also merits consideration, as does the likelihood that IHC or IHHC protocols eliciting maximally beneficial responses and adaptations may vary among individuals depending on age, sex, genetic background, physical fitness, health history, medications and other variables. The persistence of the health benefits following completion of IHC or IHHC programs is another pivotal factor. Consequently, more systematic evaluation of potentially health-promoting IHC/IHHC protocols is mandatory to maximize the benefits of these promising interventions for many diseases for which effective treatments are currently limited or unavailable.

[dicarlo2]

We seem to have a decent amount of research on the benefits and mechanisms of intermittent hypoxia + hyperoxia, is there similar exploration for exercise + intermittent hypoxia + hyperoxia? Is the benefit even greater? I know that we have some evidence in athletes, I’m mostly curious if it would be better to do these protocols with exercise or not.

I’d also love to see more about the pathways of HBOT compared to intermittent hypoxia (+ hyperoxia). We know that HBOT at 2.0ATA + 100% oxygen (and possibly as low as 1.3ATA) induces positive changes, but it seems like from the research posted it’s through different mechanisms? Could these be complementary therapies?

[Joseph_Lavelle]

It is an interesting thought experiment to consider why oxygen deprivation kills so quickly. It highlights the massive requirement for energy just to keep the lights on. Turtles have developed mechanisms to dramatically slow the need for oxygen (sleep under water), but a turtle is not a good conversationalist.

Our ability to tolerate oxygen deprivation for brief periods (during physical activity?) is probably related to better recovery or protection from oxygen deprivation damage as well as the ability to function on less oxygen when needed.

The more efficient (skillful movement) I am the faster and farther I can run on the same oxygen. The better my respiratory and cardiovascular systems, the better I can capture oxygen and get it to the cells. And the ability to tolerate higher lactate (and accompanying hydrogen ions) means I can “borrow” oxygen from the future to pay back after I get up that tree.

So better fitness once again is a top priority but what else can help for longevity? Do breathholds or low oxygen exercise or HBOT or altitude simulation sleeping tents or nasal breathing during exercise and sleeping (and more)…add anything to exercise? And does any of this matter for longevity even if I’m not running from lions or diving underwater for food?

I’m betting yes.