One more: Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans 2001
The present study investigated the effect of a single bout of exhaustive exercise on the generation of DNA strand breaks and oxidative DNA damage under normal conditions and at high-altitude hypoxia (4559 meters for 3 days).
4,559 m is about 11.5% FiO2
That’s probably got NF kappa B going.
Interesting chart + reasoning @John_Hemming: Health benefits of life at moderate altitude: does hypoxia matter? 2025
Epidemiological studies show that living at moderate altitudes, i.e., 1,000–2,500 m, is associated with beneficial health effects when compared to lower altitudes. […] However, it remains unclear how the small decrease in barometric – and associated partial oxygen – pressure at moderate altitude could provoke beneficial adaptive responses. At least in awake and resting humans, the resulting mild hypoxic conditions are not thought to induce robust hypoxic responses. This opinion article discusses why hypoxic episodes can occur even at moderate altitudes and which effects they may trigger to contribute to the beneficial health outcomes mentioned above.
The oxygen-hemoglobin dissociation curve (ODC, Figure 1) illustrates that there is an apparently negligible decline of the arterial oxygen saturation (SaO2) when moving from sea level to moderate altitudes, i.e., 1,000–2,500 m, in the provided example in Figure 1 of <2%. This is the case despite an expected large decrease of the arterial partial pressure of oxygen (PaO2) from about 100 mmHg to 70 mmHg at 2,240 m (Cid-Juárez et al., 2023). From this point (the knee of the ODC), a steep decline of SaO2 follows with each further drop in PaO2.
Depending on factors like increased temperature and decreased pH of blood, the ODC is shifted to the right during physical exercise. This results in a much more pronounced (>6%) drop in SaO2 already at moderate altitude (i.e., 2,240 m in the example of Figure 1) compared to sea level conditions. Thus, during exercise, SaO2 drops from about 95% at rest to below 90%, usually considered to indicate hypoxemia. Similarly, PaO2 also declines during mild hypoventilation (e.g., during normal sleep or sleep-disordered breathing), resulting in considerably more pronounced decreases of SaO2 at moderate altitudes than at sea level (Rojas-Córdova et al., 2023). This behavior of the ODC may be highly relevant for the more than 860 million people residing at moderate altitudes between 1,000 and 2,500 m worldwide (Tremblay and Ainslie, 2021) and also for the many millions of people annually visiting moderate altitudes for sightseeing, hiking and skiing (Burtscher et al., 2023b). Consequently, people living at or sojourning to moderate altitudes repeatedly experience physiologically relevant drops in oxygen availability, likely inducing a phenomenon similar to “hypoxia conditioning”.
=> So what is the SpO2 and paO2 of someone living at 2,000m of altitute during sleep or exercise?
Mortality was reduced in both sexes when living between 1,000 and 2,000 m compared to those living lower: by 15% (13–18%) in men and by 22% (20–24%) in women (p < 0.05).
Also Cross-posting this n=2 trial in PD: Parkinson's disease - #933 by adssx
You and I have worked this one out. The HIF response is from a change in PaO2, but there is a benefit from lower chronic PaO2 which arises from lower ROS.
Yes but I also think that:
I think you may be right.
Sexual dimorphisms in phrenic long-term facilitation following severe acute intermittent hypoxia 2025
It’s a preprint showing different effects in male vs female rats:
Rigorous pre-clinical research in male rodents defined the cellular mechanisms of respiratory neuroplasticity following brief exposures to hypoxia (acute, intermittent hypoxia; AIH). AIH elicits phrenic long-term facilitation (pLTF), a progressive increase in phrenic nerve amplitude over time. Mechanisms to AIH-induced pLTF are complex and variable depending on the severity of hypoxemia during AIH. Moderate AIH (mAIH; PaO2 ~35-45mmHg) triggers spinal serotonin receptor activation to induce pLTF expression. More severe AIH (sAIH; PaO2 ~25-30mmHg) induces pLTF through an adenosine receptor-dependent pathway. Here we assessed: 1) if sAIH-induced pLTF is expressed in female rats, and whether sAIH-pLTF is impacted by the estrous cycle; 2) if the magnitude of sAIH-induced pLTF in female rats is similar to male rats; and 3) whether GDX alters the magnitude of sAIH-induced pLTF. We hypothesized that female rats would express sAIH-induced pLTF, and that circulating steroid hormone levels would have minimal impact on sAIH-induced pLTF in either sex. Our findings reveal that female rats express robust pLTF (~106% above baseline phrenic amplitudes) in response to sAIH, with minimal effects of estrous cycle stage. Female rats also showed a nearly 50% higher magnitude in sAIH-pLTF than males (p=0.006). Following GDX, pLTF magnitude was reduced in female rats (p=0.04), while males were unable to express pLTF. These findings predict unique cellular mechanisms to pLTF in female rats following sAIH, and sex-specific impacts of steroid hormone signaling on the expression of respiratory neuroplasticity.
They conclude:
Trumbower and colleagues demonstrated this idea by showing that caffeine, a common A2A receptor antagonist, augmented AIH-induced gains in walking function in individuals with chronic spinal cord injury. Should there be unique, female-specific mechanisms to sAIH, then the chosen targets to enhance the clinical effects of AIH in women may be different.
To ascertain the effect of hypoxic/hyperoxic shifts on immunity, a series of 11 days hypobaric chamber studies were conducted at the Johnson Space Center. The living environment consisted of 8.2–9.6psi/28.5%–34% oxygen, and there were several simulated EVAs which were performed under hypobaric/hyperoxic conditions consisting of 4.3psi/85%–95% oxygen. For the current sub-study, biosamples were collected before and after simulated EVAs to ascertain the effects of hypoxia, decompression and hyperoxic stress on immunity. The sub-study consisted of 3 chamber tests, 23 total subjects.
The primary finding from this study is that, while living in a mildly hypoxic exploration atmosphere did not have a profound impact on immunity, the participation in hypobaric/hyperoxic EVA activities impacted numerous and varied immune parameters.
They used very mild hypoxia equivalent to 18-19% FiO2.
