adssx
#57
In this paper, they found that “The lifespan extension observed in IHT does not require HIF-1 but is partially blocked by loss of DAF-16/FOXO.”
And in this paper from last month, a team at Harvard created “hypoxia in a pill” by combining two drugs:
GBT440 (Voxelotor) is “an allosteric activator of oxygen affinity recently approved for sickle cell anemia”. PT2399 is an analogue of belzutifan (“a member of a new class of HIF-2α inhibitors approved for renal cell cancer”).
Preclinical studies have demonstrated the therapeutic potential of hypoxia for treating mitochondrial disorders. In the Ndufs4-KO mouse model of Leigh syndrome and the shFxn model of Friedreich’s ataxia, continuous breathing of 11% oxygen can prevent and reverse neurological disease, while 55% oxygen accelerates disease. Multiple mechanisms likely underlie the benefits of hypoxia, including attenuation of oxygen toxicity from brain hyperoxia, restoration of Fe-S clusters, and normalization of oxygen sensing. Alternative means of reducing oxygen delivery, including sublethal carbon monoxide and severe anemia, also reverse brain disease in Ndufs4-KO mice. Intermittent regimens of inhaled hypoxic air — 16 hours of 11% and 8 hours of 21% — have proven ineffective — probably due to a compensatory, HIF-2α–dependent increase in hemoglobin (Hb) that, combined with periods of 21% oxygen, may be detrimental. Collectively, these studies highlight the potential of hypoxia therapy but also underscore the need for more practical modalities that are safe and effective.
our drug combination could safely achieve tissue hypoxia
Brain MRI revealed characteristic T2-intense, Leigh-like lesions and/or hemorrhages in vestibular or cerebellar nuclei that were attenuated or even absent with the combination
Although neither drug individually affected lifespan, the combination extended median lifespan by 30% from approximately 70 to 98 days and maximum lifespan from 80 to 144 days (P < 0.0001)
Our results provide preclinical proof of concept that simultaneously enhancing Hb oxygen affinity while antagonizing HIF-2α can mimic the effects of continuous hypoxic breathing for therapeutic benefit. The regimen did not confer as impressive a lifespan rescue as continuous breathing of 11% oxygen, probably because GBT440 has a short half-life (6), and for practical reasons, we treated the mice five weekdays per week. Future studies in humans are required to evaluate the safety of this combination, given that hypoxia can be associated with acute and long-term side effects. Such safety studies could pave the path for first-in-human “hypoxia-in-a-pill” trials in patients with mitochondrial disease.
Do these two papers update your views @John_Hemming? Interesting mention of anemia, which is a protective factor in PD, together with another source of hypoxia… asthma!
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I haven’t spent a lot of time looking at HIF 2 alpha. For now I have concluded that activating HIF 1 alpha is a good thing and hence I look for tools to do that.
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adssx
#59
I’m not sure that HIF 1 alpha is the key to benefits.
See also: Hypoxia extends lifespan and neurological function in a mouse model of aging 2023
We report that chronic continuous 11% oxygen commenced at 4 weeks of age extends lifespan by 50% and delays the onset of neurological debility in Ercc1 Δ/- mice. Chronic continuous hypoxia did not impact food intake and did not significantly affect markers of DNA damage or senescence, suggesting that hypoxia did not simply alleviate the proximal effects of the Ercc1 mutation, but rather acted downstream via unknown mechanisms.
Hypoxia significantly delays the onset of replicative senescence in cultured mammalian cells. Compared to standard atmospheric conditions (21% oxygen at sea level), hypoxia extends the number of population doublings until replicative senescence in mouse embryonic fibroblasts, primary human lung fibroblasts, and even in the presence of specific senescence-inducers such as etoposide and nutlin-3a.
While the above studies come from cell culture and invertebrate models, 2 observations raise the possibility that hypoxia could slow mammalian aging. First, the naked mole rat (H. glaber), whose lifespan far exceeds that which would be predicted by phylogeny or body mass, experiences significant durations of relative ambient hypoxia because of extreme crowding in their burrows (though the precise oxygen tension has not been measured in their natural environment). Second, in genetically heterogenous HET3 mice, a hypoxia transcriptomic signature appears to be shared among myriad interventions shown to extend lifespan in both the NIA Interventions Testing Program and long-lived mutants.
An important future goal is to define the mechanism by which chronic continuous hypoxia is extending lifespan in this model, and the extent to which this mechanism overlaps with that of pathways known to be involved in aging, such as mTOR and insulin signaling. Three plausible mechanisms are the following: (i) activation of the HIF pathway; (ii) diminution of oxidative stress; and (iii) interruption of the vicious cycle of neurodegeneration and neuroinflammation. With respect to HIF pathway activation, in our prior work in the Ndufs4 KO model, we showed that HIF activation was not sufficient to recapitulate the benefits of hypoxia, and in the current work, we did not detect a signature of HIF activation in the brain based on RNA-seq.
In multiple contexts, hypoxia has been demonstrated to increased lifespan (yeast, C. elegans) or time to replicative senescence (primary human lung fibroblasts), via an increase in ROS production which then activates life-extending pathways, a form of hormesis.
At present, we do not know where in this vicious cycle between neuronal damage and inflammation hypoxia exerts its effect—through dampening the inflammatory response to neuronal injury, or conferring neuronal resilience to the stress of DNA damage and inflammation, or some combination of the two. In either case, the vicious cycle appears to be blunted.
Epidemiologic evidence suggests that lifelong oxygen restriction might slow the aging process in humans. Though there are many potential confounders to this finding, recent cross-sectional studies in Bolivia have demonstrated significant enrichment for nonagenarians and centenarians at very high altitudes. There is also intriguing data that suggests there are potential benefits of moving to altitude in adulthood. In a longitudinal study of over 20,000 soldiers of the Indian Army assigned to serve at 2 to 3 mile elevations above sea level for 3 years between 1965 and 1972, their risk of developing the major sources of age-related morbidity in modern societies—diabetes mellitus, hypertension, and ischemic heart disease—was a fraction of the risk of their comrades serving at sea level
The interplay of NAD and hypoxic stress and its relevance for ageing 2025
In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and – conversely – controlled hypoxia is a potential tool to regulate NAD homeostasis.
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There is an issue about ROS being higher with higher O2.
However, I think there is plenty of evidence for HIF 1 alpha being useful.
It may be that people would do better at 15% O2 than 21%.
I have done a post looking a bit more at Oxygen levels.
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adssx
#62
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:
- Chronic hypERoxia is bad.
- Extreme hypoxia (below 10%?) is bad, whether chronic or acute.
- Mild chronic hypoxia (17–20%) seems safe and probably beneficial.
- 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.
- Non-HIF benefits of hypoxia: we don’t know enough…
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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
#64
Ah I don’t disagree on that, I just have very limited knowledge so I can’t comment.
@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
#66
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%.
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Thanks. I cannot hold spo2 below 90% for very long. I’m happy to stay at the “safe and probably beneficial level” anyway.
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.
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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.
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.
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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.
adssx
#74
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.
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I think we can separate out the various effects of altitude
- Lower mtDNA mutations
- Problems with breathing from a shortage of oxygen
- Higher UV damage.
There probably is an optimal pO2.
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This podcast has lots of useful information on this topic
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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