I think you may be right.
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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.
Effect of Repeated-Sprint Training in Hypoxia in Female National-Level Rugby Union Players 2025
Purpose: The aim of this study was to investigate the effects of repeated-sprint training in hypoxia (RSH) versus in normoxia (RSN) in female national-level rugby union players.
Methods: In a randomized, controlled, and crossover study, 8 female rugby union players performed 5 sessions of repeated sprints either in normobaric hypoxia (RSH, simulated altitude: 3000 m; FiO2 = 14.5%) or in normoxia (RSN, terrestrial altitude: 165 m; FiO2 = 20.5%). Before (Pre) and after (Post) training, repeated-sprint ability (6 × 10-s “all-out” sprints and 20-s recovery) was evaluated on a cycle ergometer.
Results: From Pre to Post, peak power output was improved in RSH (602 [98] vs 704 [92] W; P = .007) but not in RSN (661 [91] vs 673 [76] W; P = .560). Similarly, mean power output was enhanced in RSH (445 [63] vs 532 [51] W; P = .013) but not in RSN (499 [88] vs 509 [63] W; P = .557). Sprint decrement did not change in either RSH (24.5 [8.9] vs. 24.0% [5.7%]; P = .819) or RSN (22.7 [5.9] vs 24.3% [4.8%]; P = .336).
Conclusion: As few as 5 sessions of RSH were beneficial for improving peak and mean power outputs during repeated-sprint exercise in female national-level rugby union players compared with the same training in normoxia.
May be due to reduction in serotonin in certain areas of the brain:
Hypoxia can adversely affect multiple organ systems. This study investigated the impact of intermittent hypoxia on serotonin levels and depression-like behaviors across distinct neuroanatomical regions. Sixteen adult female Wistar albino rats were divided into two groups: control (n = 8) and hypoxia (n = 8). The hypoxia group was exposed to a simulated altitude of 3000 for 5 h daily over 14 days. Behavioral assessments included locomotor activity (open field test) and depression-like behaviors (forced swimming test). Serotonin levels were quantified via ELISA in the prefrontal cortex, striatum, thalamus, hypothalamus, hippocampus, and serum. Intermittent hypoxia did not alter locomotor activity (p > 0.05) but significantly increased depression-like behavior (p < 0.05), accompanied by a pronounced reduction in swimming behavior (p < 0.0001), a marker associated with serotonergic function. Serotonin levels were significantly reduced in the prefrontal cortex (p < 0.005) and striatum (p < 0.05), while no changes were observed in other regions or serum (p > 0.05). These findings demonstrate that intermittent hypoxia induces depression-like behaviors and region-specific serotonin depletion, particularly in the prefrontal cortex and striatum. This underscores the need to evaluate hypoxia-related brain health implications in conditions such as sleep apnea and acute mountain sickness.
Canadian preprint: Resynchronization of the biological clock using exposure to low oxygen levels in humans: an exploratory study 2025
In condition 1 (Hypo), participants underwent a 2-hour normobaric hypoxic exposure (FiO2 = 12%), starting 2 h after habitual wake time. In condition 2 (Lum+Mel), participants received a 3-hour luminotherapy session (500 nm, 506 lux) at the same time point, combined with 5 mg of exogenous melatonin administered 6 hours before usual bedtime. Salivary melatonin levels were measured in each phase of the study to assess circadian phase shifts.
Salivary melatonin levels increased progressively over time in all conditions (p < 0.001), with significant differences observed between experimental conditions (p < 0.001), but no interaction effect (p = 0.854). Exposure to hypoxia significantly reduced oxyhemoglobin saturation (p < 0.05) and increased heart rate and subjective symptoms of fatigue. In terms of circadian phase, the dim light melatonin onset (DLMO) occurred 1.30 hour (78 minutes) earlier in the Lum+Mel condition compared to baseline (p=0.001). In the hypoxia condition, the DLMO occurred on average 0.58 hour (34.8 minutes) earlier than baseline, but this change did not reach statistical significance (p=0.156).
This study provides preliminary evidence that normobaric hypoxia may modestly advance the human circadian phase, although not to a statistically significant extent. In contrast, combined phototherapy and melatonin administration produced a robust and significant phase advance in salivary melatonin onset. These findings suggest that while hypoxia may influence circadian timing, established interventions like light and melatonin remain more effective for circadian realignment. Further research is warranted to elucidate the mechanisms and optimize the application of hypoxia in circadian modulation.
If hypoxia can increase melatonin secretion that’s interesting @John_Hemming.
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Its an interesting thought.
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Hypoxic conditioning in Parkinson’s disease: randomized controlled multiple N-of-1 trials 2025
It’s been a long wait… Results of the phase 1 trial of hypoxia in PD. tl;dr:
- It’s safe (based on subjective feelings and brain biomarkers)
- Intermittent hypoxia is better than continuous
- Small symptomatic improvements
- 16.3% FiO2 is better than 12.7%
Based on these results, they ran a phase 2 trial at 16.3% over several weeks. Results due to be published in the next 12 months…
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“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)”
I’m curious if anyone here has been using this protocol and taking Rapamycin. I’ve been doing it 3-4 Xs a week going between a hypoxicator and oxygen concentrator since reading the book [Undoing Lyme Disease].
Also, cycling on and off once a week Rapamycin.
3 sessions per week over an 8-week period
Sessions began with a 5-min baseline period while breathing room air, followed by seven cycles of hypoxia, each lasting 5 min interspersed with 3-min periods of normoxic breathing (Figure 2). Using a gas-mixing device (Altitrainer®, SMTEC S.A., Nyon, Switzerland), the inspired fraction of oxygen (O2) was individually adjusted during each session to achieve a target arterial O2 saturation assessed by pulse oximetry (SpO2 = 80% from week 1 to week 4; 75% from week 5 to week 8) (Radical-7®, Massimo corporation, Irvine, CA, USA). Each session ended with a 5-min normoxic phase, allowing participants to return to their pre-session physiological state. In total, each session lasted 63 min, including 35 min of hypoxic breathing.
Brachial artery FMD, cardiopulmonary exercise testing (CPET), and ambulatory 24-h blood pressure were assessed at baseline (Pre), immediately post-intervention (Post 1), and 2 months later (Post 2). FMD showed a trend toward improvement in the IHC group, being significant when normalized for baseline artery diameter (p = 0.023; ηp2 = 0.150) between Pre and Post 2. Peak ventilation during CPET increased from Pre to Post 1 (p = 0.021), with no other significant CRF changes. Daytime systolic blood pressure decreased by 6 mmHg (p = 0.070, ηp2 = 0.105). No significant alterations in these outcomes were observed in the CTL group (p > 0.05). Moderate IHC enhanced mid-term endothelial function, suggesting potential to mitigate age-related vascular decline.
Healthy young adults (N = 24) completed an IH protocol entailing 12 alternating 5-min normoxic (PETO2 = 100 mmHg) and hypoxic (PETO2 = 50 mmHg) intervals that were normocapnic and isocapnic, and on a separate day completed a time-matched normoxic control protocol. Prior to (T0), and immediately (T1) and 30 min (T2) following each protocol, EF was assessed via the antisaccade task. Antisaccades require a goal-directed eye movement (i.e., saccade) mirror-symmetrical to a target and provide the resolution to detect subtle EF changes. As expected, hypoxic intervals decreased arterial and cerebral tissue O2 saturation and increased CBF as estimated via near-infrared spectroscopy and transcranial Doppler ultrasound (ps < 0.001). In turn, antisaccade reaction times (RT) did not differ between T0 and T1 (p = 0.29); however, at T2 a reliable RT reduction was observed (p = 0.004).
Better reaction time after intermittent hypoxia @John_Hemming . They used approximately 10% FiO2! On the other hand that other paper did not find cognitive benefits:
Twelve volunteers with chronic TBI underwent four AIH sessions conducted on separate days, in which they were exposed to fifteen 30-60-s hypoxic episodes interspersed with 60-90 s of breathing ambient air. Inspired oxygen (O2) concentration during hypoxic episodes was gradually reduced from 21% (equal to ambient air, sham), to 17%, 13%, and 9%, over the course of four sessions.
No significant improvement in cognition or mood was noted after the AIH intervention.
Motor performance gradually improved over the course of the study, but no significant changes in response to TMS were found in corticospinal excitability.
AIH dosage as low as 9% O2 appears safe to use in chronic TBI, but its potential benefits remain to be investigated.
Intermittent hypoxia promotes fatty acid metabolism and improves myocardial energy homeostasis potentially via AMPKα1 pathway 2025: “IH intervention enhances fatty acid metabolism, improves mitochondrial tricarboxylic acid cycle efficiency, promotes ATP synthesis, preserves mitochondrial ultrastructure, reduces fibrosis, and improves cardiac function in MI rats, potentially through AMPKα1 pathway activation.”
I wonder if there is a differential impact of hypoxia treatment on those who permanently reside at high elevations.
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This is insane, the same team published the same paper somewhere else and the conclusion is different:
The present work does not support the potential benefits of IHC on cerebrovascular function.
Other recent papers:
Rebreathing-induced hypoxemia improves glucose tolerance in adults with type 2 diabetes 2025
Hypoxia stimulates glucose uptake in isolated skeletal muscle through an insulin-independent pathway. Intermittent hypoxia can lower glucose concentration in adults with type 2 diabetes, but its application remains limited by the use of gas tanks to induce hypoxia. The aim of this study was to examine the effect of rebreathing-induced hypoxia on glucose and insulin responses to an oral glucose tolerance test in adults with type 2 diabetes. Ten adults with type 2 diabetes performed an oral glucose tolerance test during either rebreathing-induced hypoxia or spontaneous breathing. The glucose and insulin responses to the oral glucose tolerance test did not differ between rebreathing-induced hypoxia and spontaneous breathing. However, participants who achieved hypoxemia, defined as an oxygen saturation nadir below 90%, during rebreathing-induced hypoxia (n = 5) showed lower glucose concentrations and glucose area under the curve (AUC) (20,376 ± 553 vs. 24,346 ± 639, p < 0.01) than participants who achieved an oxygen saturation nadir above 90% (n = 5). Interestingly, body weight was strongly correlated with oxygen desaturation (r = −0.87, p < 0.01) and glucose AUC (r = −0.81, p < 0.01) during rebreathing-induced hypoxia. Rebreathing-induced hypoxia may represent a promising strategy to improve glycemic control in adults with type 2 diabetes and coexisting obesity.
Exposure to acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF). We have shown that nucleus tractus solitarii (nTS) activity is necessary for both the development and maintenance of pLTF. Activation of glutamatergic N-Methyl-D-Aspartate receptors (NMDARs) and CaMKII contribute to in vitro long-term potentiation, nTS hypoxic responses and possibly to pLTF. This study investigated the role of nTS NMDARs and CaMKII to the development and maintenance of AIH-induced pLTF. Phrenic nerve and splanchnic sympathetic nerve activity (PhrNA and sSNA) were recorded in male Sprague-Dawley rats in response to AIH [10 bouts of 10% O2 (45 sec, interspersed by 5 min)]. Time controls (TC) underwent a single hypoxia bout and were monitored for two hours afterward. Following AIH, PhrNA amplitude increased compared to initial baseline (BL) and TC, indicating induction of pLTF. pLTF development was associated with increased nTS neuronal Ca2+ and action potential discharge recorded via GCaMP8 fiber photometry and an array probe, respectively. Inhibition of nTS CaMKII activity prior to AIH exposure attenuated the development of pLTF and elevation of nTS neuronal discharge. In contrast, after pLTF had developed, inhibiting nTS CaMKII activity had no effect on the maintenance of pLTF. Nevertheless, after AIH blocking NMDARs specifically in the nTS by bilateral nanoinjection of AP5 reduced the magnitude of pLTF. Altogether, these results indicate that increased nTS neuronal activity likely due to activation of NMDARs and their downstream CaMKII signaling complex are critical components for AIH-induced neuroplasticity in central cardiorespiratory output.
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The experimental group performed these tasks before and after an intermittent hypoxia session (12%, 4400 m) with the iAltitude simulator, while the control group completed them before and after normoxic conditions without hypoxia exposure.
A single session of intermittent hypoxia did not produce clear changes in executive function against control group, which suggests that it may not alter cognitive function at the acute level.
Chinese article from a random university but a good reminder of the complex effects of hypoxia: Molecular mechanisms of α-syn abnormal phase separation in cognitive impairment induced by chronic intermittent hypoxia and the neuroprotective effects of Danshensu methyl ester 2025
The IH group and DME + IH group underwent intermittent hypoxia treatment in a hypoxic chamber for six consecutive days following attaching.
The IH protocol consisted of four phases, with one cycle occurring approximately every 80 min. It involved N2 injection to decrease oxygen levels from 21% ± 1–3% ± 1% in 20 min, maintaining it for 20 min, followed by a return to 21% ± 1% for 20 min, and a 20-minute maintenance period in the fourth stage, with CO2 levels consistently at 5%.
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Not hypoxia but hypercapnia: The influence of intermittent hypercapnia on cerebrospinal fluid flow and clearance in Parkinson’s disease and healthy older adults 2025
A failure of the glymphatic pathway to clear brain byproducts implicated in neurodegeneration may contribute to the pathophysiology of Parkinson’s disease. The glymphatic pathway relies on vasomotion (rhythmic constriction and dilation of blood vessels) to drive cerebrospinal fluid through the interstitial space and clear waste from the brain. The current study demonstrated that intermittent hypercapnia, exposure to low levels of CO2 in ON-OFF cycles, elicited vasomotion-induced cerebrospinal fluid inflow in both healthy controls and individuals with Parkinson’s disease. The magnitude of the vasomotion-induced cerebrospinal fluid inflow in patients with Parkinson’s disease was reduced relative to healthy controls. However, intermittent hypercapnia, administered in three 10-minute sessions totaling approximately 30 minutes, increased the appearance of total α-synuclein, neurofilament light, glial fibrillary acidic protein, amyloid β1-42, amyloid β1-40, and phosphorylated tau 217 in the plasma of both healthy controls and individuals with Parkinson’s disease. This suggests that intermittent hypercapnia can be used to clear potentially toxic brain byproducts from the brain, highlighting its potential use as a disease modifying treatment.
It may be a useful tool, but does not necessarily fix the underlying problem.
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: Intermittent hypoxia training (IHT) stimulated hepatic Ca2+ influx and mitochondrial quality control.
IHT enhanced tolerance to subsequent hypoxic exposure.
Adenine nucleotide translocase (ANT) enhanced mitochondrial Ca2+ transport and buffering capacity.
ANT enhanced mitochondrial quality control and antioxidant defenses.
memory-enhancing acute intermittent hypoxia (meAIH; ∼10% oxygen) protocol
Results indicated that during the initial acquisition phase, the meAIH group performed significantly better on a declarative memory task than the SHAM group (p < 0.05), but not the retention phase. These novel results inform the understanding of cognitive neuroplasticity within young, healthy adults and how meAIH can be used to inform training paradigms for many populations.
In this review, we summarize current knowledge on hypoxia tolerance, oxygen transport, and oxygen consumption in humans, rats, and mice, and evaluate the extent to which findings from rodent models can be extrapolated to humans. While the anatomical, physiological, and molecular foundations of oxygen transport and utilization are broadly conserved across species, there are important quantitative differences—largely linked to body-mass variation—as well as qualitative distinctions. Mice that evolved in high-altitude environments, display remarkable hypoxia tolerance. Their physiological repertoire includes highly efficient pulmonary gas exchange, metabolic downregulation, and substantial plasticity of the mitochondrial electron transport system under hypoxic conditions. In contrast, rats exhibit heightened vulnerability in hypoxia, manifesting as right ventricular hypertrophy, excessive erythropoiesis, and myocardial injury. These interspecies differences highlight that the robust hypoxia tolerance of mice—and the potentially comparatively greater susceptibility of rats than humans—must be carefully considered when translating findings from rodent hypoxia research into human contexts.
IH is an effective and adaptable strategy to improve aerobic and anaerobic performance, as well as to enhance muscle strength and hypertrophy. These benefits often occur without consistent hematological changes. Future studies should focus on individualized approaches, standardization of terminology, and precise quantification of both hypoxic exposure and training load to optimize outcomes and ensure reproducibility.
Reminder, long-term intermittent hypoxia similar to the one in sleep apnea is detrimental: Prolonged intermittent hypoxia accelerates cardiovascular aging and mortality: insights from a murine model of OSA 2025
Current methods are live-high train-low (LHTL), live-low train-high (LLTH), and passive hypoxic conditioning (PHC).
Conclusion: LLTH showed a significant effect on VO2max in both athletic and non-athletic populations, while LHTL and PHC did not. Future studies should investigate factors driving the effects.
Chinese paper in a low-quality journal: Chronic intermittent hypoxia increases Parkinson’s disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction 2025
Results: We revealed that CIH significantly exacerbated nigrostriatal DA neurodegeneration and motor dysfunction in subtoxic PD models. Mechanistically, we identified a PPARα-dependent disruption of Mfn2-Plin5 tethering, which impaired LD-mitochondrial interactions, thereby compromising LD turnover and promoting pathological LD accumulation within DA neurons. Crucially, pharmacological interventions targeting the LD-mitochondrial axis, including strategies to enhance LD catabolism, inhibit mitochondrial fission, or restore LD-mitochondrial tethering, effectively mitigated nigrostriatal DA neurodegeneration in CIH-preconditioned subtoxic PD models.
However, it is important to recognize a number of this study’s limitations. First, we found that lipid transfer between DA neurons and microglia was primarily mediated by APOE, as competitive inhibition of LDLR reduced lipid transfer by more than 50% (Figure 3). However, intercellular lipid trafficking is not restricted to the APOE pathway. Previous studies have reported that tunneling nanotubes (TNTs) and secretory vesicles, including exosomes and microvesicles, also participate in lipid transfer between cells [53,54]. In this study, we did not evaluate the contribution of these additional pathways and future investigations should systematically assess their roles by employing microtubue inhibitors (e.g., vincristine) to disrupt TNTs formation or exosome secretion inhibitors (e.g., GW4869) in combination with lipid tracing assays. Secondly, although PPARα is known to regulate transcription by directly binding to the promoters of target genes, it can also act through non-geomic mechanisms, such as suppressing the activity of other transcription factors (e.g., NF-κB) [55]. In the current study, we did not determine whether the regulation of Mfn2 and Plin5 by PPARα is mediated through direct promoter binding or indirect signaling pathways. Future studies should address this by performing ChIP-qPCR or ChIP-seq to directly validate PPARα binding to the Mfn2 and Plin5 promoters, and by incorporating luciferase reporter assays to further clarify the transcriptional regulatory mechanisms.
Does any of this matter if you don’t have sleep apnea?
That’s the question. It shows that too much intermittent hypoxia is bad but it doesn’t say whether a bit of it is good. (Nor does it define the threshold of “too much” but given that hypoxia in OSA is daily and for hours whereas for hypoxic therapy it’s for a few minutes every other day, we can assume it’s low enough).
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