The framework rests on a simple but powerful physiological observation. Every step of the oxygen cascade shows measurable age-related decline. Starting at roughly 21 percent of inspired oxygen at sea level, the partial pressure of oxygen drops sequentially across the alveoli, the arterial blood, the microcirculation, the interstitial space, and the mitochondria. In youth, this cascade is buffered by remarkable resilience: ventilation, cardiac output, capillary recruitment, and mitochondrial function adjust continuously to match oxygen supply with metabolic demand. With age, that adaptive capacity erodes at every level simultaneously. The authors emphasize that Oxygenaging is not simply a state of oxygen deficiency. Rather, it reflects a progressive loss of resilience in the mechanisms that maintain oxygen homeostasis, leaving older organisms increasingly vulnerable to mismatches between oxygen availability and energetic requirements — mismatches that compromise cellular function, tissue integrity, and physiological reserve.

The first step of the cascade, pulmonary gas exchange, deteriorates through well-characterized structural changes. Age-related loss of elastin fibers reduces lung elastic recoil, promoting premature closure of small airways, particularly in gravity-dependent regions of the lung. These poorly ventilated but still perfused units act as functional shunts, widening the alveolar-arterial oxygen gradient and increasing ventilation-perfusion heterogeneity — quantified by the log standard deviation of perfusion distribution, which rises from roughly 0.36 in younger adults to 0.47 in older individuals. Empirical reference equations established decades ago show that age is the single most robust predictor of arterial oxygenation, with arterial oxygen partial pressure falling by approximately 15 to 20 mmHg between mid-life and old age. The review also highlights a less appreciated mechanism: systemic iron deficiency, common in aging, mimics hypoxia at the pulmonary endothelium by inhibiting prolyl hydroxylase domain enzymes, exaggerating hypoxic pulmonary vasoconstriction and placing additional strain on the right ventricle.

The second step, central hemodynamics, compounds the problem. Oxygen delivery is the product of arterial oxygen content and cardiac output, and in aging the decline in maximal heart rate — dropping roughly 25 percent, from about 200 beats per minute in youth to about 150 in old age — becomes the dominant bottleneck on peak oxygen delivery. The aging system also fails to shift the hemoglobin-oxygen dissociation curve rightward at baseline to facilitate tissue oxygen unloading; because systemic 2,3-bisphosphoglycerate levels do not rise with healthy aging, tissues depend heavily on acute stressors such as the heat and acidosis of exercise — the Bohr effect — to release oxygen from hemoglobin. Combined with the flat upper plateau of the dissociation curve, which prevents healthy lung regions from over-compensating for failing ones, these deficits translate into a measurable drop in overall arterial saturation and a progressive constraint on systemic oxygen supply.

The third and arguably most consequential step occurs in the microvasculature. Maximal oxygen uptake, the integrated measure of the entire cascade, falls by approximately 10 percent per decade, limited both by reduced central delivery and by peripheral failure of oxygen extraction. Aging brings microvascular rarefaction, endothelial dysfunction with reduced nitric oxide bioavailability, and increased diffusion distances caused by fibrosis and diminished pericyte coverage. Even when bulk blood flow appears adequate, the aged microvasculature mounts a sluggish hyperemic response to exertion, failing to raise microvascular oxygen pressure precisely when the diffusion gradient into mitochondria is needed most. Notably, the authors point to a metabolic peculiarity of endothelial cells: they rely primarily on glycolysis rather than oxidative phosphorylation, and aging disrupts this specialization, crippling the migratory and proliferative machinery required for angiogenesis. This explains why simply supplementing oxygen may fail to rescue microvascular function in older tissues.

Organ-specific evidence grounds the framework in measurable clinical data. Near-infrared spectroscopy studies show regional cerebral oxygen saturation falling from roughly 69.8 percent in young adults to 62.7 percent in older adults, driven by pericyte degeneration, blood-brain barrier leakage, and uncoupling of endothelial nitric oxide synthase within the neurovascular unit. Renal BOLD-MRI reveals progressive medullary hypoxia as peritubular capillary rarefaction and tubulointerstitial fibrosis enlarge diffusion distances. In skin, transcutaneous oxygen measurements expose a blunted neurogenic vasodilatory response to thermal stress, reflecting extracellular matrix stiffness that mechanically limits vessel expansion. In skeletal muscle, phosphorus-31 magnetic resonance spectroscopy shows that post-exercise phosphocreatine recovery slows from about 37 seconds in young muscle to about 52 seconds in aged muscle, paralleled by reduced mitochondrial content, mild uncoupling via uncoupling protein 3, and instability of respiratory supercomplexes.

At the molecular level, the review describes how the hypoxia-inducible factor system — the ancient oxygen-sensing machinery conserved across metazoans — becomes maladaptive with age. In youth, prolyl hydroxylase domain enzymes use oxygen, alpha-ketoglutarate, and iron to tag HIF-1alpha for degradation, keeping the pathway exquisitely responsive to genuine hypoxia. With aging, declining NAD+ reduces SIRT1 activity and lowers von Hippel-Lindau expression, while accumulating succinate directly inhibits PHD catalytic activity. Both routes converge on the same outcome: stabilization of HIF-1alpha under normal oxygen conditions, a state the authors term chronic pseudohypoxia. This maladaptive activation suppresses mitochondrial biogenesis through the MYC-TFAM axis, impairs mitophagy through lysosomal dysfunction, and leaves a pool of damaged, reactive-oxygen-species-leaking mitochondria. The framework also intersects with iron biology — what the authors call Ferroaging — as an expanded labile iron pool catalyzes the Fenton reaction during reoxygenation, priming vulnerable cells for ferroptosis, an iron-dependent form of cell death.

The consequences ripple through metabolism and the genome. Hyperactive mTOR signaling in aging overrides HIF-1alpha’s normal metabolic brake, forcing cells to continue energy-consuming anabolic growth despite insufficient oxygen. HIF-1alpha-mediated suppression of lipolysis — the so-called lipid lock — promotes triglyceride accumulation and hepatic steatosis. Meanwhile, oxygen availability physically constrains the dioxygenase enzymes that govern the epigenetic clock: ten-eleven translocation enzymes and JmjC-domain histone demethylases all require oxygen as a co-substrate, so declining tissue oxygen pressure may directly accelerate the accumulation of aberrant methylation patterns characteristic of cellular senescence. Supporting this, the authors’ own recent work showed that intermittent hypoxia in old mice accelerated epigenetic age in lung, spleen, and heart by up to five months — an effect that reversed after return to normoxia. Hypoxia also reshapes the RNA splicing landscape, promoting intron retention and isoform switching that, when dysregulated by age-related transcriptomic noise, may generate aberrant proteins and neoepitopes that provoke immune surveillance.

The framework’s most provocative implications are therapeutic. The authors survey emerging gerotherapies that deliberately modulate the oxygen cascade: intermittent hypoxia, which in carefully dosed protocols activates neurotrophic BDNF-TrkB signaling and enhances motor recovery after spinal cord injury; hyperbaric oxygen therapy, which exploits the hyperoxic-hypoxic paradox — the rapid pressure drop from over two atmospheres back to sea level — to trigger HIF-1alpha signaling without true hypoxia, with preliminary reports of telomere elongation exceeding 20 percent in immune cells and clearance of senescent T cells; and intermittent hypoxic-hyperoxic training, which alternates low and high oxygen to drive mitophagy-based mitochondrial selection. The authors caution, however, that the hormetic dose-response curve likely shifts with age: interventions beneficial in young organisms may prove toxic in frail older adults whose NRF2-mediated antioxidant buffering is compromised. Sex differences, frailty, and individual variability in hypoxic ventilatory response further narrow the therapeutic window. Their prescription for the field is rigorous: define therapeutic windows tailored to biological rather than chronological age, monitor real-time biomarkers of oxidative stress and mitochondrial function during therapy, and conduct randomized controlled trials stratified by frailty status. Oxygen-sensing pathways, they argue, represent a high-leverage gerotherapeutic target — one that could help decouple chronological age from biological decay and chart a roadmap toward extending human healthspan.

Subject of Research: Age-related decline in the oxygen transport cascade and its role in the biology of aging

Article Title: Oxygenaging: A Physiological Framework for Geroscience

Article References: Donega, S., Fishbein, K. W., Dominelli, P., Herman, A. B., de Cabo, R., Gorospe, M., & Ferrucci, L. (2026). Oxygenaging: A Physiological Framework for Geroscience. Aging Cell, 25(9), Article e70664. https://doi.org/10.1111/acel.70664

Image Credits: AI Generated

DOI: 10.1111/acel.70664

Keywords: Oxygenaging, geroscience, oxygen cascade, HIF-1alpha, mitochondrial dysfunction, microvascular rarefaction, pseudohypoxia, ferroptosis, hyperbaric oxygen therapy, intermittent hypoxia, epigenetic aging, Aging Cell

Vascular cognitive impairment, characterized by deficits in memory, attention, and executive function, occurs as a consequence of chronic cerebral hypoperfusion. Hypoperfusion leads to progressive neuronal damage, increased neuroinflammation, and subsequent cognitive deterioration. Traditional treatment strategies have largely been symptomatic, with limited success in modifying underlying pathophysiology. By leveraging HBOT—a method established for enhancing tissue oxygen saturation—scientists have investigated its potential to restore cerebral microenvironment homeostasis and counteract VCI progression at a molecular level.

Hyperbaric oxygen therapy functions by delivering oxygen at pressures exceeding atmospheric levels, significantly increasing plasma oxygen content and fostering elevated tissue oxygenation. This phenomenon is crucial for neurorepair mechanisms in ischemic and hypoxic brain conditions. In the present research, the therapeutic regimen consisted of controlled HBOT sessions applied to a well-validated mouse model of VCI induced by bilateral common carotid artery stenosis, simulating prolonged cerebral hypoperfusion. This design ensures translational relevance, as it mirrors vascular contributions to cognitive dysfunction observed clinically.

Central to the study’s novel findings is the modulation of microRNA-137-3p (miR-137-3p), a small non-coding RNA molecule known to regulate gene expression post-transcriptionally. The researchers discovered that HBOT significantly upregulated miR-137-3p levels in the hippocampus and cortex—regions critically involved in learning and memory. This upregulation was linked to downstream inhibition of tumor necrosis factor receptor-associated factor 3 (TRAF3), a pivotal adaptor protein that orchestrates inflammatory signaling pathways, including NF-κB and MAPK cascades, thereby influencing neuroinflammation and cell survival.

Analyzing neuroinflammatory markers, the team reported a robust decrease in pro-inflammatory cytokines such as TNF-α and IL-1β post-HBOT, correlating with reduced microglial activation. Microglia, the brain’s resident immune cells, are known to exacerbate neuronal injury when chronically activated. This inflammatory suppression via the miR-137-3p/TRAF3 axis highlights a critical neuroprotective mechanism by which HBOT mitigates secondary damage resulting from hypoperfusion-induced inflammation.

Notably, behavioral assessments in the treated mice revealed pronounced improvements in spatial memory and cognitive flexibility, as evaluated by the Morris Water Maze and Y-maze tests. These behavioral outcomes provide functional validation for the molecular alterations observed, firmly positioning HBOT as a potential disease-modifying intervention rather than merely symptomatic relief. The cognitive benefits evidenced in the mouse model evoke optimism for clinical adaptability in human populations suffering from vascular contributions to cognitive impairment and dementia (VCID).

Further histopathological examination elucidated that HBOT promoted neuronal survival and synaptic integrity. Quantitative analyses displayed increased expression of synaptic proteins, such as PSD-95 and synaptophysin, alongside attenuation of apoptotic markers like cleaved caspase-3 in treated animals. Preservation of synaptic connectivity is essential for maintaining neuronal circuitry that underpins cognition, reinforcing the therapeutic promise of HBOT in neurodegenerative diseases marked by synaptic loss.

The translational implications of this study resonate profoundly within the neuroscience and clinical communities. Current pharmacological interventions for VCI lack robust efficacy and are often accompanied by adverse effects. In contrast, HBOT is emerging as a non-invasive strategy with the potential to target multiple pathogenic facets of vascular cognitive impairment. Its capacity to modulate microRNA expression and dampen neuroinflammation introduces a paradigm shift in therapeutic design, paving the way for next-generation precision medicine.

From a mechanistic perspective, the delineation of the miR-137-3p/TRAF3 pathway unravels new targets for drug development. MicroRNAs are attractive candidates for therapeutic manipulation due to their fine-tuning capabilities of gene networks. Understanding the intricacies of their regulation by oxygen levels and inflammatory signals could inspire novel combinatorial treatments that synergize with HBOT, amplifying neuroprotective outcomes.

Equally, the study ignites curiosity about the duration, dosage, and timing parameters of HBOT to maximize efficacy and minimize possible oxygen toxicity. Optimization of these protocols in preclinical models can accelerate forward translation into human trials testing HBOT for mild cognitive impairment (MCI) and early-stage dementia attributed to vascular pathology. Safety profiles of HBOT are well-documented in other contexts, supporting its feasibility as a viable clinical intervention for neurological conditions.

The intricate balance between oxygen supply, oxidative stress, and cellular metabolism forms a biochemical milieu crucial to brain health. By enhancing oxygen availability, HBOT may recalibrate this balance, restoring mitochondrial function and energy production impaired in chronic hypoperfusion states. This metabolic restoration likely complements the anti-inflammatory and gene regulatory effects observed, creating a multidimensional therapeutic landscape.

Moreover, the research underlines the importance of mitochondrial dynamics and energy homeostasis linked to microRNA regulatory networks. Such insights expand the conceptualization of neuroprotection beyond classical inflammatory suppression to encompass broader metabolic resilience mechanisms orchestrated at the epigenetic and post-transcriptional levels.

In summary, the investigation conducted by Yang and colleagues compellingly argues for hyperbaric oxygen therapy as a formidable intervention against vascular cognitive impairment through molecular modulation of the miR-137-3p/TRAF3 pathway. The synthesis of neuroinflammatory control, synaptic preservation, and functional cognitive improvements underscores a holistic neuroprotective strategy with transformative clinical potential.

Future research should aim to explore synergistic effects between HBOT and emerging neurorestorative agents, potentially harnessing multimodal approaches for combating VCI. Longitudinal studies assessing sustained cognitive improvements and quality of life metrics will be crucial to cement HBOT’s role in standard care protocols. Additionally, investigations into patient stratification biomarkers may help personalize therapy to those most likely to benefit from oxygen-based modulation of microRNA pathways.

The findings herald a new chapter in neurovascular therapeutics, where oxygen—a fundamental element—proves to be a powerful modulator of gene expression and inflammatory circuits, capable of rewiring the brain’s response to injury. As the global burden of vascular dementia rises with aging populations, such innovative treatments offer a beacon of hope for millions affected by cognitive decline worldwide.

Subject of Research: Neuroprotective effects of hyperbaric oxygen therapy on vascular cognitive impairment in hypoperfused mice via miR-137-3p/TRAF3 pathway

Article Title: Neuroprotective effects of hyperbaric oxygen therapy on vascular cognitive impairment in hypoperfused mice via miR-137-3p/TRAF3 pathway

Article References:
Yang, L., Zhu, HZ., Xie, L. et al. Neuroprotective effects of hyperbaric oxygen therapy on vascular cognitive impairment in hypoperfused mice via miR-137-3p/TRAF3 pathway. Transl Psychiatry (2025). https://doi.org/10.1038/s41398-025-03771-z

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-025-03771-z