Aging disrupts the oxygen cascade—the physiological pathway delivering oxygen from atmosphere to mitochondria—through three converging mechanisms: impaired oxygen transport, microvascular dysfunction, and maladaptive molecular responses. This framework, termed "Oxygenaging," positions oxygen homeostasis as a primary driver of age-related cellular decline rather than a passive consequence, with implications for understanding mitochondrial instability and designing targeted interventions.
Key Points
- Oxygen delivery and utilization decline with age, destabilizing mitochondrial function
- Microvascular rarefaction creates persistent mismatches between oxygen supply and tissue demand
- Adaptive capacity to hypoxic stress diminishes, reducing cellular quality control resilience
Longevity Analysis
The oxygen cascade—spanning pulmonary gas exchange, vascular delivery, and mitochondrial utilization—operates as an integrated regulatory system whose degradation accelerates multiple aging hallmarks. Rather than treating oxygen homeostasis as peripheral to geroscience, this framework identifies it as a linchpin connecting energy production capacity to genomic stability and cellular repair mechanisms. Interventions targeting oxygen availability (intermittent hypoxia, hyperbaric therapy, hypoxic-hyperoxic training) demonstrate that adaptive stress can restore tolerance, but the therapeutic window remains narrow; optimization requires precise dosing and monitoring rather than broad application. Understanding how age-related microvascular decline and endothelial dysregulation reduce oxygen sensing and mitochondrial signaling directly informs both preventive strategies and the interpretation of why certain stressors benefit younger versus older populations differently.
Original published by Wiley Aging Cell, by Stefano Donega, Kenneth W. Fishbein, Paolo Dominelli, Allison B. Herman, Rafael de Cabo, Myriam Gorospe, Luigi Ferrucci .