Oxygenaging: A Physiological Framework for Geroscience

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Publication Details

Journal
Aging Cell
Published
2026-08-28
DOI
https://doi.org/10.1111/acel.70664
Primary Topic
High Altitude and Hypoxia
Type
article
Field-Weighted Citation Impact
0.00

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article

Oxygenaging: A Physiological Framework for Geroscience

Kenneth W. Fishbein, Luigi Ferrucci, Stefano Donegà, Allison B. Herman et al.
Aging Cell
High Altitude and Hypoxia
article

Oxygenaging: A Physiological Framework for Geroscience

Kenneth W. Fishbein, Luigi Ferrucci, Stefano Donegà, Allison B. Herman, Rafael de Cabo, Myriam Gorospe, Paolo Dominelli
article en

Abstract

The stepwise movement of oxygen from the atmosphere to the mitochondria, the "oxygen cascade", is one of the most tightly regulated systems in physiology. Despite decades of mechanistic study, it has remained quite unexplored in Geroscience. This oversight should be reconsidered. In young organisms, hypoxic stress (whether environmental or tissue-specific) activates a complex adaptive response to preserve energetic stability via restraining anabolic pathways, optimizing mitochondrial performance, and reinforcing cellular quality control systems. With advancing age, angiostatic signaling increases, endothelial metabolism becomes dysregulated, and overall alveolar ventilation and pulmonary gas exchange (ventilation-perfusion matching and diffusion capacity) become less efficient. These changes promote microvascular rarefaction and low-grade but persistent mismatches between oxygen delivery and demand at the tissue level, ultimately destabilizing cellular function. In this review, we propose that the gradual erosion of oxygen homeostasis is not simply a byproduct of aging, but also a driver of molecular damage and functional decline. We examine the aging oxygen cascade through the framework of resilience biology, focusing on mechanisms such as mitochondrial electron leaks, oxidative stress amplification, iron dyshomeostasis, ferroptosis, and epigenetic remodeling. We also discuss interventions that alter oxygen availability, such as intermittent hypoxia, hyperbaric oxygen therapy, and hypoxic-hyperoxic training. These approaches demonstrate adaptive potential, but they also highlight the narrow margin between beneficial stress and injury. We propose "Oxygenaging" as a unifying framework in which aging associates with the progressive loss of equilibrium across the oxygen cascade, linking systemic oxygen transport to mitochondrial function, genomic stability, and cellular resilience.

Aging CellVol. 25(9)
University of Calgary (CA), Roland Park Country School (US), ID Genomics (United States) (US), National Information Standards Organization (US), National Institute on Aging (US)
U.S. Department of Health and Human Services, National Institutes of Health
Openalex Percentile: Top 10%
High Altitude and Hypoxia
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