OZONE THERAPY: ITS METABOLIC AND TRANSLATIONAL ROLE IN THE HALLMARKS OF AGING

Aging is a complex biological process characterized by the progressive loss of cellular and systemic homeostasis and is currently organized into twelve interconnected hallmarks comprising genomic instability, telomere(definition) attrition, epigenetic alterations, loss of proteostasis(definition), disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction(definition), cellular senescence(definition), stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Ozone therapy has been proposed as a controlled oxidative intervention capable of eliciting adaptive redox responses rather than acting simply as an exogenous antioxidant. This review aimed to critically examine the metabolic and translational interfaces between the biological effects attributed to medical ozone and the molecular networks involved in the Hallmarks of Aging(definition). The available evidence indicates that mild ozonation can activate the Keap1/Nrf2/ARE pathway and influence endogenous antioxidant systems, while experimental and disease-specific human studies report modulation of glutathione metabolism, inflammatory mediators, NF-κB signaling, and, in preclinical models, the AMPK/mTOR(definition)-autophagy(definition) axis. These mechanisms provide biologically plausible connections particularly with mitochondrial dysfunction, disabled macroautophagy, deregulated nutrient sensing, chronic inflammation, and altered intercellular communication. In contrast, evidence linking ozone therapy directly to genomic instability, telomere attrition, epigenetic alterations, stem cell exhaustion, cellular senescence, or age-related dysbiosis remains limited or indirect. Importantly, mechanistic convergence with aging pathways should not be interpreted as evidence that ozone therapy reverses biological aging or its hallmarks. Current clinical evidence remains heterogeneous, and differences in administration routes, ozone concentrations, therapeutic protocols, populations, and outcome measures restrict direct comparisons and causal inference. Ozone therapy may therefore represent an investigational hormetic and metabolic strategy capable of modulating selected redox and inflammatory networks associated with aging; however, adequately controlled clinical studies using validated biomarkers of biological aging are required before its potential geroscience applications can be established.