The complex relationship between oxidative stress and aging: new perspectives on similarities and differences

The association of oxidative stress with aging is considered one of the key theoretical cornerstones in aging research, but accumulating evidence has cast some doubt on the validity of a single "cumulative oxidative damage" hypothesis as its mechanism. This review aims to provide a comprehensive and updated overview of the complex interplay between oxidative stress and aging, with a particular focus on their shared mechanisms and context-dependent effects. ROS should not be regarded only as deleterious metabolic waste, but indeed act as pivotal signaling mediators in metabolic, stress, and cell fate regulation within the frame of physiological ranges. In addition, emerging evidence highlights the dual roles of ROS in maintaining cellular homeostasis and mediating stress responses depending on their concentration and spatial distribution. Only when the fine-tuned equilibrium that usually couples ROS production and disposal is perturbed and quality-control activity becomes defective does this signaling network gradually shift from a physiological into a pathological source of stress promoting cellular senescence and tissue malfunction. Aging should thus be considered the outcome of structural derangement in homeostatic regulatory networks caused by chronic stress. This view of the aging process is developed through a discussion of key events comprising oxidative DNA damage, mitochondrial dysfunction, decline in autophagy and lysosomal degradation, as well as senescent cell secretion (SASP), indicating that their reciprocal interactions together define phenotypic features characterizing the aging cell. This network-centric model further mechanistically justifies why peripheral effects of broad-spectrum antioxidant interventions are heterogeneous, and points to rolling back the damage with compensatory quality-control mechanisms and homeostatic regulation as a more effective path toward understanding how to restore homeostasis. These insights may contribute to the development of more precise therapeutic strategies targeting aging-related diseases and improving healthspan. Future research should further clarify the spatiotemporal dynamics of ROS signaling and its integration with cellular stress-response networks. Moreover, elucidating the threshold-dependent and context-specific effects of oxidative signaling may provide a conceptual basis for precision interventions in aging and age-related diseases.