Stem Cell and EV/sEV Strategies for Neuroimmune Niche Reprogramming in Selected CNS Disorders: Mechanisms, Engineered Delivery, and Translational Readiness

Aging has traditionally been interpreted through the accumulation of oxidative damage. However, reactive oxygen species (ROS) also act as regulated signals that support immune activation, metabolic adaptation, stress resistance, inflammatory resolution, and cell-fate decisions. We define redox signaling fidelity as the accuracy with which a specified physiological input is converted into a source-specific, spatially confined, temporally patterned, chemically reversible, proportionately decoded, and appropriately resolved redox response.

This critical narrative review develops redox signaling fidelity as a testable systems framework rather than as a synonym for oxidative stress, redox homeostasis, oxidative eustress, hormesis, the redox code, or Redox-stress Response Capacity. The framework organizes redox information flow into five linked layers: generation, encoding, transmission, decoding, and resolution/reset. Aging may lower fidelity through source uncoupling, persistent cysteine oxidation, microdomain leakage, decoder bias, and defective autophagic, mitophagic, lysosomal, or proteostatic reset. Immune aging and the aging brain are used as cross-scale test cases in which physiological ROS pulses must be distinguished from chronic redox noise. We propose operational readouts, including source coupling, redox signal-to-noise ratio, reversibility, spatial leakage, decoder proportionality, mutual information, and resolution kinetics, and map these readouts to single-cell imaging, redox proteomics, spatial and single-cell omics, and dynamic modeling.

The fidelity framework predicts that lowering bulk ROS is not sufficient to restore redox function. More decisive studies should pair controlled inputs with compartment-resolved redox dynamics, reversible molecular encoding, pathway output, and functional recovery in the same young-versus-aged system. Interventions should be evaluated by whether they reduce pathological redox noise while preserving physiological pulses, spatial routing, adaptive decoding, and timely resolution.