Targeting Reduced Glutathione (GSH) to Promote Metabolic Health: Insights on the Role of Bioactive-Rich Foods and Fasting Protocols.

The ever-increasing disparity between lifespan and healthspan represents a challenging global issue, with metabolic dysregulation playing a central role in the initiation and progression of chronic non-communicable diseases (NCDs). This review highlights the importance of maintaining optimal redox homeostasis, with particular emphasis on reduced glutathione (GSH), for preserving metabolic health during aging. GSH participates in several physiological processes, including antioxidant defense, xenobiotic detoxification, redox signaling, and metabolic regulation. Diminished GSH levels are consistently reported in obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver, and cardiovascular diseases. Current evidence from human clinical studies indicates that foods rich in bioactive constituents can enhance GSH levels and stimulate GSH-dependent enzyme activity, with the Nrf2/Are signaling pathway being a central mechanistic link. Fasting may promote adaptive redox responses by inducing mild oxidative stress and activating the same molecular mechanism, although the effects on GSH-related antioxidant mechanisms remain heterogeneous across fasting protocols and study populations. Altogether, the available clinical evidence suggests that these nutritional and lifestyle interventions exhibit more consistent beneficial effects in individuals characterized by increased oxidative burden and underlying metabolic dysfunction. Interindividual differences in GSH responses further underscore the need for targeted, tailor-made approaches that account for genetic, epigenetic, and lifestyle factors. Collectively, targeting GSH homeostasis through nutritional and lifestyle interventions represents a promising strategy for improving metabolic health and may further contribute to healthy aging, positioning redox biology at the forefront of aging research and NCD prevention.