Nutritional modulation of cellular redox signaling in the management of age-associated disorders: NRF2 as a prime target

Oxidative stress caused by excessive reactive oxygen species generation is considered a major contributor to aging and several age-related disorders, including cancer, neurodegeneration, cardiovascular diseases, and diabetes. Numerous small molecules including antioxidant vitamins have exhibited preventive or therapeutic potential in preclinical studies. However, longevity studies in multiple model organisms failed to demonstrate that antioxidants prevent/delay aging processes Notably, accumulated oxidative damage does not directly correlate with aging severity. Thus, oxidative stress-induced structural damage alone is not sufficient to satisfactorily explain the age-associated functional losses. Optimal levels of reactive oxygen species act as second messengers in intracellular signal transduction and also play roles in adaptive survival responses to oxidative stress. It is now recognized that aging is influenced by cellular redox status rather than by generally accepted oxidative stress mechanisms. A new ‘redox stress hypothesis’ proposes that age-associated functional losses are primarily caused by a progressive pro-oxidizing shift in the redox state of the cells, which leads to the disruption of the redox-regulated signaling mechanism. Recent interest has focused on maintenance of physiological magnitude of redox signaling in aging cells. Dietary/nutritional modulation of defective redox signaling pathways in a way to restore their function will provide effective solutions to degenerative health complications of elderly. NRF2 is a key transcription factor responsible for the expression of genes involved in redox regulation. Its activity declines with age, which potentially contributes to age-related disorders. As disrupted adaptive cellular redox homeostasis is a critical hallmark of aging, precise understanding of the role will help develop a better strategy to promote healthy aging.