Investigating hormesis, aging, and neurodegeneration: From bench to clinics

Abstract

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

Keywords: C. elegans; Nrf2; antioxidants; hormesis; longevity; mitochondrial medicine.

Figure 1

Dose–response curve depicting the quantitative features of hormesis.

Figure 2

The Keap1/Nrf2/ARE pathway. (a) Under basal conditions, Nrf2 is bound to Keap1, a cytoplasmic repressor that targets Nrf2 for ubiquitination and proteasomal degradation. (b) Polyphenols, as molecules inducers, react with cysteine residues of Keap1, which operate as sensors, and hence induce stabilization of Nrf2, via entering into nucleus, where this transcriptional factor, by binding to the ARE, promotes transcriptional activation of cytoprotective vitagenes.