The vertebrate transcription factor Nrf2 (NFE2-related factor 2) and its invertebrate homologs, including SKN-1 (C. elegans) and CncC (D. melanogaster) have emerged as master regulators of cellular detoxification responses and redox status. These stress-sensing transcription factors are members of the cap’n’collar family. They function both in situations of acute challenge and as regulators of baseline antioxidant activity. In mice and in human cultured cells, many protective genes are induced in response to oxidative and electrophile chemical challenges in an Nrf2-dependent manner. Among Nrf2-regulated gene products are phase II detoxification enzymes as well as a broad range of redox regulators that includes enzymes for glutathione synthesis, glutathione S-transferases, thioredoxin, peroxyredoxins, NAD(P)H quinone oxidase 1 (NQO1), heme oxygenase 1 (HO1), and many others.
Under non-stressed conditions, proteasomal degradation of Nrf2 is the default state. It is facilitated by interaction with of Nrf2 with a cognate substrate adaptor, Keap1, and its associated Cul3-based ubiquitinligase system. The inhibitory effect of Keap1 on Nrf2 is dependent on the redox status of Keap1 cysteins (which function as redox sensors), such that Nrf2 ubiquitination and proteolysis are inhibited in oxidized conditions. It is clear, however, that additional mechanisms of Nrf2 activation exist, such as the phosphorylation of Nrf2 by stress-activated kinases, and the redox regulation of its shuttling between the nucleus and cytoplasm.
Consistent with this tenet and the established role of Nrf2 and its invertebrate homologs as master regulators of antioxidant gene expression, a number of studies support a function for the Nrf2 pathway in the regulation of lifespan. In both C. elegans and D. melanogaster, the genetic activation of the Nrf2 signaling can cause significant increases in longevity. For example, the beneficial effects of CR and decreased insulin signaling may in part be explained by a decrease in oxidative stress sensitivity and a delay in the accumulation of oxidative damage with age. Recent evidence from a variety of model systems points to the Nrf2 pathway as an effector of longevity signaling. These experiments elucidated a new and in hindsight plausible regulatory connection between biological systems that sense and regulate both the activity of the Nrf2 system and the metabolic state.