Regulation of Nrf2 Signaling and Longevity in Naturally Long-Lived Rodents
The longer-lived mammal and the genetically modified one are both more resistant to toxins that can cause cancer or age-related diseases. It is still unclear how stress resistance develops. We found that rodents with longer lifespans had higher levels of nuclear factor erythroid 2 related factor (Nrf2) signaling activity. This increase in cytoprotective signals was due to differences between species in Kelch like ECH-Associated Protein 1(Keap1), and b-transducin-repeat-containing protein (bTrCP), which regulate Nrf2 activity. These two negative regulators are much lower in long-lived species. We may be able identify new therapies for aging, and age-associated illnesses such as cancer, by targeting proteins that regulate Nrf2, rather than Nrf2.
Like other species with long lifespans, the preternaturally-long-lived mole-rat is resistant to environmental and endogenous stressors (e.g. reactive oxygen species). It also resists age related diseases like cancer, cardiovascular disease and neurodegeneration. However, the mechanisms that underlie the universal resilience to stress of longer-lived species remain elusive. This resilience may be linked to the activity a nuclear factor erythroid 2 related factor (Nrf2), a highly-conserved transcription factor. Nrf2 regulates transcription of hundreds of cytoprotective molecules including antioxidants and detoxicants as well as molecular chaperones. Nrf2 is tightly controlled by mechanisms which either increase its activity or decrease its degradation.
Source:
https://www.pnas.org/content/112/12/3722
