Contribution of NRF2-signaling to cytoprotection, cancer resistance, and longevity in the naked mole-ra

Stress resistance is a common attribute of long-lived animals and plants. I have hypothesized that the longest-lived rodent, the naked mole-rat, is no exception in this regard. During its almost 32-year lifespan, naked mole-rats experience very little change in many of the characteristics typically associated with aging, including physiological function as well as genome and proteome maintenance. These mouse-sized, hairless, subterranean rodents are also very resistant to spontaneously occurring cancers; only one case has ever been found in 3000+ necropsies and during 35+ years of study. I hypothesize that the naked mole-rat exhibits pronounced resistance to various stressors both in vitro and in vivo. Moreover, I predict that the nuclear factor erythroid 2-related factor [NRF2] signaling pathway, a key cytoprotective mechanism conserved throughout the animal kingdom, is of critical importance in this regard. NRF2 regulates a myriad of antioxidant and detoxification molecules, which help prevent and/or remove damaged macromolecules within a cell. NRF2 activity is tightly regulated by a number of molecules that may not only enhance and stabilize NRF2-signaling activity, but also regulate its degradation. I tested the hypothesis that NRF2-signaling activity is a key component of species longevity by examining the differences in NRF2-signaling activity between naked mole-rats and nine other rodents with divergent longevities. In addition, using the two rodents at the extremes of maximum species lifespan, the naked mole-rat and mouse, I examined their resistance to xenobiotic compounds and stressors both in vivo and in vitro and assessed if both species showed similar NRF2-signaling responses to these toxins.;This study has revealed that NRF2 activity is of key importance in species longevity and that constitutive levels essentially prime the organism to deal with acute exposure to potentially lethal toxins. Divergent responses of short-lived mice and long-lived naked mole-rats after toxin exposure may highlight the fact that the protective effects of NRF2 represent a "double-edged sword" and that once the immediate problems associated with the toxic effects have been ablated; a decline in NRF2 may be protective by preventing further cell cycle proliferation with damaged macromolecules and thus changes in NRF2 signaling are likely to be of critical importance in the maintenance of somatic integrity and the prevention of tumorigenesis. Short-lived mice have few defenses against cancer and appear to lack constitutive protective mechanisms to ward off various toxins. Rather, after exposure they increase NRF2 signaling to detoxify and remove the accrued damage and as a consequence have lower levels of protection against proliferation with damaged cells. As such, mutations may accumulate and their somatic integrity may become compromised further contributing to the ease of cancer induction in this traditional animal model. (Abstract shortened by ProQuest.).