Regulation of Nrf2 signaling and longevity in naturally long-lived rodents

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (12), p.3722-3727
• Main Authors: Lewis, Kaitlyn N., Wason, Emily, Edrey, Yael H., Kristan, Deborah M., Nevo, Eviatar, Buffenstein, Rochelle
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; beta-Transducin Repeat-Containing Proteins - physiology; Biological Sciences; Cricetinae; Female; Gene expression; Gene Expression Regulation; Gerbillinae; Guinea Pigs; Heat shock proteins; Intracellular Signaling Peptides and Proteins - physiology; Kelch-Like ECH-Associated Protein 1; Life expectancy; Liver - metabolism; Longevity; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - physiology; Rats; Reactive Oxygen Species - metabolism; Rodents; Signal Transduction; Species Specificity; Stress response; Xenobiotics
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1417566112

The preternaturally long-lived naked mole-rat, like other long-lived species and experimental models of extended longevity, is resistant to both endogenous (e.g., reactive oxygen species) and environmental stressors and also resists age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The mechanisms behind the universal resilience of longer-lived organisms to stress, however, remain elusive. We hypothesize that this resilience is linked to the activity of a highly conserved transcription factor, nuclear factor erythroid 2-related factor (Nrf2). Nrf2 regulates the transcription of several hundred cytoprotective molecules, including antioxidants, detoxicants, and molecular chaperones (heat shock proteins). Nrf2 itself is tightly regulated by mechanisms that either promote its activity or increase its degradation. We used a comparative approach and examined Nrf2-signaling activity in naked mole-rats and nine other rodent species with varying maximum lifespan potential (MLSP). We found that constitutive Nrf2-signaling activity was positively correlated ( P = 0.0285) with MLSP and that this activity was also manifested in high levels of downstream gene expression and activity. Surprisingly, we found that species longevity was not linked to the protein levels of Nrf2 itself, but rather showed a significant ( P < 0.01) negative relationship with the regulators Kelch-like ECH-Associated Protein 1 (Keap1) and β-transducin repeat-containing protein (βTrCP), which target Nrf2 for degradation. These findings highlight the use of a comparative biology approach for the identification of evolved mechanisms that contribute to health span, aging, and longevity. Significance Both genetically altered and naturally long-lived mammals are more resistant to toxic compounds that may cause cancer and age-associated diseases than their shorter-lived counterparts. The mechanisms by which this stress resistance occurs remain elusive. We found that longer-lived rodent species had markedly higher levels of signaling activity of the multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) and that this increase in cytoprotective signaling appeared to be due to species differences in Kelch-like ECH-Associated Protein 1 (Keap1) and β-transducin repeat-containing protein (βTrCP) regulation of Nrf2 activity. Both of these negative regulators of Nrf2-signaling activity are significantly lower in longer-lived species. By targeting the proteins