Deletion of Nrf2 shortens lifespan in C57BL6/J male mice but does not alter the health and survival benefits of caloric restriction

• Published in: Free radical biology & medicine 2020-05, Vol.152, p.650-658
• Main Authors: Pomatto, Laura C.D., Dill, Theresa, Carboneau, Bethany, Levan, Sophia, Kato, Jonathan, Mercken, Evi M., Pearson, Kevin J., Bernier, Michel, de Cabo, Rafael
• Format: Article
• Language: English
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.01.005

Caloric restriction (CR) is the leading non-pharmaceutical dietary intervention to improve health- and lifespan in most model organisms. A wide array of cellular pathways is induced in response to CR and CR-mimetics, including the transcriptional activator Nuclear factor erythroid-2-related factor 2 (Nrf2), which is essential in the upregulation of multiple stress-responsive and mitochondrial enzymes. Nrf2 is necessary in tumor protection but is not essential for the lifespan extending properties of CR in outbred mice. Here, we sought to study Nrf2-knockout (KO) mice and littermate controls in male C57BL6/J, an inbred mouse strain. Deletion of Nrf2 resulted in shortened lifespan compared to littermate controls only under ad libitum conditions. CR-mediated lifespan extension and physical performance improvements did not require Nrf2. Metabolic and protein homeostasis and activation of tissue-specific cytoprotective proteins were dependent on Nrf2 expression. These results highlight an important contribution of Nrf2 for normal lifespan and stress response. [Display omitted] •Loss of Nrf2 results in shortened lifespan in C57BL/6J male mice.•Calorie restriction-mediated lifespan extension is independent of Nrf2.•Unabated positive health outcomes of calorie restriction in Nrf2-null mice•Reduced expression of cytoprotective and mitochondrial proteins in Nrf2-null mice