Overexpression of <scp>CYB</scp>5R3 and <scp>NQO</scp>1, two <scp>NAD</scp>⁺‐producing enzymes, mimics aspects of caloric restriction

Abstract

Summary Calorie restriction ( CR ) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH ‐dehydrogenases, namely NAD (P)H:quinone oxidoreductase 1 ( Nqo1 ) and cytochrome b 5 reductase 3 ( Cyb5r3 ), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR , and defects in their activity are linked to aging and several age‐associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH ‐dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR . Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD + /sirtuin pathway. The results highlight the importance of these NAD + producers for the promotion of health and extended lifespan.