Overexpression of CYB5R3 and NQO1, Two NAD+ -Producing Enzymes, Mimics Aspects of Caloric Restriction

Alberto Diaz-Ruiz, National Institutes of Health
Michael Lanasa, National Institutes of Health
Joseph Garcia, National Institutes of Health
Hector Mora, National Institutes of Health
Frances Fan, National Institutes of Health
Alejandro Martin-Montalvo, National Institutes of Health
Andrea Di Francesco, National Institutes of Health
Miguel Calvo-Rubio, University of Córdoba, Spain
Andrea Salvador-Pascual, University of Valencia, Spain
Miguel A. Aon, National Institutes of Health
Kenneth W. Fishbein, National Institutes of Health
Kevin J. Pearson, University of Kentucky
Jose Manuel Villalba, University of Córdoba, Spain
Placido Navas, Universidad Pablo de Olavide, Spain
Michel Bernier, National Institutes of Health
Rafael de Cabo, National Institutes of Health

Published in Aging Cell, v. 17, issue 4, e12767, p. 1-13.

© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


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 b5 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.