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Aging Cell. 2018 Aug;17(4):e12767. doi: 10.1111/acel.12767. Epub 2018 Apr 28.

Overexpression of CYB5R3 and NQO1, two NAD+ -producing enzymes, mimics aspects of caloric restriction.

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Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Nutritional Interventions Group, Precision Nutrition and Aging, Institute IMDEA Food, Madrid, Spain.
Department of Cell Biology, Physiology and Immunology, Agrifood Campus of International Excellence, ceiA3, University of Córdoba, Córdoba, Spain.
Department of Physiology, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain.
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Graduate Center for Nutritional Sciences, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
Centro Andaluz de Biologia del Desarrollo, and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC, Sevilla, Spain.


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.


CYB5R3; NQO1; aging; calorie restriction; metabolic homeostasis

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