Journal
AGING CELL
Volume 17, Issue 4, Pages -Publisher
WILEY
DOI: 10.1111/acel.12767
Keywords
aging; calorie restriction; CYB5R3; metabolic homeostasis; NQO1
Categories
Funding
- Intramural Research Program of the NIA
- NIH
- Institut de Salud Carlos III [FIS PI14-01962]
- Spanish Ministerio de Economia y Competitividad [BFU2015-64630-R]
- Spanish Ministerio de Educacion, Cultura y Deporte [FPU14/ 06308, FPU 14/00098]
- NATIONAL INSTITUTE ON AGING [ZIAAG000362] Funding Source: NIH RePORTER
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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.
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