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https://onlinelibrar...1111/acel.12767
SummaryCalorie 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.
2.3 Overexpression of NAD(P)H dehydrogenases modulates NAD+metabolismSustained glycolysis requires the replenishment of the cellular pool of NAD+, a cofactor for several metabolic enzymes, including the class III histone deacetylases known as sirtuins. Because of the essential role of the NAD+/sirtuin pathway in the metabolic regulation of aging (Grabowska, Sikora & Bielak‐Zmijewska, 2017), we hypothesized that the overexpression of NQO1 and CYB5R3, two NAD+‐producing enzymes, may affect either NAD+metabolism, sirtuin expression and/or activity, or both. As expected, NAD+ and NADP+ levels were significantly higher in RedTg vs. Wt muscle (Figure 4a), accompanied by an accumulation of SIRT1 protein and a trend toward lower total lysine‐acetylated protein levels in RedTg muscle (Figure 4b,c). Likewise, the buildup of nicotinamide in RedTg livers (Figure 4d) was consistent with active NAD+ consumption by sirtuins and the transfer of reducing equivalents important for metabolic use. The RedTg livers had significantly more SIRT1 protein and lower content of total lysine‐acetylated proteins compared to Wt livers (Figure 4e,f).
