This study shows that SIRT1 activity in liver is decreased during DR and moreover, knock out SIRT1 in liver protective against physiological decline when fed a high-fat diet.Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.
You could imagine for oral intake of NMN, most of them will be concentrated (even arrested) in the liver, which might have no effect (or even have a negative effect). Meanwhile, sublingual intake can bypass liver and deliver more NMN to other tissues.