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NAD +  is mainly synthesized from nicotinamide (Nam) by the rate-limiting enzyme Nam phosphoribosyltransferase (Nampt) and degraded to Nam by NAD + -degrading enzymes in mammals. Numerous studies report that tissue NAD +  levels decrease during aging and age-related diseases and suggest that NAD +  replenishment promotes healthy aging. Although increased expression of Nampt might be a promising intervention for healthy aging, forced expression of Nampt gene, inducing more than 10-fold increases in the enzyme protein level, has been reported to elevate NAD +  levels only 40–60% in mammalian cells. Mechanisms underlying the limited increases in NAD +  levels remain to be determined. Here we show that Nampt is inhibited in cells and that enhanced expression of Nampt activates NAD +  breakdown. Combined with the measurement of each cell’s volume, we determined absolute values (μM/h) of the rates of NAD +  synthesis (R S ) and breakdown (R B ) using a flux assay with a  2 H (D)-labeled Nam, together with the absolute NAD +  concentrations in various mammalian cells including primary cultured cardiomyocytes under the physiological conditions and investigated the relations among total cellular Nampt activity, R S , R B , and the NAD +  concentration. NAD +  concentration was maintained within a narrow range (400–700 μM) in the cells. R S  was much smaller than the total Nampt activity, indicating that NAD +  synthesis from Nam in the cells is suppressed. Forced expression of Nampt leading to 6-fold increase in total Nampt activity induced only a 1.6-fold increase in cellular NAD +  concentration. Under the conditions, R S  increased by 2-fold, while 2-fold increase in R B  was also observed. The small increase in cellular NAD +  concentration is likely due to both inhibited increase in the NAD +  synthesis and the activation of its breakdown. Our findings suggest that cellular NAD +  concentrations do not vary dramatically by the physiological fluctuation of Nampt expression and show the tight link between the NAD +  synthesis and its breakdown.

plos one

Quantitative analysis of the effects of nicotinamide phosphoribosyltransferase induction on the rates of NAD+ synthesis and breakdown in mammalian cells using stable isotope-labeling combined with mass spectrometry