NAD+ flux is maintained in aged mice despite lower tissue concentrations

NAD(+) is an essential coenzyme for all living cells. NAD(+) concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD(+) metabolism across tissues. In aged mice, we observed modest tissue NAD(+) depletion (median decrease similar to 30%). Circulating NAD(+) precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD(+) pool was modestly faster such that absolute NAD(+) biosynthetic flux was maintained, consistent with more active NAD(+)-consuming enzymes. Calorie restriction partially mitigated age-associated NAD(+) decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD(+) by impairing synthesis in both young and aged mice. Thus, the decline in NAD(+) with normal aging is relatively subtle and occurs despite maintained NAD(+) production, likely due to increased consumption.

Automated summary

NAD(+) concentrations decline with age, but the synthesis of NAD(+) in cells is not significantly affected, primarily due to increased consumption. Calorie restriction can partially mitigate this decline, while acute inflammatory stress can accelerate the decrease in NAD(+).