NAD+ Flux and Resiliency in Aged Mice

Abstract

NAD+ is an essential coenzyme found in all living cells. NAD+ concentrations decline during aging, but whether this reflects impaired production or accelerated consumption remains unclear. Here we employed isotope tracing and mass spectrometry to probe NAD+ metabolism across tissues in aged mice. In 25‐month‐old mice, we observe modest tissue NAD+ depletion (median decrease ~30%) without significant changes in circulating NAD+ precursors. Isotope tracing showed unimpaired synthesis of circulating nicotinamide from tryptophan, and maintained flux of circulating nicotinamide into tissue NAD+ pools. Although absolute NAD+ biosynthetic flux was maintained in most tissues of aged mice, fractional tissue NAD+ labeling from infused labeled nicotinamide was modestly accelerated, consistent with increased activity of NAD+ consuming enzymes. Long‐term calorie restriction partially mitigated age‐associated NAD+ decline despite decreasing NAD+ synthesis, suggesting that calorie restriction reduces NAD+ consumption. Acute inflammatory stress induced by LPS decreased NAD+ by impairing synthesis in both young and aged mice. Thus, age‐related decline in NAD+ is relatively subtle and driven by increased NAD+ consumer activity rather than impaired production.