Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation.

Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD⁺) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD⁺ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD⁺ synthesis depleted NAD⁺, suppressed mitochondrial NAD⁺-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD⁺ synthesis by limiting the conversion of downstream quinolinate to NAD⁺, a profile recapitulated in aging macrophages. Increasing de novo NAD⁺ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD⁺ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD⁺ synthesis may underlie declining NAD⁺ levels and rising innate immune dysfunction in aging and age-associated diseases.