NAD⁺ Circuits in Aging, Tissue Repair and Fibrosis

Aging remodels compartmentalized nicotinamide adenine dinucleotide (NAD⁺) circuits in ways that influence stress responses, senescence, tissue repair and susceptibility to fibrosis. Beyond its classical role as a redox cofactor, NAD⁺ fuels sirtuins, PARPs and CD38, linking cellular metabolism to chromatin remodeling, DNA repair, calcium signaling and cell fate. A central translational question is whether modulating NAD⁺ in a given tissue and time window will favor regeneration, restrain fibrotic remodeling, or support malignant adaptation. In this review, we define NAD⁺ as a compartmentalized, high-turnover metabolic circuit whose topology, timing and cell-type specificity shape tissue trajectories during aging, repair and fibrosis. We first describe how aging reshapes these circuits through CD38 upregulation, PARP-sirtuin competition, extracellular eNAMPT amplification, and altered mitochondrial NAD⁺ transport, which redistributes NAD⁺ between compartments without necessarily changing bulk tissue concentration. We then summarize how de novo, Preiss-Handler Handler (including niacin/GPR109a) and nicotinamide salvage pathways are organized across nuclear, cytosolic, mitochondrial and extracellular compartments, and how key consumers including sirtuins, PARPs, CD38 and SARM1 govern these pools. We then examine how these circuits operate across acute injury, chronic senescence-associated remodeling, and malignant microenvironments in heart, lung, liver, kidney, skin, muscle and brain. Finally, we integrate emerging human data on NAD⁺ precursors and enzyme-directed strategies and propose a framework for NAD⁺-based interventions that prioritizes timing, compartmental targeting and oncologic stratification.