While the precise ways NAD+ supplementation benefits health are still being investigated, research suggests it may play a role in healthy aging, age-related diseases, metabolic disorders, and addiction. NAD+ replenishment is thought to counteract the age-related decline of NAD+ and its precursor, NMN, primarily caused by the enzyme CD38, thereby maintaining mitochondrial function and energy production. However, NAD+ also influences various other metabolic pathways through NAD+-dependent enzymes.

These enzymes include PARPs, which are crucial for DNA repair; CD38 and CD157, involved in cell signaling; sirtuins, which regulate cellular metabolism and stress responses, and have been linked to longevity; and SARM1, implicated in neuronal aging. Research on progeroid syndromes, particularly Werner syndrome (WS), has shed light on NAD+’s role. WS, characterized by premature aging and metabolic dysfunction, is linked to a deficiency in the WRN gene, which affects NAD+ production. Studies have shown that NAD+ depletion in WS leads to impaired mitophagy (mitochondrial recycling), and NAD+ replenishment restores mitochondrial function, reduces oxidative stress, and extends lifespan in animal models.

Furthermore, studies on cells overexpressing CD38, an enzyme that degrades NAD+, show mitochondrial dysfunction and reduced energy production. Conversely, in CD38-deficient animals, NAD+ levels and mitochondrial function remain stable with age. These findings reinforce the importance of NAD+ in maintaining mitochondrial and metabolic health.