Promising Results With <scp>NAD</scp> Supplementation in Rare Diseases With Premature Aging and <scp>DNA</scp> Damage

Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.