INTRODUCTION
Oral supplementation of nicotinamide (NAM), a water-soluble vitamin B3 derivative, decreases incidence of keratinocyte carcinomas (KC), and decreases the size, number, and incidence of actinic keratoses (AKs) in high-risk skin cancer patients.1-3 An analysis of 386 high-risk skin cancer patients treated with oral NAM demonstrated a significant 23% reduction in the incidence of new KCs vs placebo.3
NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and is used to create NAD+. NAD+ is cationic and unable to be directly supplemented orally. NAD+ acts as a cofactor in glycolysis and has a critical role in adenosine triphosphate (ATP) production. ATP, in turn, is essential for many basic cellular functions, including DNA repair. Pathways leading to NAD+ production are thus essential and interwoven into basic cellular metabolism. Interestingly, animal and human models have shown that physiologic levels of NAD+ naturally decrease with aging and in certain disease states, leading to the hypothesis that reduced NAD+ may be one causative factor in age-associated functional decline and disease.4,5 Consistent with this hypothesis, ultraviolet radiation (UV) exposure further depletes NAD+, resulting in inhibition of glycolysis and a scarcity of ATP. The subsequent inhibition of DNA repair due to ATP scarcity predisposes cells to oncogenic DNA damage and tumor formation.4,5
Recent work demonstrates that keratinocytes supplemented with NAM in vitro had increased NAD+ levels, increased DNA repair, and reduced UV-induced inflammation.6-8 This work prompted the hypothesis that NAM supplementation may replenish depleted NAD+ found in states associated with UV exposure, ultimately replenishing cellular ATP and promoting the repair of damaged DNA. This theory has gained widespread acceptance and is the primary proposed mechanism for NAM’s effect in reducing KC.6
NAD+ biology is a strong focus of modern research into aging and age-associated disease. Given that NAD+ cannot be directly absorbed from the diet, research has been focused on alternative sources or intermediates from which NAD+ can be synthesized; specifically, niacin, NAM, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) (Figure 1).9,10 These NAD+ intermediates exhibit varying and unique effects on metrics of metabolism and health.10-12 NR and NMR are more direct precursors in the biosynthetic pathway of NAD+ synthesis and increase NAD+ more effectively than NAM,13 which, along with other results, has led investigators to believe NR and NMN are more potent anti-aging and anti-cancer molecules than NAM.4,10 Here, we perform a narrative review investigating whether NR and NMN may have an equal or greater effect on KC chemoprevention to that of NAM.
NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and is used to create NAD+. NAD+ is cationic and unable to be directly supplemented orally. NAD+ acts as a cofactor in glycolysis and has a critical role in adenosine triphosphate (ATP) production. ATP, in turn, is essential for many basic cellular functions, including DNA repair. Pathways leading to NAD+ production are thus essential and interwoven into basic cellular metabolism. Interestingly, animal and human models have shown that physiologic levels of NAD+ naturally decrease with aging and in certain disease states, leading to the hypothesis that reduced NAD+ may be one causative factor in age-associated functional decline and disease.4,5 Consistent with this hypothesis, ultraviolet radiation (UV) exposure further depletes NAD+, resulting in inhibition of glycolysis and a scarcity of ATP. The subsequent inhibition of DNA repair due to ATP scarcity predisposes cells to oncogenic DNA damage and tumor formation.4,5
Recent work demonstrates that keratinocytes supplemented with NAM in vitro had increased NAD+ levels, increased DNA repair, and reduced UV-induced inflammation.6-8 This work prompted the hypothesis that NAM supplementation may replenish depleted NAD+ found in states associated with UV exposure, ultimately replenishing cellular ATP and promoting the repair of damaged DNA. This theory has gained widespread acceptance and is the primary proposed mechanism for NAM’s effect in reducing KC.6
NAD+ biology is a strong focus of modern research into aging and age-associated disease. Given that NAD+ cannot be directly absorbed from the diet, research has been focused on alternative sources or intermediates from which NAD+ can be synthesized; specifically, niacin, NAM, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) (Figure 1).9,10 These NAD+ intermediates exhibit varying and unique effects on metrics of metabolism and health.10-12 NR and NMR are more direct precursors in the biosynthetic pathway of NAD+ synthesis and increase NAD+ more effectively than NAM,13 which, along with other results, has led investigators to believe NR and NMN are more potent anti-aging and anti-cancer molecules than NAM.4,10 Here, we perform a narrative review investigating whether NR and NMN may have an equal or greater effect on KC chemoprevention to that of NAM.
