more effectively than NAM. Consequently, we hypothesize that NR and NMN supplementation will lead to similar or greater reductions in KC rates in high-risk skin cancer patients compared with supplementation with NAM. Supporting this hypothesis, recent work using animal models has shown that both NR and NMN supplementation can mitigate DNA damage, improve cellular metabolic function, and reduce age-associated disease more effectively than NAM supplementation.
Chen et al recently published a model to investigate NAM on keratinocyte chemoprevention in high-risk human subjects, which can be adapted to investigate and compare the alternative NAD+ intermediates.3 Specifically, we propose a randomized controlled trial, as the strongest level of evidence, with participants randomized to one of 4 groups: placebo, NAM, NR, or NMR. At present, it is unclear if either NR or NMN is superior, and thus both should be included in initial studies compared with NAM. Power analyses indicates that at least 400 to 500 participants should be enrolled. Participants will be supplemented for 18 months at 1000 mg/day, a concentration shown to be safe in prior studies.10,24,25 The main outcomes would be development of AKs, BCCs, and SCCs. Participants would be evaluated by dermatologists at 3-month intervals for the duration of the study. Groups will be evaluated in a blind fashion with intention-to-treat analysis. Group differences would be analyzed at study end using an ANOVA with significance set to P<0.05. This study design would allow the impact of NR or NMR to be compared against both placebo and NAM for the reduction of skin cancers. Results should be presented at national and international levels, and ultimately can help influence our prophylactic and therapeutic management of patients with skin cancers.
Chen et al recently published a model to investigate NAM on keratinocyte chemoprevention in high-risk human subjects, which can be adapted to investigate and compare the alternative NAD+ intermediates.3 Specifically, we propose a randomized controlled trial, as the strongest level of evidence, with participants randomized to one of 4 groups: placebo, NAM, NR, or NMR. At present, it is unclear if either NR or NMN is superior, and thus both should be included in initial studies compared with NAM. Power analyses indicates that at least 400 to 500 participants should be enrolled. Participants will be supplemented for 18 months at 1000 mg/day, a concentration shown to be safe in prior studies.10,24,25 The main outcomes would be development of AKs, BCCs, and SCCs. Participants would be evaluated by dermatologists at 3-month intervals for the duration of the study. Groups will be evaluated in a blind fashion with intention-to-treat analysis. Group differences would be analyzed at study end using an ANOVA with significance set to P<0.05. This study design would allow the impact of NR or NMR to be compared against both placebo and NAM for the reduction of skin cancers. Results should be presented at national and international levels, and ultimately can help influence our prophylactic and therapeutic management of patients with skin cancers.
CONCLUSIONS AND PERSPECTIVES
KCs are the most common malignancies in the US and worldwide, and rates continue to increase with the growing elderly population.26,27 More than 4.9 million adults were treated annually for skin cancer from 2007 to 2011 in the US, with annual costs peaking at $8.1 billion.28 The significant population-level morbidity and associated healthcare costs of KC means that any effective intervention to treat or reverse early KC has the potential to be hugely beneficial for patient outcomes and for reducing system costs.29 Current methods for primary prevention of KC are largely through sun protection. However, most adults do not routinely use sunscreen despite decades of encouragement by dermatologists and public health campaigns.30 Reasons for this include the perceived inconvenience of application and the perceived incompatibility of sun protective behaviors with outdoor activities.31,32 Oral methods of skin cancer prevention may be more convenient and address these patient concerns.
Among the oral supplements for skin cancer chemoprevention currently under investigation, NAM is one of the best candidates.33 A recent survey indicated that 76.9% of Mohs surgeons recommend NAM to prevent keratinocytes in their current patients.34 Given the ubiquity of KC, if NR or NMN even confer a minimally superior effect reducing KC over NAM, this would lead to a meaningful decrease in KCs on a population level with a concordant decrease in healthcare system costs given the relative low cost of NMN and NR supplements in comparison to surgical interventions for KC.
A special population that may especially benefit from treatment with NAD+ intermediates is the organ transplant recipient (OTR) patients. OTRs develop SCC up to 250 times the rate of the general population.1 Prevention of AKs and the reduction of risk of developing KC would have a valuable impact on these patients. Drago et al demonstrated a reduction in AKs and showed a decreased rate of AK progression to SCC in a small randomized controlled trial of transplant patients on NAM.1 NR or NMN would be a valuable tool for dermatologists to reduce morbidity and mortality in OTR as well as other high-risk populations if they were to demonstrate greater efficacy than NAM in KC reduction.
Among the oral supplements for skin cancer chemoprevention currently under investigation, NAM is one of the best candidates.33 A recent survey indicated that 76.9% of Mohs surgeons recommend NAM to prevent keratinocytes in their current patients.34 Given the ubiquity of KC, if NR or NMN even confer a minimally superior effect reducing KC over NAM, this would lead to a meaningful decrease in KCs on a population level with a concordant decrease in healthcare system costs given the relative low cost of NMN and NR supplements in comparison to surgical interventions for KC.
A special population that may especially benefit from treatment with NAD+ intermediates is the organ transplant recipient (OTR) patients. OTRs develop SCC up to 250 times the rate of the general population.1 Prevention of AKs and the reduction of risk of developing KC would have a valuable impact on these patients. Drago et al demonstrated a reduction in AKs and showed a decreased rate of AK progression to SCC in a small randomized controlled trial of transplant patients on NAM.1 NR or NMN would be a valuable tool for dermatologists to reduce morbidity and mortality in OTR as well as other high-risk populations if they were to demonstrate greater efficacy than NAM in KC reduction.
DISCLOSURES
No funding was received for this manuscript and the authors
state no conflict of interest. The content has not been previously
presented.
REFERENCES
1. Drago F, Ciccarese G, Cogorno L, et al. Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study. Eur J Dermatol. 2017;27(4):382-385. doi:10.1684/ejd.2017.3025
2. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132:1497-1500. doi:10.1038/jid.2011.459
3. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-26. doi:10.1056/NEJMoa1506197
4. Yoshino J, Baur J, Imai SI. NAD(+) Intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;6;27(3):513-528. doi: 10.1016/j. cmet.2017.11.002. Epub 2017 Dec 14.
5. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22(2):119-141. doi: 10.1038/s41580-020-00313-x. Epub 2020 Dec 22.
6. Snaidr VA, Damian DL, Halliday GM. Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety. Exp Dermatol. 2019;28 Suppl 1:15-22. doi:10.1111/exd.13819
7. Bierman JC, Laughlin T, Tamura M, et al. Niacinamide mitigates SASP-related inflammation induced by environmental stressors in human epidermal keratinocytes and skin. Int J Cosmet Sci. 2020;42(5):501-511. doi: 10.1111/ ics.12651. Epub 2020 Aug 20.
8. Liu Z, Chiang CY, Nip J, et al. Nicotinamide effects on the metabolism of human fibroblasts and keratinocytes assessed by quantitative, label-free fluorescence imaging. Biomed Opt Express. 2021;12(10):6375-6390. doi: 10.1364/BOE.432561. eCollection 2021 Oct 1.
9. Chini EN. Of Mice and Men: NAD(+) Boosting with niacin provides hope for mitochondrial myopathy patients. Cell Metab. 2020;31(6):1041-1043. doi: 10.1016/j.cmet.2020.05.013
10. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018:27:529-547. doi:10.1016/j. cmet.2018.02.011
11. Zhang H, Ryu D, Wu Y, et al. NAD⺠repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436- 43. doi:10.1126/science.aaf2693. Epub 2016 Apr 28.
12. Mitchell SJ, Bernier M, Aon MA, et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 2018;27(3):667-676.e4. doi:10.1016/j.cmet.2018.02.001
2. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol. 2012;132:1497-1500. doi:10.1038/jid.2011.459
3. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-26. doi:10.1056/NEJMoa1506197
4. Yoshino J, Baur J, Imai SI. NAD(+) Intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;6;27(3):513-528. doi: 10.1016/j. cmet.2017.11.002. Epub 2017 Dec 14.
5. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22(2):119-141. doi: 10.1038/s41580-020-00313-x. Epub 2020 Dec 22.
6. Snaidr VA, Damian DL, Halliday GM. Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety. Exp Dermatol. 2019;28 Suppl 1:15-22. doi:10.1111/exd.13819
7. Bierman JC, Laughlin T, Tamura M, et al. Niacinamide mitigates SASP-related inflammation induced by environmental stressors in human epidermal keratinocytes and skin. Int J Cosmet Sci. 2020;42(5):501-511. doi: 10.1111/ ics.12651. Epub 2020 Aug 20.
8. Liu Z, Chiang CY, Nip J, et al. Nicotinamide effects on the metabolism of human fibroblasts and keratinocytes assessed by quantitative, label-free fluorescence imaging. Biomed Opt Express. 2021;12(10):6375-6390. doi: 10.1364/BOE.432561. eCollection 2021 Oct 1.
9. Chini EN. Of Mice and Men: NAD(+) Boosting with niacin provides hope for mitochondrial myopathy patients. Cell Metab. 2020;31(6):1041-1043. doi: 10.1016/j.cmet.2020.05.013
10. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018:27:529-547. doi:10.1016/j. cmet.2018.02.011
11. Zhang H, Ryu D, Wu Y, et al. NAD⺠repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436- 43. doi:10.1126/science.aaf2693. Epub 2016 Apr 28.
12. Mitchell SJ, Bernier M, Aon MA, et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 2018;27(3):667-676.e4. doi:10.1016/j.cmet.2018.02.001
