David M. Brady, ND, CCN, DACBN, IFMCP, FACN and Cristiana Paul, MS

Introduction

Recently a small, preclinical study by Maric T et. al., 2022¹ has gained a lot of media attention, due to claims that the study has found a potential link between supplementation with nicotinamide riboside (NR) and the risk of developing cancer and metastasis in immunocompromised mice inoculated with an aggressive type of breast cancer cells.

This, and any individual study’s findings, need to be considered alongside the totality of evidence available to date. This animal study alone cannot be used as a predictor of human reactions in various cancer-related circumstances. There are other studies that arrived to opposing conclusions and arguments regarding the potential effects of NR on cancer development, cancer treatment and its side-effects, as well as long term risk of developing cancer.^2-10

These effects should be put in perspective with the rationale of supplementing with NR, a precursor to nicotinamide adenine dinucleotide (NAD). The goal of such supplementation is to mitigate its age-related reduction in NAD tissue contents.^16-19 This, in turn may promote healthy aging, mitigate age-related degenerative diseases, and reduce some of the age-related decline in various organ functions.^20-55 This is not surprising since NAD is a key player in cellular metabolism, being found in the nucleus, cytosol, and mitochondria.  It participates in thousands of biochemical reactions, notably ATP synthesis and repair of damaged DNA.^48,50

Questionable Methods Used in the Study by Maric T et al., 2022¹

The form of NR used in the in vitro study was stated to be NR chloride salt, which was shown to have an enhanced uptake by cancer cells. As cancer cells tend to have a higher metabolic activity, it is not surprising they have a higher demand of mitochondrial cofactors such as NAD precursors. However, the in vitro application of NR chloride salt may not represent what happens when this compound is taken orally, after which it is cleaved from the chloride ion in the gut during absorption and processed by the liver. It is not clear how the in vitro concentration of NR chloride salt translates into oral NR doses.

The mouse diet in the Maric T. et al. 2022¹ study was high in carbohydrates (the standard chow “SAFE 150” contains 66% carbs from 72% cereals) and may have contributed to the aggressive cancer development in mice that were already predisposed being immunocompromised. Many types of tumors have been found to thrive on glucose, but less so on lower carbohydrate or ketogenic diets. NAD is a cofactor in glucose processing, so its effects on the metabolism of tumor cells greatly depend on the glucose/carbohydrate intake.

Injecting many aggressive tumor cells at once into an immunocompromised organism does not replicate the typical natural development of tumors, from initial mutations that may or may not escape the immune surveillance to further mutations that translate into higher proliferation and/or defective apoptosis (which is a mitochondrial function) and lastly metastasis.^56-58

Higher Doses Than Typical NR Supplements Used in the Study by Maric T et al., 2022¹

The study used a mouse dose of 400 mg NR/kg body weight per day. The human dose equivalent to the animal dose is calculated as follows: Human dose = 400 mg/kg (animal body weight per day)  / 12.3 (conversion factor) = 32.5 mg/kg human body weight per day.¹⁶ For a 60 kg person, the 32.5 mg/kg body weight dose translates into approx. 2000 mg NR per day. This is 6.6 x higher than the typically recommended doses of 100-300 mg/day for NR supplements.¹⁹

Problems with Statistical Significance in the Study by Maric T et al., 2022¹ 

The sample sizes were very small (groups of 10 vs 9 and 11 vs 12 in the two experiments). The association with tumor prevalence is not statistically significant in this study, and the authors’ usage of the term “significant” is misleading as a Chi-square test reveals a 0.52 p-value. The data are insufficient to support their conclusion that tumor prevalence was significantly increased with NR supplementation and extrapolation of their results to humans is not reasonable based on this data. Furthermore, the press release stated false conclusions not consistent with the study findings and omitted important contextual information.

Attenuating Effects of NR Supplementation on Tumor Growth (With or Without Chemotherapy), Cancer Cachexia, and Chemotherapy-Induced Neuropathy

A study titled “Nicotinamide riboside relieves paclitaxel-induced peripheral neuropathy and enhances suppression of tumor growth in tumor-bearing rats”² investigated a NR dose of 200 mg/kg body weight (equivalent to approx. 1000 mg NR), which was half of the equivalent dose used in the study by Maric T et al.

The authors concluded: “Unexpectedly, concomitant administration of NR during paclitaxel treatment further decreased tumor growth. Administration of NR also decreased the percentage of Ki67-positive tumor cells in these rats. Once daily administration of NR did not seem to alter tumor growth or the percentage of Ki67-positive tumor cells in rats that were not treated with paclitaxel and followed for 3 months. These results further support the ability of NR to play a protective role after nerve injury. They also suggest that NR may not only alleviate peripheral neuropathy in patients receiving taxane chemotherapy, but also offer an added benefit by possibly enhancing its tumor-suppressing effects.”²

A study titled “Nicotinamide riboside alleviates cisplatin-induced peripheral neuropathy via SIRT2 activation” concluded: “NR may provide increased protection from cancer treatment toxicity in select patients or clinical settings, and NAD+ expression could act as a predictive marker for toxicity risk and chemotherapy response.”³

A study titled “Nicotinamide Riboside Vitamin B3 Mitigated C26 Adenocarcinoma–Induced Cancer Cachexia”⁴ concluded “Dietary intake of the NR-containing pellet diet significantly attenuated cancer cachexia in a mouse model”⁴

Studies Exploring the Link Between NR Administration and Risk of Cancer with Positive Outcomes

Reversing NAD age-related decline has been advocated as a rational strategy to reduce cancer risk by optimizing DNA repair, which is known to decline with aging.^{8, 17} This approach reduces the age-related accumulation of oxidative DNA damage and mutations, along with increased lipid peroxidation. A paper by Massoudi reported that skin DNA damage content was associated with PARP-mediated NAD depletion and loss of SIRT1 activity in rodents. It also found that tissue NAD decline was directly correlated with increasing age in humans.¹⁷

A review titled “A Narrative Review of Nicotinamide Adenine Dinucleotide NAD Intermediates Nicotinamide Riboside and Nicotinamide Mononucleotide for Keratinocyte Carcinoma Risk Reduction”⁵ concluded: “NAD has protective cellular effects and is a necessary cofactor for DNA repair, helping to prevent potentially oncogenic mutations.” and it proposes that correction of NAD depletion will likely reduce the risk of developing skin cancer.⁵

An in vitro study investigated the molecular mechanisms of a particular type of hepatocellular carcinoma (HCC). It was found that reduction of intracellular NAD increased DNA damage at early stages of tumorigenesis. They concluded: “Restoring NAD (+) pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation…human HCC is associated with poor survival and correlates negatively with the L-tryptophan catabolism pathway. Our results suggest that boosting NAD(+) can be prophylactic or therapeutic in HCC.”⁶

Nicotinamide and nicotinamide riboside both boost intracellular NAD.^18,48,50 A study looked at the rate of cancer incidence in rats treated with the carcinogen N-nitrosodimethylamine and three diets differing in the nicotinamide content of food at 0 mg/kg, 50 mg/kg and 500 mg/kg.⁷ The results showed a dose-dependent effect, with the diet containing the highest amount of nicotinamide associated with the lowest rate of cancer incidence, while the total rate of cancer occurrence was the same by the end of life. This may be interpreted as nicotinamide intake dose-dependently delaying cancer occurrence throughout the rat life span.⁷

NAD is an important cofactor involved in immune function.⁵⁰ Thus, the age-related decline in NAD may be responsible, in part, for a corresponding age-related decline in immunity. This in turn may contribute to the well-recognized age-related increase in cancer risk.

A review titled “The Key Role of NAD⁺ in Anti-Tumor Immune Response: An Update” highlights the T cell’s functional dependence on intracellular NAD levels, the use of NAD precursors to boost anti-tumor T cell responses, and how such molecules may be employed as adjuvant therapies in combination with standard treatments.”⁸

A study demonstrated “a positive effect of NAD⁺-boosting strategies on blood stem cells and unveiling the potential of NR to improve recovery of patients suffering from hematological failure, including post chemo- and radiotherapy.”⁹

Another interesting study titled “Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion”¹⁰ states, “Strikingly, administration of alginate-mixed NR via intratumoral injection induced robust suppression of melanoma growth…melanoma and colon tumor growth was significantly impeded in NR-fed mice, and combined treatment with the NR diet and immune checkpoint blockade elicited additive antitumor responses”; “…supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses.”¹⁰

Additional studies investigating NR for various benefits, including during or post-cancer cancer treatment, are ongoing.^11-15

Rationale for NR Supplementation Throughout Lifespan for Health Span Extension

NR is a naturally occurring form of vitamin B3 in the human body and in animal and vegetarian foods and has a long track record of safety.^19,40,50 NR has regulatory acceptance for Niagen® NR, the leading commercial NR material, as a supplement and in foods, in seven global markets including the US, Canada, EU, Australia, New Zealand, Brazil, and Turkey. Niagen has been safely studied to date in 21 published human clinical trials revealing beneficial effects on mitochondrial function, inflammatory markers, and physical function in various models of diseases such as neurodegenerative conditions or heart failure.^19-39

The goal of NR supplementation with 100-300 mg NR daily is to normalize nicotinamide adenine dinucleotide (NAD) in the body corresponding to the amount present during youth, not to overdose. This strategy helps mitigate age-related decline in NAD levels, which may be responsible for many detrimental age-related alterations in physiology. Studies have shown an approximately 42% age-related decline in skin concentration of NAD levels for people in the 51-70 age range compared to those in the 30-50 age range.¹⁷ Fortunately, a daily dose of 100-300 mg of NR has been demonstrated to raise blood levels of NAD by 22-51%, which can compensate for its age-related decline.¹⁹

Figure 1 depicts concentration of age-related levels of NAD+ in human skin biopsies, which decrease three-fold by the age of young adult and another 2.5-fold through middle age.¹⁷ The study concludes that a lower content of NAD in tissues “may play a major role in the aging process, by limiting energy production, DNA repair and genomic signaling.”¹⁷ A lower intracellular level of NAD may be the result of NAD being used to repair damaged DNA and by increased inflammation, both of which rise with aging, as well as impaired NAD synthesis.

Figure 2 illustrates the extent of tissue NAD+ depletion observed during aging and with specific conditions compared to controls.¹⁸

A review claims that “calorie restriction (CR) represents the most efficacious intervention to promote longevity.”⁴⁸ However, NR supplementation was found to increase the lifespan of all species tested so far, including mice without caloric restriction.⁵⁰ This may be a consequence of NR raising intracellular NAD and activating SIRT1, which mimic essential cellular events occurring during CR. Hence, NR is among many molecules considered CR mimickers.

Numerous reviews discuss the benefits of optimizing NAD levels in various tissues.^{18, 40-55} For example, a 2022 review titled “Emerging Role of Nicotinamide Riboside in Health and Diseases“⁴⁰ highlights studies investigating NR effects with impressive findings: reduced circulatory levels of inflammatory cytokines IL-2, IL5, IL-6, TNF-alpha in many human trials, improved physical performance and decreased oxidative stress in old individuals, rejuvenated intestinal stem cells in aged mice by activating SIRT1, changes in hematopoietic stem cells composition of aged mice towards a more youthful state, and improved mitochondrial membrane potential and function in muscle cells in old mice.⁴⁰ In animal and human models, NR supplementation was shown to reduce markers of neuroinflammation, fatty liver, liver and heart fibrosis, as well as improve mitochondrial function in heart failure and models of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, or ALS. ^19-40

The authors also point out that reduced NAD+ levels have been shown to promote inflammation and increase cellular injury during viral infections, which may explain, at least in part, the higher mortality rates in patients that are older and/or have pre-existing medical conditions, such as respiratory diseases, cardiovascular diseases, and diabetes.⁴⁰ Other authors have also reviewed the potential benefits of optimizing NAD in preventing or fighting viral diseases such as COVID-19.^41,42

Conclusion

The inaccurate press release from the University of Missouri related to the Maric T. et al., 2022 study resulted in a one-sided, sensationalist and misleading story that does a disservice to consumers. Prominent NAD+ researcher, Dr. Carles Canto, also a coauthor on the same study, Tweeted, the University press release “is clickbait material and totally inaccurate from a scientific standpoint. The experiment in Maric et al. does not allow for this conclusion.” He also described the results of the study as “preliminary” and “such headlines are worrisome and should be avoided until more conclusive studies are performed….”

The science of nutrient supplementation for optimizing quality of life during aging is rapidly evolving. Based on all facts present, we cannot conclude that the reported results from the Maric T. et al., 2022¹ study can be translated into concerns regarding supplementation with daily doses of 100-300 mg of NR in healthy subjects, which has the potential to provide numerous benefits for aging individuals that want to maintain health and extend optimal function throughout lifespan. Considerations for supplementing with nutrients during active cancer or cancer treatment should be based on the up-to-date state of science and clinical judgement in concordance with patient wishes when balancing quality of life with cancer outcomes.

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Published April 22, 2023

About the Authors

David M. Brady, ND, CCN, DACBN, IFMCP, FACN is Chief Medical Officer for Designs for Health, Inc. (Palm Coast, Florida) and Diagnostic Solutions Laboratory, LLC. (Alpharetta, Georgia. He is also Director of The Nutrition Institute and Professor Emeritus, University of Bridgeport (Bridgeport, Connecticut.

Cristiana Paul, MS, is an independent nutrition research consultant and scientific consultant for Designs for Health, Inc. (Palm Coast, Florida).