Does NR Cause Cancer?
Updated: 7 hours ago
No, despite the headlines, that is not what the science is telling us.
Boosting NAD can help your immune system repair DNA and fight cancer. But if you already have cancer, then the situation with respect to NAD boosting gets instantly complex...
Many Studies Show That NAD Can Be Protective
In 2013, Dr. Brunie Felding of the Felding Lab at Scripps published research showing that NR protected against breast cancer. Specifically, they found that lower NAD levels increased metastasis, and increasing NAD levels reduced metastasis:
NAD+ precursor treatment inhibits metastasis and spontaneous breast cancer progression...This striking antimetastatic effect was confirmed in an independent cell model that preferably seeds brain metastases from the bloodstream...Brain metastasis was significantly reduced in animals receiving NAM treatment
Next, Felding's team decided to test whether NAD precursor treatment could prevent recurrence after removal of a breast cancer tumor. The found that an NAD booster significantly increased survival after removal of a highly aggressive metastatic breast cancer tumor.
To challenge our concept that NAD+ precursor treatment can interfere with tumor growth and metastatic activity, we asked whether this therapeutic approach might inhibit spontaneous metastasis and prolong animal survival after surgical removal of a primary breast tumor....NAM treatment starting after primary tumor surgery significantly increased animal survival in this model of highly aggressive metastatic breast cancer
Finally, the team concluded that NAD replenishment inhibited metastasis, improved survival, and blocked breast cancer development by inducing autophagy:
We demonstrated that enhancing NAD+ levels through NAD+ precursor treatment effectively inhibited experimental metastasis of human breast cancer cells in xenograft models. Importantly, this treatment also inhibited spontaneous metastasis and increased animal survival when the therapy was begun after surgical removal of primary tumors. Furthermore, NAD+ precursor treatment strongly interfered with oncogene-driven breast cancer development and progression in transgenic MMTV-PyMT mice. Our results provide evidence that the mechanism involves induction of autophagy.
This experiment was run with NAM, ten years ago, but apparently the Felding Lab's work has continued, and apparently showed similar results with NR, because the lab's website now specifically names "nicotinamide riboside" as a precursor delivering these results, and Felding herself is on ChromaDex's scientific advisory board.
Moreover, these results were largely confirmed in a study earlier this year by a different team that found NAM suppressed tumor growth in triple-negative breast cancer. The scientists found that the cancer cells had down-regulated the mitochondrial self-destruction signaling that would have told a cancer cell to self-destruct, but NAM reversed that down-regulation and caused the cancer cells to self-destruct. That's consistent with what the Felding lab found -- "induction of autophagy." The researchers were excited enough to suggest that NAM ought to be repositioned as a novel anti-tumor agent:
We showed strong evidence that NAM suppresses tumour growth and metastasis in Triple Negative Breast Cancer (TNBC). These findings indicate a promising potential of repositioning NAM supplement as a novel agent targeting cancer metabolism in TNBC...The activities of the key apoptosis-inducing processes upregulated by NAM are generally decreased in TNBC, supporting a potential therapeutic value of NAM in patients with TNBC...The growth of all TNBC cells was decreased in a dose-dependent manner after NAM treatment...We believe that future studies should include clinical trials of NAM by involving TNBC patients to determine the efficacy of NAM supplementation and optimize the dose of NAM in the clinical setting.
And these studies do not stand alone. Another study earlier this year examined the mechanisms behind how cancers rely on mitochondrial dysfunctions that allow tumors to grow. They discovered that in a type of tumor for which there is a common genetic predisposition called NF1, the lack of neurofibromin allows the cancer cells to depress NAD levels, which impairs Sirt3 activity. But raising NAD levels with an NAD precursor like NAM or NA rescues Sirt3 activity and reduces tumor growth. The reduction in abnormal growths resulting from neurofibromin was mimicked by the administration of NAD precursors.
Upon neurofibromin loss, hyperactivation of Ras/MEK/ERK signaling inhibits complex I, causing a decrease in the NAD+/NADH ratio and the ensuing SIRT3 repression. Raising the NAD+/NADH ratio via NDI1 expression has an antineoplastic effect through the enhancement of SIRT3 activity...These observations point toward a bona fide tumor suppressor role for SIRT3, which is abrogated by respiratory complex I inhibition and the ensuing decrease of NAD+/NADH ratio in NF1-related tumor cells...We envision that enhancement of SIRT3 activity and replenishment of NAD+ levels result in a multifaceted metabolic rewiring, which can oppose NF1-related cancer growth by affecting multiple bioenergetic pathways.
New Study Shows A Different Result
But a controversial new study from the University of Missouri this week claims to have reached the opposite result, suggesting that nicotinamide riboside increases metastasis of breast cancer. The researchers injected human breast cancer cells into a mouse heart and tracked metastasis to the brain. The mice taking NR did worse. In previous studies—including large human trials—B3 supplementation has been cancer preventative. But not in this study:
Our results demonstrate that NR supplementation results in a significant increase in cancer prevalence and metastases of TNBC to the brain. These results outline the important role of powerful nutraceuticals like NR in cancer metabolism and the need to personalize their use in certain patient populations.
We are assuming that when they say "significant increase" that they are referring to statistical significance, but a number of commenters have questioned whether statistical significance was in fact established in the study, which involved fewer than two dozen mice split into two groups with somewhat similar results. If the differences observed were not statistically significant, then the study did not find anything. One professor of neurobiology challenged the paper on this statistical ground, stating, "The result is not (statistically) significant...How is this acceptable science?" But let's assume for the moment that statistical significance was established.
Notice that the researchers did not say that NR causes cancer. All they say is that in this model where they injected human breast cancer cells into a mouse heart and added NR, metastasis to the brain was accelerated, which is different from what the Felding Lab saw.
One problem here is that the experimental conditions 0f injecting breast cancer cells into mouse heart tissue isn't a good model of anything in humans.
But perhaps more fundamental, these researchers are not studying oncogenesis, which is the complicated, multi-step process that leads normal cells to turn into cancer cells. So they certainly did not discover that NAD boosters cause cancer. Indeed, the researchers themselves caused the cancer by injecting it into the mice.
What they are studying is cancer metabolism, which is how cancer cells grow and multiply, typically battling the immune system.
The difficulty with cancer metabolism is that there isn't just one type of cancer. There are many cancer types, and different types of cancer cells have different attack and defense strategies.
So, for example, one type of cancer might use NAD to power its operations, and essentially convince cells to produce more NAD, or stop them from consuming NAD, so that the cancer can grow faster. In that case, adding NAD might be essentially the same as throwing gas on a fire and lead to bad results. And, conversely, lowering NAD levels could destroy the cancer. That's what researchers describe in these studies:
The rationale for reducing NAD+ levels in tumors is that they will be less able to repair DNA damage, thereby increasing their sensitivity to chemotherapeutic agents.
Due to aberrant metabolism, cell growth, and proliferation, tumor cells require higher NAD production with respect to healthy tissues to support the increased activity of NAD-degrading enzymes. Therefore, interfering with the NAD biosynthetic machinery was conceived as a promising therapeutic strategy against cancer. The depletion of NAD strongly affects multiple cellular metabolic pathways, leads to a rapid decline in adenosine triphosphate (ATP) levels, and ultimately causes cancer cell death
Silencing CD38, a key molecule that consumes NAD+, is seemingly the right strategy for fast-dividing [prostate] cancer cells to increase NAD+ availability. This notion is consistent with our finding that NAD+ depletion by CD38, in turn, was fatal to prostate cancer cells.
Another type of cancer might do the opposite, depressing NAD levels to impair the body's immune system from fighting back against the cancer. In that case, adding NAD might help the immune system fight the cancer. Specifically, T cells fight cancer, but they need energy to do so:
The other approach to treating cancer has been to increase NAD+ levels, the rationale being that an excess of NAD+ will boost mitochondrial respiration and downregulate glycolysis, counteracting the Warburg metabolism that cancer cells prefer. Increased NAD+ would also boost the activity of SIRT1 and SIRT6, both of which can inhibit tumors...
These studies indicate that high levels of NAD+, negatively regulated by CD38, preserve T cell function against tumors cells
This study also showed that T-cells attempting to attack tumors become exhausted, but that supplementing with nicotinamide riboside strengthened the T cells and improved anti-tumor activity:
Antitumor activity of tumor-infiltrating T lymphocytes (TILs)..supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness....Supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved...T cell antitumor immunity
So What's Really Going On?
Both possibilities existed -- that NAD boosting can help the immune system fight cancer or help the cancer reproduce -- and researchers knew they existed before the recent study, but the possible approaches relate to different types of cancer that have different types of metabolism. That's why the researchers in the new, controversial study concluded, "These results outline the important role of powerful nutraceuticals like NR in cancer metabolism and the need to personalize their use in certain patient populations." (emphasis added)
Some newsletters seem to have picked up this story and run too hard with it. Dr. Carles Canto, a leading researcher in the NAD field, who is also listed as a co-author on the study, clarified some of these points. He said that the conclusion that NR causes a cancer risk is "totally inaccurate from a scientific standpoint:"
The title of the news article 'Popular Dietary Supplement Causes Cancer Risk and Brain Metastasis' is clickbait material and totally inaccurate from a scientific standpoint. The experiment...does not allow for this conclusion.
Dr. Canto went on to say that the cancer cell implantation model was not the right way to test whether NR influences brain metastasis, and indeed was not intended to do that:
I know the main authors used a cancer cell implantation model as a PoC for the probe's utility, not to conclusively test if NR influences brain metastasis. There are far better models to test the latter.
Dr. Canto added that the results were counterintuitive, because the researchers were expecting protection against cancer, and this result conflicts with other published studies. Therefore, dramatic headlines like this are bad and premature:
The results were counterintuitive, as me and others were expecting protection. Interesting...but preliminary. Other publications point in the opposite direction. Therefore, such dramatic headlines are worrisome and should be avoided until more conclusive studies are performed, IMO
Shrill headlines that are totally scientifically inaccurate should be ignored. And until the methodology and statistical conclusions in this study are validated, it's not at all clear that these researchers discovered anything about NR's effects. All we have learned so far is a cautionary tale about science journalism run amok.
Indeed, Dr. Charles Brenner, the leading authority on NAD metabolism, when asked whether the claim that NR causes cancer were "baloney," said, "There's no link to cancer in human or in any well conducted rodent study. There are links to cancer prevention in well conducted studies."
The studies showing the protective effect of NR in cancer situations did not make big headlines. One set of studies demonstrate that NAD boosting makes chemotherapy more effective, or at least limits the collateral damage caused by chemotherapy.
For example, this study showed that using an NAD booster (NRH) to increase NAD levels in the cells of an incurable brain cancer (glioblastoma, the most prevalent and lethal brain tumor type, often treated with the DNA alkylating agent temozolomide (TMZ)) increased the effectiveness of the TMZ by blocking the cancer cells' ability to repair themselves.
We found that combining TMZ with an NAD+ precursor (dihydronicotinamide riboside) and a PARG inhibitor strongly inhibited BER and overcame TMZ resistance. This combination treatment regimen provides a novel approach to consider for glioblastoma...This report demonstrates that enhancing tumor cell levels of NAD+ by the addition of NRH strongly increases the cytotoxicity of TMZ + PARGi co-treatment....The combination of NRH + TMZ + PARGi suppressed the survival signaling from p-AKT and activated apoptosis signaling. (emphasis added)
And this study showed that NR can protect against the collateral damage caused by chemotherapy:
We demonstrated that NR intravenous administration decreases cardiac-muscle fibrous-tissue formation in chronic doxorubicin-induced cardiotoxicity development.
And NAD boosting has been shown to help protect against skin cancer:
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...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.
Indeed, this Phase 3, double-blind, randomized, controlled human study published in the New England Journal of Medicine found that NAD boosting prevented skin cancer:
In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months...Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients (emphasis added)
The state of California keeps a list of chemicals known to the state of California to cause cancer (the Proposition 65 List). There are almost a thousand chemicals on the list. Nicotinamide Riboside is not on the list. No form of vitamin B3 is on the list. In fact, no vitamin at all is on the list, because we do not believe that vitamins are carcinogenic.
But that does not prevent frenzied science writers on some website from propagating misleading headlines that include phrases like "cause cancer risk" and "increase the risk of developing breast cancer," even though we do not see where the study they are summarizing says that, or how it could have any basis for saying that, and one of the study's most prominent co-authors has expressly rejected that interpretation.
A lie can travel half way around the world
before the truth even gets its shoes on
There is no reason to pick on just a single publication. The entire click-bait news industry mindlessly repeats what it hears without ever investigating to find out whether one of the listed authors expressly refutes the interpretation.
Notice that the three articles in the middle all use the phrase "arbitrary" vitamin use, which is meaningless in this context. The word "arbitrary" does not come from the research, and reflects the kind of careless copying that would even reproduce a typo or a misspoken word. As long as spell-check approves, it's fit to print.
There may be an opportunity here, though. Internet journalism is typically about sensationalism and outrage, largely because advertising money is so tightly correlated with page views, and you don't have to say true things to get lots of views.
In fact, the truth is often quite boring. You are not going to get very many clicks for saying, "We have just learned that cancer metabolism varies more than previously recognized; even within the same tissue type different effects of NAD balance may be observed, at least under novel experimental conditions, and the use of health supplements should vary person to person."
The reason we made this Science of NAD website was to help cut through all the unfounded assertions based on inadequate or incomplete reference to the underlying science. The scientists are doing a great job trying to figure this stuff out, and we citizens should be good listeners and try to hear accurately what they are telling us.
So if we start to see a lot of vitamin-causes-cancer memes echoing around the web, we can maybe keep track of which journalists are trying to give us a clear look at what is going on, and which ones are giving us a more sensationalized look at what is going on, and then decide who to trust.
NAD and Cancer
With that said, let's be extra clear that we do not give medical advice on this website, and we are specifically not saying that if you might have cancer that you should or should not take an NAD booster. There is lots of evidence that NAD boosters can influence cancer metabolism -- that's what this study is telling us; the study describes the "important role of powerful nutraceuticals like NR in cancer metabolism." Maybe sometimes the role is protective, maybe sometimes the role is aggravating, maybe sometimes it doesn't make a difference. We don't know. And if you might have cancer then you need to talk to experts about what is going on in your case and what to do (or not to do) in your case. You don't want to make any medical decisions based on what you read on a website like this one.
But what you could reasonably do is to compare our efforts with others' efforts to explain what is actually going on, and then figure out who is best at helping you get the story straight, and adjust your gaze accordingly.
READ MORE: Research studies involving NAD and Cancer