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Does Nicotinamide Riboside Fuel Cancer Growth?
Tackling a brand new study hot off the press that raises concern.
I am not a medical doctor and this is not medical advice. Please see the full disclaimer at the bottom.
A hot-off-the-press new study published in the journal Biosensors and Bioelectronics raises concern that nicotinamide riboside (NR) could fuel cancer growth.
The authors used nicotinamide riboside chloride, obtained from Biosynth for cell studies and from Thorne for animal studies. This is the same ingredient in Niagen.
NR is a form of vitamin B3, also known as niacin, that is found in cow’s milk, yeast, and beer. NR is also formed during the digestion of NADH and NADPH, two of the major forms of niacin found in all foods.
The main biological significance of niacin is that it is an essential building block of NAD+ and NADP+. These are carriers of electrons that, when fully loaded with those electrons, are called NADH and NADPH. NAD+ is used to break things down in a process known as catabolism. NADPH is used to build things up or recycle them in a process known as anabolism. Niacin also plays roles in cellular longevity, DNA repair, and neurotransmission. The specific interest in NR is that supplying it may be a more effective way to boost NAD+ than supplying other forms of niacin. For more detailed background on niacin, see Part 1 and Part 2 of my long-form niacin podcast.
Back to the paper at hand, the authors created an innovative biosensor system that could look at the uptake of NR in cells and tissues of live animals in real-time. They used a cancer model to show the usefulness of this system, which is why the study is published in the journal Biosensors and Bioelectronics.
In order to measure real-time NR transport, they had to modify the NR by adding nitrogen to it. This results in a new compound called azido-NR. Azido-NR is transported similarly as natural NR, but it cannot be turned into NAD+. In fact, azido-NR actually inhibits the formation of NAD+ from natural NR.
Given this difference, they mixed and matched approaches using azido-NR to measure real-time transport, and using natural NR to see the physiological effects of supplying an NAD+ precursor in different conditions.
These authors were primarily interested in whether NR uptake influences the outcomes of triple-negative breast cancer. Triple-negative breast cancer is negative for three proteins of interest: the estrogen receptor, the progesterone receptor, and a growth factor called HER2. Each of these proteins is a target of a treatment option, leaving triple-negative breast cancer with fewer treatment options than other types of breast cancer. Women who are younger than 40, Black, or who have risk variations of the BRCA1 gene are more likely to develop this form of cancer. In addition to having fewer treatment options, it grows and spreads faster, and is associated with worse outcomes.
First, the authors compared two triple negative cell lines with two cell lines that were from other types of breast cancer. The triple-negative cells took up four times as much azido-NR as the other cancer cells.
This is consistent with previous research showing that triple-negative breast cancer cells obtain NAD+ by recycling its breakdown products, which are nicotinamide, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). By contrast, other types of breast cancer cells obtain NAD+ by making it from nicotinic acid — the form of niacin found mainly in plant foods and most supplements labeled as “niacin” — or by making it from the amino acid tryptophan.
Together, these findings raise the concern that NR supplementation could be a particular risk for fueling the growth of triple-negative breast cancer, while high protein intake or supplementation with nicotinic acid might pose a greater risk for fueling the other types of breast cancer. Similarly, since nicotinamide is disproportionately found in animal foods while nicotinic acid is disproportionately found in plant foods, one might imagine that niacin intake from animal foods could fuel triple-negative breast cancer growth while niacin from plant foods could fuel the growth of other types of breast-cancer.
Next, the authors looked at whether NR supplementation could fuel the growth and metastasis of triple-negative breast cancer cells in mice.
Mice were fed either a standard diet as controls, or the same diet supplemented with NR. The NR was mixed into the diet at a concentration that was expected to yield an average daily dose of 400 milligrams NR per kilogram bodyweight.
After two weeks on these respective diets, the mice of both groups had triple-negative breast cancer cells injected into their backs.
By week 10, 7 out of 10 mice in the NR group but only 5 out of 9 mice in the control group formed detectable tumors. This represents a 27% relative increase in tumor prevalence.
They then repeated this experiment but injected the cancer cells into the hearts of the mice instead of into their backs and looked for tumors in other organs. This was a model of metastasis. Brain metastases were found in 9 out of 11 mice fed NR, but only 3 out of 12 control mice had any metastases, mainly in liver and lung. This is a near tripling of the rate of metastasis as a result of NR supplementation, and a biasing of metastasis toward the brain.
Is the Dose Reasonable?
When assessing the dose, we need to normalize to bodyweight and then also divide by several safety factors utilized in standard risk assessment:
Divide by 12.3 because to adjust for the difference in surface area between mice and humans.
Divide by 10 to account for differences among humans (that is, some humans might be ten times more vulnerable than others).
Divide by 10 to account for this being a short-term study (that is, had this been carried on for the lifetime of a mouse, a ten times lower dose might have provided the same effect).
We start with 400 milligrams per kilogram per day, and we divide by 1,230 to arrive at 325 micrograms per kilogram per day.
For the 70-kilogram “standard reference man,” this is a daily dose of 23 milligrams.
For the average 197.9-pound male, this is a daily dose of 29 milligrams.
For an average adult woman weighing 166.2 pounds, this is a daily dose of 25 milligrams.
These doses are way under the smallest capsules of NR on the market, 150 milligrams, the typical recommended dose of 300 milligrams, or the up to 2000 milligrams used in some short-term human studies.
Thus, these doses are completely reasonable for assessing the potential risks of commonly used doses of NR.
None of this is to say that this study shows that 23-29 milligrams of NR per day is dangerous.
The study doesn’t show anything about what happens to human taking NR at any dose.
However, the study does raise a safety concern that as little as 23-29 milligrams of NR per day could fuel cancer growth and metastasis in specific patient populations to whom we believe this mouse model might be generalized.
Notably, the purpose of the safety factors is to try to catch the edge case, the lowest dose that might possess some of this effect that shows up in someone. So this is not meant to say that 23-29 milligrams would be the typical dose that would fuel serious advancements in growth and metastasis. Rather, if this study generalizes to humans, 23-29 milligrams per day would be higher than the lowest dose that would cause some aggravation of growth and metastasis in some people.
What Is the Relevance of This Model?
This is a model that assumes the existence of cancer.
This study did not show healthy mice could become cancer-burdened mice through NR supplementation. It showed that if cancer cells are injected into the mice, they are more likely to form tumors and metastasize if fueled with NR supplementation.
Most narrowly, this model raises concerns for women diagnosed with triple-negative breast cancer.
However, the rationale of the model is based on triple-negative cancers relying on the the recycling of NAD+, nicotinamide, NMN, and NR to fuel their metabolic needs, while other breast cancers rely on synthesis from protein or nicotinic acid. So this model implies that women with other types of breast cancer should be similarly concerned about protein intake or supplementation with nicotinic acid, usually simply called “niacin.”
Moreover, if we take into account research on how different cancers obtain NAD+, we can acknowledge that all forms of cancer depend on some way of supplying NAD+. They get it from protein, nicotinic acid, the recycling pathway used by triple-negatives, or some combination of these.
In theory, we may be able to take each cancer, see how it obtains NAD+, and then try to meet our niacin requirement from the opposite pathway. For example, if triple-negative breast cancer relies on the recycling pathway, it might be a helpful strategy to eat a diet low in nicotinamide while meeting our basic niacin requirement from nicotinic acid.
However, we have to keep in mind that cancerous cells, like normal cells, require many different things for growth. It is unclear how much we can restrict their growth simply by getting niacin from the form they cannot use.
The strongest implication from this research is that, unless and until this is contradicted by other research, especially human studies, women with a diagnosis of triple-negative breast cancer should avoid supplementation with nicotinamide, NMN, or NR, unless they have a very strong reason to use it, and they should be cautious about the possibility that such supplementation could fuel cancer growth and metastasis.
Notably, NR is currently being evaluated in over 50 clinical trials, and some of those are aimed at mitigating adverse effects of cancer therapy. So, we should eventually have human evidence to help flesh this out further.
Outside of this implication, it is critical to emphasize that this does not raise the concern that NR supplementation in a healthy person could make them more likely to develop cancer in the future.
Why? Because we have long had tremendous reason to believe that the path to cancer prevention is completely different from the path to treating cancer.
Cancer Prevention Versus Cancer Treatment
It is my very firm belief that the diet and lifestyle approach to maintain health in the cancer-free state and to prevent cancer is radically different from the diet and lifestyle approach that will support cancer treatment.
In 2010 and 2011, I wrote several articles on the significant body of animal research done by T. Colin Campbell of “China Study” fame. Although I was very critical of the China Study, which promotes a vegan diet, Campbell’s animal experiments are very much worthwhile to pay attention to. Here are my articles:
Campbell’s animal experiments showed as follows:
A high-protein diet protects against cancer when it is fed before and during carcinogen exposure.
A high-protein diet promotes cancer growth when it is fed after carcinogen exposure.
The best outcomes are obtained when animals eat high-protein diets before and during carcinogen exposure and switch to low-protein diets afterward.
The worst outcomes are obtained when animals eat low-protein diets before and during carcinogen exposure and switch to high-protein diets afterward.
The reason for this pattern is that protein promotes the detoxification of carcinogens, rendering them impotent. However, if a cancer has taken hold, protein allows it to grow faster.
These, first of all, show that what you want to eat when you have cancer is, at least with respect the protein content, the complete opposite of what you want to eat to prevent cancer.
Second of all, however, this model is only useful when we know the discrete timing of our carcinogen exposure. And the only time we ever have a discrete period of carcinogen exposure responsible for our entire cancer risk is during exceedingly rare industrial accidents.
Most of us are exposed to low doses of a broad mix of carcinogens continuously throughout our lives.
While Campbell focused on discrete periods of carcinogen exposure, other groups tested the effect of protein on continuous low-dose carcinogen exposure.
The results were unambiguous: under conditions of chronic, low-dose carcinogen exposure, protein is protective.
If we were to generalize this principle to the NR study, NR is likely to be protective for those of us who aren’t diagnosed with cancer.
Notably, 500 milligrams of nicotinamide (not riboside) twice a day was effective at reducing the risk of new melanoma in patients who had developed two or more cases of melanoma in the past. Nicotinamide does not fuel melanoma growth in vitro, so this is not directly comparable to NR and triple-negative breast cancer. However, physiologically relevant concentrations of nicotinamide do not kill melanoma cells, so what is of interest in this case is that the nicotinamide must have helped by supporting energy metabolism and immune function.
Supporting energy metabolism and immune function is likely to be generally protective in the prevention of any cancer.
Another angle to consider is when a nutrient can be harnessed to help kill cancer cells.
High-dose intravenous vitamin C (HIVC) acts as a pro-oxidant, and can synergize with oxidative chemotherapy to help kill cancer cells.
This role of HIVC is completely different from its role in sepsis patients. In healthy people and cancer patients, HIVC reaches very high supraphysiological concentrations that have a pro-oxidant effect. Sepsis patients, by contrast, are extremely depleted in vitamin C and need HIVC simply to bring these levels into the normal range.
Animal experiments suggest that if glutathione is included in the IV, it will abolish the ability of vitamin C to reduce tumor size. However, it still promotes the survival of the animals. The likely implication is that vitamin C and glutathione should be alternated: HIVC should be paired with oxidative chemotherapy to kill tumor cells; in between these doses, as far from them as possible, glutathione should be given to support the health of the patient.
I would synthesize these principles as follows:
The path to cancer prevention is to nourish detoxification and immune surveillance.
When this fails, we need to shift our focus to restraining cancer growth and killing cancer.
We know we have reached this point of failure if we are diagnosed with cancer.
At this point, it is still important to nourish detoxification and immune surveillance, but we must realize that many things that do this will also promote cancer growth or interfere with our efforts to kill the cancer. Since restraining cancer growth and killing the cancer now take priority, we must redesign our health program to make those goals central. This may mean restricting protein and other nutrients that would otherwise be healthy to consume abundantly.
Some nutrients can be used strategically to help kill the cancer (like high-dose intravenous vitamin C, when paired with oxidative chemotherapy).
Nutrients that have a risk of promoting cancer growth or protecting cancer from being killed may be strategically alternated with cancer-killing therapy. If the cancer-killing therapy neutralizes the cancer for a period of time, this allows a window wherein focus can shift to nourishing the patient.
We all may be wondering, what if I am on the edge of being diagnosed? How do I know I haven’t crossed that boundary already?
There is obviously a gray area in the pre-diagnosis phase. However, I would defer back to the animal experiments showing protein is universally protective when carcinogen exposure is low-dose and chronic, and I would point out that the supporting of detoxification and immune surveillance has to fail before the focus needs to shift. Therefore, I think the absence of a cancer diagnosis, while not a perfect signal that all focus should be on nourishment, is a sufficient signal that this is the greatest probability.
The best hedge against this ambiguity is a fasting practice. Periodic abstention from protein and other cancer fuels during a fasting period that is alternated with an equally robust feeding period is what I suggested could be useful in my position on Protein and Longevity.
One set of nutrients that stand out as likely to help across the board, before cancer, during, and after, are vitamins A, D, and K2. This is because these vitamins have important roles in helping cells maintain their proper identity.
It is the building blocks of cellular growth, such as protein and energy; the nutrients that facilitate growth and energy metabolism, such as B vitamins; and the nutrients that protect cells, such as glutathione; it is these that pose risk of fueling the growth of existing cancers or protecting the cancer cells we are trying to kill.
For these, I am optimistic about strategic restriction. I imagine a fasting program, where these nutrients are still kept to moderate levels even during the refeeding periods. If used with a cancer-killing therapy, I would think a more restrictive phase of the program could be used during the cancer-killing timeframe, while a more nourishing phase of the program could be used to nourish the patient in between. This would have to be balanced with the risk of wasting that occurs in cancer cachexia.
Nevertheless, someone who is not diagnosed with cancer should overwhelmingly focus on nourishment.
The Bottom Line
This new study raises the concern that as little as 23-29 milligrams of nicotinamide riboside per day could possibly fuel cancer growth and metastasis in women with triple-negative breast cancer.
More broadly, it raises the possibility that other forms of breast cancer might be fueled with nicotinic acid (often labeled “niacin”) or high protein intakes.
However, this is a mouse model and it cannot be used to confirm anything about what happens in humans.
More importantly, we have strong reasons to believe that what prevents cancer is radically different from what treats cancer. Many things that may fuel the growth of an established cancer are our best strategies to prevent a cancer from ever becoming established.
This study should not be used to suggest healthy people may develop cancer as a result of supplementing with nicotinamide riboside. In fact, we should be very interested in the possibility that nicotinamide riboside could help prevent cancer. Nicotinamide (not riboside) has actually been shown to help reduce the risk of melanoma in high-risk subjects.
I believe that women diagnosed with triple-negative breast cancer should avoid supplementing with nicotinamide riboside unless they have a very strong reason to do so, and should be aware that it might fuel cancer growth or metastasis. This is a low-confidence judgment. Future studies in humans could be used to confirm, refute, or revise this. Until such studies exist, future animal studies may contradict this one and cause me to put this judgment on hold.
More broadly, I believe we should investigate the potential for fasting and restriction of growth-promoting nutrients, as well as alternation between cancer-killing therapies and nourishment regimes, to help with established cancer.
We should all have some form of fasting-feeding cycle, but those of us without diagnosed cancer should focus primarily on meeting our nutrient needs and should not worry about this nicotinamide riboside study.
I am not a medical doctor and this is not medical advice. My goal is to empower you with information. Please make all health decisions yourself, consulting sources you trust, including a caring health care professional.
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