NAD Replenishment for Preventing Cancer: New Evidence
Updated: Aug 11
There is good evidence that NAD replenishment can help prevent cancer.
First, the theory makes scientific sense -- our immune system's anti-tumor mechanisms and DNA repair mechanisms run on NAD, and they need adequate NAD for top performance. Second, there is actual human clinical evidence showing precisely that: A Phase 3, double-blind, randomized, controlled human study published in the New England Journal of Medicine -- perhaps the most prestigious medical journal in the world -- found that NAD boosting prevented skin cancer.
But the effect of NAD replenishment on active cancers is a different matter. Although the immune system's defense mechanisms are working overtime during cancer, and need to be powered, the cancer cells are looking for energy, too. So you have to wonder, when you are energizing your cells, exactly which cells you are energizing? Which side of the fight are you on?
Ten years ago, the Felding Lab at Scripps showed that NAD replenishment inhibited metastasis, improved survival, and blocked breast cancer development.
That finding was confirmed earlier this year when a different team published in the journal Oncogene that NAD+ supplementation suppressed tumor metastasis in triple-negative breast cancer, by activating SIRT1, which, among other things, has a role in DNA repair.
Another study last year showed a "bona fide tumor suppressor role for SIRT3, which is abrogated" when NAD levels dropped, and activated by the administration of NAD+ precursors, in a different kind of cancer.
Although it makes intuitive sense that cancer cells need energy, so starving your body of NAD will starve the cancer, it doesn't seem to work that way.
Inhibiting the rate-limiting enzyme nicotinamide phosphoribosyl transferase (NAMPT) to block NAD+ synthesis has been extensively studied preclinically to restrain tumor growth. However, early-phase clinical trials of NAMPT inhibitors yielded modest results with significant toxicities.
Instead, combining NAD replenishment, to help your body fight the cancer, along with other anti-tumor therapies, maybe be more promising:
Alternative methods, such as identifying sensitive populations and combining NAMPT inhibitors with other therapies, are warranted. Furthermore, recent studies have revealed new concepts of NAD+ metabolism, including its involvement in signal transduction, posttranslational modifications, and epigenetic regulation. For instance, NAD+ promoted the expression of programmed cell death 1 ligand 1 (PD-L1) through epigenetic mechanisms in hepatocellular carcinoma (HCC), contributing to tumor immune evasion. Combining NAD+ replenishment with anti-PD-L1 therapy effectively repressed tumor growth in preclinical models. The controversial role of NAD+ metabolism reflects the complexity of regulating redox metabolism for cancer therapy. [Emphasis added]
That doesn't mean if you have a cancer diagnosis you should try an NAD booster. First, we don't recommend any kind of treatment on this site. We're not your doctor. We're not any kind of doctor; we're a journalist-lawyer.
But more important, the science around active cancer is quite complicated. Other studies published last year have considered the opposite approach -- starving cells of NAD in order to starve the cancer of energy: "Depletion of NAD...ultimately causes cancer cell death" and "NAD+ depletion...was fatal to prostate cancer cells."
We don't know whether people with cancer should be trying to raise their NAD levels or lower their NAD levels, and it may depend on which type of cancer is involved, what other therapies are being used concurrently, and/or other factors.
But we were not surprised to see yet another study last month showing that NAD replenishment using nicotinamide riboside reduced the progression and metastasis of liver cancer in mice:
Targeting Nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a promising anti-cancer strategy; we aimed to explore the health benefits of boosting NAD levels with nicotinamide riboside (NR) on hepatocellular carcinoma (HCC) [liver cancer]...We found that NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice in both subcutaneous xenograft and hematogenous metastasis models. NR supplementation decreased metastasis to the bone and liver in the hematogenous metastasis model. NR supplementation also significantly decreased the size of allografted tumors and extended the survival time in C57BL/6J mice...In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of HCC progression.
The researchers said they were interested in Nicotinamide Riboside (NR) because NR had previously been shown to be protective against liver diseases and could promote liver regeneration, but they did not know about its effect on liver cancer:
Previous studies have shown that NR supplementation can attenuate alcohol-induced liver injuries, protect against liver fibrosis, and promote liver regeneration . However, only a few studies have investigated the potential prophylactic or therapeutic role of NR in cancer, and none have explored its effect on cancer metastasis.
Or, as leading NAD researcher Dr. Charles Brenner has said,
Because liver cancer usually develops from fatty and inflammatory liver conditions, and we’ve observed in preclinical models for many years that NR protects the liver from these conditions, it made a lot of sense to test NR as a molecule that could protect mice from liver cancer in this preclinical study.
The researchers first noted that cancer cells need a lot of NAD:
Cancer cells have a large demand for nicotinamide adenine dinucleotide (NAD) and its metabolites to support various crucial cellular processes, such as biosynthesis, energy metabolism, and antioxidant defense.
Interestingly, though, the researchers found that NAD levels were reduced in the tissues of liver that had cancer:
NAD levels in HCC tissues were found to be significantly lower than those in normal liver tissues. Similarly, NADP levels were remarkably decreased in HCC tissues compared to normal liver tissues
So the researchers administered NR, and the mice did better. The tumors did not shrink, but they also were less likely to grow, plus the mice did not lose as much weight, and perhaps most important, the tumors were less likely to metastasize.
Based on the reduction of NAD content in HCC tissues, we applied NR, a potent NAD precursor, to restore NAD levels for exploring the role of NAD in HCC progression...At the end of the intervention, the NR-treated mice had an 11.8% decrease in body weight, which was considerably lower than the 18.61% decrease from the control mice...NR treatment significantly decreased the number and area of lung metastasis nodules in mice compared to the control mice. The incidence rate of tumor metastasis was significantly lower in the NR (28.6%, 2/7) group comparing to the control group.
In other words, NR did not make the cancer go away, but it did slow its spread and alleviate some of the cancer's negative effects, in mice:
In this study, we report for the first time that nicotinamide riboside (NR) supplementation could alleviate cancer metastasis in tumor-bearing mice and enhance the maintenance of body weight at the late stage of cancer. Our results reveal that NAD precursor may be a novel treatment for the prevention of [liver cancer] progression.
We don't always make that much of mouse studies, because the animal results don't always translate directly to humans. However, although there are good reasons to believe that NAD replenishment may help prevent cancer, people sometimes wonder, if they have an undetected active cancer, whether taking vitamin B3 might do more harm than good?
We still don't know the answer to that question -- we're just starting to get mouse studies, and we certainly do not have human studies. But the most recent results suggest that at least some mice, with some types of cancer, are better off with an NAD booster than without.