How vitamin B-3 protects and even helps repair your DNA
by W. Todd Penberthy, PhD, Andrew W. Saul, and Robert G. Smith, PhD
Orthomolecular Medicine News Service, January 23, 2021
Although an individual's DNA sequences cannot be changed, the expression of genes can be modified by diet, including supplementation with high-dose niacin to boost NAD levels.
Cells that have had DNA damage are frequently transformed into cancer cells due to mutation. When our tumor suppressor genes are mutated, they can no longer function, and cells can grow without regulation and become cancerous. In a healthy situation, when a cell has DNA damage, poly-ADP ribose (PAR) is added to the DNA, and the cell will stop dividing. If the DNA can be repaired, the cell may continue dividing normally. If the damage is too much, then the cell will die by apoptosis. If the DNA damage is too extreme and acute, then the cell will die by the uncontrollable and messy process of necrosis, which will then adversely affect neighboring cells, likely causing greater collateral damage to them. When the PAR polymer is formed, NAD can become depleted, and cell death occurs because cells cannot live more than a minute or two without NAD.
Niacin, PAR and Sirtuins
Poly-ADP ribose (PAR) is a polymer that is made starting from NAD, which is made from vitamin B3 (niacin, niacinamide).1 PAR is produced especially in response to any damage to DNA as with radiation oncology treatments, UV sunlight, many chemotherapeutics, and other DNA damaging environmental toxins. When the DNA damage is extreme, unless there is adequate vitamin B3 (niacin or niacinamide), NAD can become so depleted that cells die by apoptosis (programmed cell death) or with more extreme damage by necrosis. PARP-1 is the enzyme responsible for this enzymatic activity and inhibitors of PARP1 will prevent this as well, thus keeping the cell alive, but at great cost.
The two primary niacin/niacinamide concentration-responsive pathways are defined by poly-ADP-ribose polymerase-1 and the sirtuins.
While PARP1 is more studied in the context of DNA damage repair, genome stability, and cancer research, the other major NAD epigenetics pathway involves the sirtuins, of which there are 7 genes in humans. These genes are most known for their roles in lifespan across the animal kingdom, even in yeast. Generally, there has been a tremendous amount of research focused on identifying small molecule activators of sirtuins for many types of therapeutics as well as longevity focused supplements, where resveratrol, pterostilbenes, and polyphenols in general are the most well-known molecules.
Sirtuins work on DNA by removing a 2-carbon molecule (deacetylation), from the higher order structure of DNA wrapped around histone solenoid-like structures on chromosomes. This activity resembles that which is seen in caloric restriction, the only method shown to increase lifespan in all animal models. Sirtuins use NAD as their substrate for their activity and sirtuin activity is increased simply by keeping NAD levels up - which can be accomplished by adequate doses of niacin.
Here's where niacin/niacinamide comes in
Vitamin B3 is the essential molecular precursor to nicotinamide adenine dinucleotide (NAD). All roads in longevity research consistently point to the importance of NAD in controlling lifespan, the most bioenergetically demanding processes (muscle & nerve), and susceptibility to all disease, including cancer.
NAD is made starting from niacin/niacinamide
The NAD precursors are niacin (or chemically, nicotinic acid), niacinamide (nicotinamide), nicotinamide riboside, or nicotinamide mononucleotide. These are all commercially available as supplements, with niacin or niacinamide as the cheapest, oldest, and most studied forms.
Niacin or niacinamide was the first form of vitamin B3 to be discovered. These have been fortified in flour since the 1940s eradication of the pellagra epidemics that were endemic during the first decades of the 20th century United States.
NAD
In basic biology courses we learn about the central role that NAD plays in bioenergetics, where NAD is shorthand for nicotinamide (or niacinamide) adenine dinucleotide. Its reduced form, NADH, is used to create the voltage gradient for mitochondria that generate energy for cells, ultimately producing 3ATPs per NADH with conversion to NAD+.
However, molecular genetics research also reveals that NAD is required for the function of over 400 genes, which is far more than any other vitamin.2,3 Moreover, NAD is involved in most of the 55 human cytochrome P450 drug-metabolizing enzymes. This family of phase 1 detoxification enzymes is widely known for its role in drug metabolism, but also functions normally in detoxification of environmental chemicals as well as the metabolism of steroids, prostaglandins, and some other vitamins. Research on NAD is ongoing and complex. Here we focus on NAD-related cellular transformation leading to the development of clinical cancer.
Niacin, Cancer, DNA, and Chemotherapy
The involvement of niacin in preventing cancer and chemotherapeutic side effects is not commonly recognized, but decades of research has established that niacin deficiency is common in cancer patients and cancer patients require larger amounts of niacin to correct deficiency.4
Generally, studies indicate that NAD functions as a preservative protecting cellular DNA from mutation and also preventing mutated cancer cells from surviving. Niacin deficiency promotes cancer by decreasing genomic stability, increasing the chances both for mutation and survival of mutated cancer cells.
Studies indicate that niacin deficiency delays DNA repair, promotes accumulation of DNA strand breaks, chromosomal translocations, telomere erosion typical of aging, and promotes cancer. Rat model studies indicate that most of these aspects of genomic instability are all minimized by the recommended levels of niacin.5 Niacin deficiency also increases levels of the tumor suppressor p53.6 Studies in mice indicate that mild niacin deficiency can cause an increased incidence of ultraviolet-B induced skin cancer.7
Kirkland concluded after decades of niacin deficiency cancer research, "With exposure to stressors, like chemotherapy or excess sunlight, supraphysiological [large] doses of niacin may be beneficial." 4
Studies have found that essentially all cancer patients are niacin deficient at first diagnosis, and almost half are still deficient after supplementation with RDA levels of niacin.5 This strongly supports supplementation with a high-dose NAD precursor (e.g. niacinamide 3x 500mg/d). Adequate dosing is likely to be beneficial for the health of all cancer patients.
Niacin and chemotherapies
Most cancer chemotherapies work by damaging the DNA of the rapidly dividing cells. Like most cancer chemotherapeutics, studies in rats have shown that niacin deficiency on its own causes anemia.7 and in also increases the severity of mutagen-induced anemia and the development of cancer.
Chemotherapeutics targeting the NAD biosynthetic enzyme NAMT (NAMPTi) are currently in clinical trials.8,9 All NAMPTi clinical trials to date have shown dose-limiting toxicity presentations resembling severe niacin deficiency, or pellagra. Pellagra killed over 100,000 people in the southern United States 1900-1920, and prompted the discovery of niacin.9 Moreover, no NAMPTi trial has demonstrated a reduction in tumor burden. Thus, the results of NAMPTi clinical trials do not support the idea of NAMPT targeting as a beneficial approach to treating cancer.
The amino acid glutamine plays an interesting role in cancer as there are glutamine-dependent tumors, and glutamine is required in the final step of biosynthesis to NAD starting from niacin or tryptophan, but not from niacinamide.
Thus, niacinamide or niacin supplementation is critically important for cancer patients. The beneficial effect of adequate niacin supplementation has been proven by studies showing that niacin supplementation can protect a cancer patient's bone marrow cells from the side effects of genotoxic chemotherapy drugs.
The role of NAD in the bioenergetics of cancer is huge. Cancer cells perform glycolysis at exceptionally high rates, demanding and taking glucose at the expense of healthy cells. There are distinct advantages and differences in the NAD precursor pathways as related to cancer. Niacinamide would appear to be most preferred with respect to bioenergetic perspective of cancer. This is planned to be briefly presented in a future OMNS release, but a summary and consistent practical takeaway suggestion that takes this into conclusion is included below.
Summary
Supplementation with vitamin B3 (niacin), the precursor to NAD, can lower the risk of cancer. NAD deficiencies are observed nearly all cancer patients, likely due to the energy draining component of suffering from hyper-proliferative cells. Chemotherapeutics commonly cause additional NAD deficiencies. There have been concerted efforts and considerations of targeting the NAD biosynthetic pathways as a novel patentable approach to the development of chemotherapeutics, but the results to date are in no way encouraging or exceptional, where dose-limiting toxicities resemble that of the deadly NAD deficiency disease pellagra. Many decades of research focused on using NAD precursors to favorably alter epigenetics via PARP1 and now sirtuin pathways indicate that supraphysiological doses of niacin will preserve the integrity of the genome, prevent mutation, and help prevent the rogue survival and proliferation of transformed cancer cells. In short, niacin prevents cancer and metastasis. NAD research is both complex and likely highly rewarding, and we still have much to learn regarding which NAD precursors are the best for addressing cancer. Nonetheless, studies strongly support high-dose NAD precursor supplementation. That means taking niacin, starting with low dosages, 100-200mg niacin, to get accustomed to the flush, and working up to 500 mg three times a day (1,500 mg total). During treatment for cancer, however, niacinamide may be the preferred form since it is not dependent on glutamine for the synthesis of NAD and glutamine restriction is helpful in treatment of cancer. The authors recommend this measure as potentially highly beneficial to saving the health of all cancer patients.
Summary:
- NAD deficiency is associated with greater risk for mutagenesis with cancer and this is likely best avoided using daily niacin, e.g. starting with 3x100-200mg/d to get to the know the flush and then working up to 3x500-1,000mg/d.
- For cancer patients, chemotherapy commonly causes NAD deficiency, which is best rescued with niacinamide; e.g. 3x500mg/d.
- Dietary relevance, glutamine restriction with niacinamide; glucose restriction and ketogenic diet is recommended.10,11
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References:
1. Other forms of niacin include: nicotinamide riboside and nicotinamide mononucleotide. This article focuses on niacin/niacinamide.
2. Penberthy WT, Kirkland JB. Niacin [Internet]. In: Present Knowledge in Nutrition. John Wiley & Sons, Ltd, [cited 2021 Jan 1] ; 293-306.https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119946045.ch19
3. Penberthy WT (2021) Vitamin B1, B2, & B3 Functions [cited 2021 Jan 1] https://www.phrs-usa.com/vitamin-b1-b2-b3-functions
4. Kirkland JB. (2012) Niacin requirements for genomic stability. Mutation Research, 733: 14-20.https://pubmed.ncbi.nlm.nih.gov/22138132
5. Spronck JC, Nickerson JL, Kirkland JB. (2007) Niacin deficiency alters p53 expression and impairs etoposide-induced cell cycle arrest and apoptosis in rat bone marrow cells. Nutrition and Cancer, 57: 88-99.https://pubmed.ncbi.nlm.nih.gov/17516866
6. Koshland DE. (1993) Molecule of the year. Science, 262: 1953.https://pubmed.ncbi.nlm.nih.gov/8266084/
7. Boyonoski AC, Gallacher LM, ApSimon MM, et al. (1999) Niacin deficiency increases the sensitivity of rats to the short and long term effects of ethylnitrosourea treatment. Molecular and Cellular Biochemistry, 193: 83-87.https://pubmed.ncbi.nlm.nih.gov/10331642
8. Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA. (2020) Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy. Frontiers in Pharmacology, 11:656.https://pubmed.ncbi.nlm.nih.gov/32477131
9. Heske CM. (2019) Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy. Frontiers in Oncology, 9:1514.https://pubmed.ncbi.nlm.nih.gov/32010616
10. Mukherjee P, Augur ZM, Li M, et al. (2019) Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Communications Biology, 2:200.https://pubmed.ncbi.nlm.nih.gov/31149644
11. Seyfried TN, Mukherjee P, Iyikesici MS, et al. (2020) Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer. Frontiers in Nutrition, 7:21.https://pubmed.ncbi.nlm.nih.gov/32219096