Particular caution should be used for NAD+-boosting supplements by those with cancer, a personal or strong family history of cancer and perhaps also by those with inflammatory disorders and certain active infections.
Risks of NAD+ Boosting Supplements
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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Most of the reported side effects for NAD+ precursors, like NAM, NR, and NMN, are relatively rare and minor––for example, diarrhea, nausea, rashes, hot flashes, and leg cramps. Both NR and NMN raise NAM levels, so may share in the same concerns regarding sirtuin inhibition, methyl depletion, and potential adverse effects of NAM breakdown products.
Another theoretical concern of NAD+ boosting is the exacerbation of infections by a group of bacteria called Haemophilus (from the Greek meaning “blood-loving,” though they can also cause infections of the lungs, brain, throat, flesh, and joints). Haemophilus bacteria lack the ability to make NAD+, so rely on host levels, raising the possibility that higher blood levels might worsen the disease course of infected individuals. Ironically, elevated NAD+ levels may also fuel immune system overreaction in cases of auto-immune and inflammatory disease.
When fully activated, the immune system is voracious. The immune reaction to a blood infection or extensive burns can burn 4,000 calories a day, approximating military training in the Arctic. Since NAD+ is used by cells to produce energy, it’s no surprise that we find the primary NAD+ synthesizing enzyme strongly upregulated in tissues that are actively inflamed. For example, the enzyme NAMPT is elevated in colonoscopy biopsies taken from inflamed areas in patients with inflammatory bowel disease, and higher levels are correlated with greater disease severity. So, for those suffering from chronic autoimmune diseases, such as rheumatoid arthritis, NAD+ boosting could potentially have a “profound negative impact.” This explains why tamping down NAD+ with NAMPT inhibitors has been shown to ameliorate colitis and arthritis in mice. But this has yet to be tested in people. Such NAD+ depleting drugs have, however, been used in cancer patients.
Malignancy is another heavily energy-consuming process. NAD+ may, therefore, have a tumor-promoting effect by promoting cancer cell growth and spread. For example, NAMPT, the NAD+-forming enzyme, is highly expressed in cancerous brain tumors, and correlates with decreased patient survival. This has led to attempts to use NAD+-depleting therapies to try to starve cancer progression. But this approach is confounded by rapid onset injury to another energy-intensive tissue, the retina, risking blindness.
Giving NMN to mice with pancreatic cancer accelerates the progression of the cancer, thought due to the aggravation of inflammation. The researchers conclude that consumers of NAD+ supplements must “balance the advantageous anti-ageing effects with the potential detrimental pro-tumorigenic side effects.” Perhaps this explains why the best NAD+ boosters have ever been able to do is increase mice lifespan by five percent.
On the other hand, as you’ll remember, NAM successfully prevented human skin cancers, and has been found to reduce the incidence of a variety of carcinogen-induced tumors in rodents. The disparate results may in part be due to the disparate impact sirtuin activation may have on different cancers. Sirtuin activity can be overexpressed in some cancers (like thyroid carcinomas and lung metastasis), but reduced in others (like brain, bladder, prostate, and ovarian tumors).
The bottom line is that particular caution should be used for NAD+ boosting supplements by those with cancer, or a personal or strong family history of cancer, and perhaps also by those with inflammatory disorders and certain active infections.
Please consider volunteering to help out on the site.
- Poljsak B, Kovač V, Milisav I. Healthy lifestyle recommendations: do the beneficial effects originate from NAD+ amount at the cellular level? Oxid Med Cell Longev. 2020;2020:8819627.
- Oakey LA, Fletcher RS, Elhassan YS, et al. Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD + depletion. Wellcome Open Res. 2018;3:147.
- Braidy N, Liu Y. NAD+ therapy in age-related degenerative disorders: a benefit/risk analysis. Exp Gerontol. 2020;132:110831.
- Liu Y, Clement J, Grant R, Sachdev P, Braidy N. Quantitation of NAD+: Why do we need to measure it? Biochim Biophys Acta Gen Subj. 2018;1862(12):2527-2532.
- Gerner RR, Klepsch V, Macheiner S, et al. NAD metabolism fuels human and mouse intestinal inflammation. Gut. 2018;67(10):1813-1823.
- Almajwal A, Alam I, Zeb F, Fatima S. Energy metabolism and allocation in selfish immune system and brain: a beneficial role of insulin resistance in aging. FNS. 2019;10(01):64-80.
- Starr AE, Deeke SA, Ning Z, et al. Proteomic analysis of ascending colon biopsies from a paediatric inflammatory bowel disease inception cohort identifies protein biomarkers that differentiate Crohn’s disease from UC. Gut. 2017;66(9):1573-1583.
- Busso N, Karababa M, Nobile M, et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS One. 2008;3(5):e2267.
- von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol. 2010;65(6):1165-1172.
- Ruszkiewicz JA, Bürkle A, Mangerich A. Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity. J Biol Chem. 2022;298(6):102037.
- Gujar AD, Le S, Mao DD, et al. An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proc Natl Acad Sci U S A. 2016;113(51):E8247-E8256.
- Palmer RD, Vaccarezza M. Nicotinamide adenine dinucleotide and the sirtuins caution: Pro-cancer functions. Aging Med (Milton). 2021;4(4):337-344.
- Zabka TS, Singh J, Dhawan P, et al. Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase. Toxicol Sci. 2015;144(1):163-172.
- Nacarelli T, Lau L, Fukumoto T, et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019;21(3):397-407.
- Mendelsohn AR, Larrick JW. Interacting NAD+ and cell senescence pathways complicate antiaging therapies. Rejuvenation Res. 2019;22(3):261-266.
- Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-1626.
- Buqué A, Bloy N, Kroemer G, Galluzzi L. Possible mechanisms of cancer prevention by nicotinamide. Br J Pharmacol. 2021;178(10):2034-2040.
- Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15(10):608-624.
Motion graphics by Avo Media
Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Most of the reported side effects for NAD+ precursors, like NAM, NR, and NMN, are relatively rare and minor––for example, diarrhea, nausea, rashes, hot flashes, and leg cramps. Both NR and NMN raise NAM levels, so may share in the same concerns regarding sirtuin inhibition, methyl depletion, and potential adverse effects of NAM breakdown products.
Another theoretical concern of NAD+ boosting is the exacerbation of infections by a group of bacteria called Haemophilus (from the Greek meaning “blood-loving,” though they can also cause infections of the lungs, brain, throat, flesh, and joints). Haemophilus bacteria lack the ability to make NAD+, so rely on host levels, raising the possibility that higher blood levels might worsen the disease course of infected individuals. Ironically, elevated NAD+ levels may also fuel immune system overreaction in cases of auto-immune and inflammatory disease.
When fully activated, the immune system is voracious. The immune reaction to a blood infection or extensive burns can burn 4,000 calories a day, approximating military training in the Arctic. Since NAD+ is used by cells to produce energy, it’s no surprise that we find the primary NAD+ synthesizing enzyme strongly upregulated in tissues that are actively inflamed. For example, the enzyme NAMPT is elevated in colonoscopy biopsies taken from inflamed areas in patients with inflammatory bowel disease, and higher levels are correlated with greater disease severity. So, for those suffering from chronic autoimmune diseases, such as rheumatoid arthritis, NAD+ boosting could potentially have a “profound negative impact.” This explains why tamping down NAD+ with NAMPT inhibitors has been shown to ameliorate colitis and arthritis in mice. But this has yet to be tested in people. Such NAD+ depleting drugs have, however, been used in cancer patients.
Malignancy is another heavily energy-consuming process. NAD+ may, therefore, have a tumor-promoting effect by promoting cancer cell growth and spread. For example, NAMPT, the NAD+-forming enzyme, is highly expressed in cancerous brain tumors, and correlates with decreased patient survival. This has led to attempts to use NAD+-depleting therapies to try to starve cancer progression. But this approach is confounded by rapid onset injury to another energy-intensive tissue, the retina, risking blindness.
Giving NMN to mice with pancreatic cancer accelerates the progression of the cancer, thought due to the aggravation of inflammation. The researchers conclude that consumers of NAD+ supplements must “balance the advantageous anti-ageing effects with the potential detrimental pro-tumorigenic side effects.” Perhaps this explains why the best NAD+ boosters have ever been able to do is increase mice lifespan by five percent.
On the other hand, as you’ll remember, NAM successfully prevented human skin cancers, and has been found to reduce the incidence of a variety of carcinogen-induced tumors in rodents. The disparate results may in part be due to the disparate impact sirtuin activation may have on different cancers. Sirtuin activity can be overexpressed in some cancers (like thyroid carcinomas and lung metastasis), but reduced in others (like brain, bladder, prostate, and ovarian tumors).
The bottom line is that particular caution should be used for NAD+ boosting supplements by those with cancer, or a personal or strong family history of cancer, and perhaps also by those with inflammatory disorders and certain active infections.
Please consider volunteering to help out on the site.
- Poljsak B, Kovač V, Milisav I. Healthy lifestyle recommendations: do the beneficial effects originate from NAD+ amount at the cellular level? Oxid Med Cell Longev. 2020;2020:8819627.
- Oakey LA, Fletcher RS, Elhassan YS, et al. Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD + depletion. Wellcome Open Res. 2018;3:147.
- Braidy N, Liu Y. NAD+ therapy in age-related degenerative disorders: a benefit/risk analysis. Exp Gerontol. 2020;132:110831.
- Liu Y, Clement J, Grant R, Sachdev P, Braidy N. Quantitation of NAD+: Why do we need to measure it? Biochim Biophys Acta Gen Subj. 2018;1862(12):2527-2532.
- Gerner RR, Klepsch V, Macheiner S, et al. NAD metabolism fuels human and mouse intestinal inflammation. Gut. 2018;67(10):1813-1823.
- Almajwal A, Alam I, Zeb F, Fatima S. Energy metabolism and allocation in selfish immune system and brain: a beneficial role of insulin resistance in aging. FNS. 2019;10(01):64-80.
- Starr AE, Deeke SA, Ning Z, et al. Proteomic analysis of ascending colon biopsies from a paediatric inflammatory bowel disease inception cohort identifies protein biomarkers that differentiate Crohn’s disease from UC. Gut. 2017;66(9):1573-1583.
- Busso N, Karababa M, Nobile M, et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS One. 2008;3(5):e2267.
- von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol. 2010;65(6):1165-1172.
- Ruszkiewicz JA, Bürkle A, Mangerich A. Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity. J Biol Chem. 2022;298(6):102037.
- Gujar AD, Le S, Mao DD, et al. An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proc Natl Acad Sci U S A. 2016;113(51):E8247-E8256.
- Palmer RD, Vaccarezza M. Nicotinamide adenine dinucleotide and the sirtuins caution: Pro-cancer functions. Aging Med (Milton). 2021;4(4):337-344.
- Zabka TS, Singh J, Dhawan P, et al. Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase. Toxicol Sci. 2015;144(1):163-172.
- Nacarelli T, Lau L, Fukumoto T, et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019;21(3):397-407.
- Mendelsohn AR, Larrick JW. Interacting NAD+ and cell senescence pathways complicate antiaging therapies. Rejuvenation Res. 2019;22(3):261-266.
- Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-1626.
- Buqué A, Bloy N, Kroemer G, Galluzzi L. Possible mechanisms of cancer prevention by nicotinamide. Br J Pharmacol. 2021;178(10):2034-2040.
- Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15(10):608-624.
Motion graphics by Avo Media
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Title
Risks of NAD+ Boosting Supplements
LicenseCreative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Content URLDoctor's Note
This is the eighth video in my NAD+ series. If you missed any of the previous ones, see:
- Do NAD+ Levels Decline with Age?
- Can NAD+ Boosters Increase Lifespan and Healthspan?
- Risks and Benefits of Nicotinic Acid (NA), a NAD+ Booster
- Risks and Benefits of Nicotinamide (NAM), a NAD+ Booster
- Risks and Benefits of Nicotinamide Riboside (NR), a NAD+ Booster
- Risks and Benefits of Nicotinamide Mononucleotide (NMN), a NAD+ Booster
- Lesser-Known NAD+ Boosting Supplements—Tryptophan, NADH, NMNH, and NRH
Stay tuned for Which NAD+ Booster Is Best? and The Third Way to Boost NAD+.
For more on aging, go to your local public library and check out my longevity book, How Not to Age, available in print, e-book, and audio. (All proceeds I receive from the book are donated directly to charity.)
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