Life Extension Magazine®

Scientist studying effects of NAD+ on damaged DNA

“Next Generation” Vitamin Provides Hope To Aging Societies Worldwide

The fatigue and loss of motivation that accompanies aging is often caused by reduced levels of the compound NAD+. An innovative cell-boosting technology can maximize NAD+ benefits that include DNA repair, increased life span, and activation of anti-aging sirtuin enzymes.

Scientifically reviewed by: Dr. Carol Campi, RN, DC, in October 2024. Written by: Scott Rahway.

 

Revolutionary Form Of Vitamin B3 “Turns Off” Aging Genes

Normal aging is accompanied by a noticeable increase in both mental and physical fatigue, along with a loss of motivation.1 The tiredness we outwardly feel reflects inward impairment of cellular functions critical to sustaining life.

This is in part the result of reduced levels of a compound called NAD+, found in every cell in the body and essential to life.2,3 NAD+ enables the transfer of energy from the foods we eat to vital cell functions4 and is required to turn “off” genes that accelerate degenerative aging processes.5,6

Published research confirms that NAD+ levels decline as we age7,8 and represent a fundamental, systemic contributor of aging.9

Finding a way to boost NAD+ levels, therefore, could help promote youthful vitality and even extend life span.

For the past 13 years, we at Life Extension® have been searching for an efficient way for aging humans to affordably boost their cellular NAD+ levels. We came close in 2001, when one of our researchers developed an effective NAD+ boosting sublingual lozenge; unfortunately, it only maintained stability for a short time period.

Now, after more than a decade of searching, an effective NAD+ cell-boosting technology has finally become available.

Nicotinamide Riboside Boosts NAD+

The most effective way to boost NAD+ levels in the body is through a newly discovered form of vitamin B3 called nicotinamide riboside.10 Studies have shown that nicotinamide riboside, acting of as an NAD+ precursor, switches “off” the genes of aging, extends life span, increases endurance, improves cognitive function, activates beneficial sirtuins, and enhances cellular energy.5,11

What makes this patented form of vitamin B3 so unique is its ability to convert readily into NAD+.

Why NAD+ Is So Important

Why NAD+ Is So Important  

NAD+ is the term used in the scientific literature to describe a cellular compound called nicotinamide adenine dinucleotide. Compelling research shows that NAD+ has a unique ability to protect tissues, induce DNA repair, and increase life span.3,12,13 These features have led prominent universities to investigate NAD+ as a potential therapy for various degenerative diseases associated with the aging process.14

NAD+ battles aging in two different and important ways:

  1. The first has to do with cellular energy. NAD+ plays an important role in transferring energy released from the foods we eat to the mitochondria so that it can be converted into cellular energy.3,15 Mitochondria are the tiny intracellular “furnaces” that power cellular processes.16 As NAD+ levels decline, mitochondrial function is impaired, which results in fewer mitochondria surviving, and ultimately may lead to many of the physical symptoms of aging. Fortunately, by increasing intracellular NAD+ levels, age-related mitochondrial dysfunction can be reversed.9
  2. Second, NAD+ activates3 key anti-aging enzymes called sirtuins.9,17,18 Sirtuins, specifically SIRT1 and SIRT3, are intimately related to longevity through their control of gene expression and require NAD+ for their activity.3,5,19,20-22

By activating these sirtuins, we’re able to gain control over one of our body’s anti-aging “switches.” SIRT enzymes “turn off” certain genes that promote aging, such as those involved in inflammation,23,24 in fat synthesis and storage,25,26 and in blood sugar management.25,26

Consequences Of Falling NAD+ Levels

Nicotinamide Riboside  

The age-related decrease in NAD+ causes defects in both energy- and gene-related functions to accumulate. These defects feed on one another to produce the disorders we typically identify as aging.19

The consequences of a decline in NAD+ levels and subsequent reduction in SIRT1 and SIRT3 enzymes include:

  • Neurodegeneration in the brain,19,27,28
  • Vascular inflammation, producing damage to heart and blood vessels that can result in stroke or heart attack,29-31
  • Increased fat storage in the liver, which could lead to nonalcoholic fatty liver disease (NAFLD),32-34
  • Increased fat production and deposition in white adipose tissue (the primary fat storage form found in dangerous belly fat),35,36
  • Growing insulin resistance, and
  • Fatigue, loss of muscle strength and decreased fatty acid oxidation.39,40

To avoid these degenerative processes, it is essential that steps be taken to optimize the amount of NAD+ in our bodies.

A Natural NAD+ Booster

Nicotinamide riboside has been scientifically proven to maintain robust levels of NAD+ in cells, thereby both supporting vital cellular energy functions and activating the anti-aging enzymes SIRT1 and SIRT3.11,41 As a result, NAD+ provides an extraordinary range of longevity benefits that add up to a system-wide slowing and reversal of certain aging processes. In addition, nicotinamide riboside accomplishes this NAD+ boosting effect without the irritating skin flushing and rash caused by the standard forms of vitamin B3.42

Directly boosting NAD+ with nicotinamide riboside presents a new and effective strategy for preventing the natural decline in cellular energy as we age by promoting youthful vitality.

A Novel Form of Vitamin B3 Switches “Off” Aging Genes
A Novel Form of Vitamin B3 Switches “Off” Aging Genes
  • Normal aging is in part the result of declining levels of NAD+, an essential compound found in every cell. Boosting levels can promote youthful vitality and even extend life span.
  • The most effective way to boost NAD+ levels is through nicotinamide riboside, a newly discovered form of vitamin B3.
  • Studies have found that enhancing NAD+ levels with nicotinamide riboside supplementation switches “off” the genes of aging, increases endurance, improves cognitive function, activates the key anti-aging sirtuins SIRT1 and SIRT3, enhances cellular energy, and extends life span.
 

Initial Studies On Nicotinamide Riboside

Nicotinamide riboside works through multiple mechanisms to promote life extension. Most dramatic, are its effects on longevity and metabolism, as shown by recent laboratory studies.

In their early investigations into the effects of nicotinamide riboside on life span, scientists used a strain of yeast known to have a relatively short average life span of about 8.3 generations.5,43 When the yeast was treated with nicotinamide riboside, the average life span nearly doubled, to 16.1 generations.

And in a model commonly used to study life span modifications, researchers discovered that the roundworm C. elegans could be made to survive, on average, 16% longer when supplemented with nicotinamide riboside; this life span extension was demonstrated to result from a roughly 50% increase in mitochondrial oxygen consumption, a measure of mitochondrial efficiency.44

When pursuing additional lab studies, scientists found that supplementing mice with nicotinamide riboside reduced many dangerous factors of aging. For one particular study, the mice were fed a high-fat diet with either no supplementation (control), or nicotinamide riboside for 12 or 16 weeks. The supplemented mice showed healthy weight loss, increased energy, and improved insulin sensitivity, all of the factors that indicate optimal vitality. The scientists also demonstrated that nicotinamide riboside supplementation increased energy metabolism while protecting the animals against the metabolic abnormalities induced by a high-fat diet.11

Remarkably, these beneficial results were attained without any differences in food intake or total physical activity between supplemented and control mice.11 The supplemented animals lost weight, performed better at exercise, and managed their blood glucose better purely as a result of nicotinamide riboside-induced increases in calorie-burning (measured by increased oxygen consumption rates).

Detailed analysis of the mice in this study revealed that supplementation with nicotinamide riboside had produced a marked increase in essential NAD+ levels, resulting in the activation of the critical life span-extending enzymes SIRT1 and SIRT3.11 Supplementation with nicotinamide riboside also improved the numbers and function of mitochondria.

Nicotinamide Riboside Protects Brain Cells

Nicotinamide Riboside Protects Brain Cells  

As cases of dementia and Alzheimer’s reach epidemic proportions in the aging population, pharmaceutical companies are aggressively researching neuroprotective compounds.45,46 Nicotinamide riboside, with its ability to directly increase NAD+, is providing promising brain benefits.

A recent lab study demonstrated the ability of nicotinamide riboside to protect brain cells in advanced age.15 For the study, mice that were engineered to develop Alzheimer’s disease were treated with nicotinamide riboside beginning at middle age (5 to 6 months) and lasting into old age (10 to 11 months). At the end of the study, the supplemented animals had significant improvements in their cognitive function.15 The mechanisms by which these effects were achieved were found to include significant increases in brain levels of NAD+ (the result of supplementation with nicotinamide riboside) and the consequent activation of enzymes involved in cellular energy production and energy release from glucose.15

Nicotinamide Riboside  

In a similar study of neuroprotection, nicotinamide riboside was shown to delay the degeneration of axons, the “communications cables” of nerve cells that carry impulses over long distances.47,48 When these communication cables deteriorate, tingling, weakness, numbness, and loss of motor function can occur as a result.49-51

Other studies in mammalian cells in culture demonstrate that nicotinamide riboside treatment increases NAD+ concentrations inside of cells by up to 2.7-fold,52 and that administering nicotinamide riboside can improve NAD+-related deficiencies in animal and yeast cells.53

Summary

Nicotinamide riboside is a unique form of vitamin B3 that has been found to provide an extraordinary range of impressive longevity benefits that promise to change how science approaches the reduction of aging.

By boosting levels of a powerful molecule called NAD+, nicotinamide riboside switches “off” many deleterious genes of aging, extends life span, increases endurance, improves cognitive function, activates sirtuins, and enhances cellular energy.

Directly boosting NAD+ with nicotinamide riboside presents a new and effective strategy for preventing the natural decline in cellular energy as we age by promoting youthful vitality.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Editor's Note

Science continues to evolve, and new research is published daily. As such, we have a more recent article on this topic: Power a Longer Life via NAD+ Restoration

References

  1. Egerton T. Self-reported aging-related fatigue: a concept description and its relevance to physical therapist practice. Phys Ther. 2013 Oct;93(10):1403-13.
  2. 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 May 21;3(5):e2267.
  3. Sauve AA. NAD+ and vitamin B3: from metabolism to therapies.J Pharmacol Exp Ther. 2008 Mar;324(3):883-93.
  4. Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008 Feb;10(2):179-206.
  5. Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007 May 4;129(3):473-84.
  6. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb 17;403(6771):795-800.
  7. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012;7(7):e42357.
  8. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One. 2011 Apr 26;6(4):e19194.
  9. Gomes AP, Price NL, Ling AJ, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013 Dec 19;155(7):1624-38.
  10. Khan NA, Auranen M, Paetau I, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014 Apr 6;6(6):721-31.
  11. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47.
  12. Satoh MS, Poirier GG, Lindahl T. NAD(+)-dependent repair of damaged DNA by human cell extracts. J Biol Chem. 1993 Mar 15;268(8):5480-7.
  13. Anderson RM, Bitterman KJ, Wood JG, et al. Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J Biol Chem. 2002 May 24;277(21):18881-90.
  14. Available at: http://investors.chromadex.com/phoenix.zhtml?c=212121&p=irol-newsArticle&ID=1936672&highlight=. Accessed October 10, 2014.
  15. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013 Jun;34(6):1581-8.
  16. Smith CP, Thorsness PE. The molecular basis for relative physiological functionality of the ADP/ATP carrier isoforms in Saccharomyces cerevisiae. Genetics. 2008 Jul;179(3):1285-99.
  17. Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors. 2012 Sep-Oct;38(5):349-59.
  18. Landry J, Sutton A, Tafrov ST, et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA. 2000 May 23;97(11):5807-11.
  19. Imai SI, Guarente L. NAD and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
  20. Hirschey MD, Shimazu T, Huang JY, Schwer B, Verdin E. SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:267-77.
  21. Chen Y, Fu LL, Wen X, et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis. 2014 Feb 6;5:e1047.
  22. Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 2007 Apr 15;21(8):920-8.
  23. Kotas ME, Gorecki MC, Gillum MP. Sirtuin-1 is a nutrient-dependent modulator of inflammation. Adipocyte. 2013 Apr 1;2(2):113-8.
  24. Gallí M, Van Gool F, Leo O. Sirtuins and inflammation: Friends or foes? Biochem Pharmacol. 2011 Mar 1;81(5):569-76.
  25. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. Int J Biol Sci. 2011 Feb; 7(5):575-87.
  26. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014 Mar;25(3):138-45.
  27. Sebastián C , Satterstrom FK,Haigis MC, Mostoslavsky R. From sirtuin biology to human diseases: an update. J Biol Chem. 2012 Dec 14;287(51):42444-52.
  28. Min SW, Sohn PD, Cho SH, Swanson RA, Gan L. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci. 2013 Sep 25;5:53.
  29. Sebastián C , Satterstrom FK,Haigis MC, Mostoslavsky R. From sirtuin biology to human diseases: an update. J Biol Chem. 2012 Dec 14;287(51):42444-52.
  30. Oellerich MF, Potente M. FOXOs and sirtuins in vascular growth, maintenance, and aging. Circ Res. 2012 Apr 27;110(9):1238-51.
  31. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95.
  32. Kemper JK, Choi SE, Kim DH. Sirtuin 1 deacetylase: a key regulator of hepatic lipid metabolism. Vitam Horm. 2013;91:385-404.
  33. Tao R, Wei D, Gao H, Liu Y, DePinho RA, Dong XC. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem. 2011 Apr 22;286(16):14681-90.
  34. Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. Ann Med. 2011 May;43(3):198-211.
  35. Ahn J, Lee H, Jung CH, Jeon TI, Ha TY. MicroRNA-146b promotes adipogenesis by suppressing the SIRT1-FOXO1 cascade. EMBO Mol Med. 2013 Oct;5(10):1602-12.
  36. Pang W, Wang Y, Wei N, et al. Sirt1 inhibits akt2-mediated porcine adipogenesis potentially by direct protein-protein interaction. PLoS One. 2013;8(8):e71576.
  37. Frojdo S, Durand C, Molin L, et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol Cell Endocrinol. 2011 Mar 30;335(2):166-76.
  38. Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology. 2010 Jun;151(6):2556-66.
  39. Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008 Nov;8(5):347-58.
  40. Green MF, Hirschey MD. SIRT3 weighs heavily in the metabolic balance: a new role for SIRT3 in metabolic syndrome. J Gerontol A Biol Sci Med Sci. 2013 Feb;68(2):105-7.
  41. Belenky P, Christensen KC, Gazzaniga F, Pletnev AA, Brenner C. Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. J Biol Chem. 2009 Jan 2;284(1):158-64.
  42. Belenky P, Stebbins R, Bogan KL, Evans CR, Brenner C. Nrt1 and Tna1-independent export of NAD+ precursor vitamins promotes NAD+ homeostasis and allows engineering of vitamin production. PLoS One. 2011 May 11;6(5):e19710.
  43. Belenky PA, Moga TG, Brenner C. Saccharomyces cerevisiae YOR071C encodes the high affinity nicotinamide riboside transporter Nrt1. J Biol Chem. 2008 Mar 28;283(13):8075-9.
  44. Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell . 2013 Jul 18;154(2):430-41.
  45. Larson EB, Yaffe K, Langa KM. New insights into the dementia epidemic. N Engl J Med. 2013 Dec 12;369(24):2275-7.
  46. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007 Jul;3(3):186-91.
  47. Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006 Aug 16;26(33):8484-91.
  48. Tempel W, Rabeh WM, Bogan KL, et al. Nicotinamide riboside kinase structures reveal new pathways to NAD+. PLoS Biol. 2007 Oct 2;5(10):e263.
  49. Wolfe GI, Baker NS, Amato A, et al. Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics. Arch Neurol. 1999 May;56(5):540-7.
  50. Van Asseldonk JT, Van den Berg LH, Kalmijn S, et al. Axon loss is an important determinant of weakness in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry. 2006 Jun;77(6):743-7.
  51. Hanada T, Weitzer S, Mair B, et al. CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature. 2013 Mar 28;495(7442):474-80.
  52. Yang T, Chan NY, Sauve AA. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem. 2007 Dec 27;50(26):6458-61.
  53. Lu SP, Kato M, Lin SJ. Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae. J Biol Chem. 2009 Jun 19;284(25):17110-9.