Description

Nicotinamide Adenine Dinucleotide (NAD+)

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme found in all living cells that plays fundamental roles in cellular metabolism, energy production, DNA repair, and cellular signaling. The molecule exists in oxidized (NAD+) and reduced (NADH) forms, functioning as a critical electron carrier in redox reactions throughout cellular metabolism.

NAD+ is a dinucleotide composed of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other contains nicotinamide. The molecule participates in hundreds of enzymatic reactions and serves as a substrate for several enzyme families that regulate cellular function and longevity.(1)

Overview

NAD+ has been extensively investigated for its central role in cellular bioenergetics and its involvement in critical physiological processes. Research indicates that NAD+ functions as a coenzyme in oxidation-reduction reactions, particularly in glycolysis, the citric acid cycle, and oxidative phosphorylation. The molecule also serves as a substrate for NAD+-consuming enzymes including sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38.(2)

Studies have demonstrated that NAD+ levels decline with aging across multiple tissues and organisms. This age-related decline has been associated with various metabolic and functional impairments, prompting extensive research into NAD+ supplementation and precursor molecules. Investigations have explored the potential of NAD+ restoration to influence healthspan, metabolic function, and age-related physiological decline.(3)

Chemical Makeup

Molecular Formula: C21H27N7O14P2
Molecular Weight: 663.43 g/mol
Other Known Titles: Coenzyme I, DPN, Diphosphopyridine nucleotide, β-Nicotinamide adenine dinucleotide

Research and Clinical Studies

NAD+ and Cellular Bioenergetics

Research examining NAD+ in cellular energy metabolism has demonstrated its essential role as an electron acceptor in catabolic processes. Studies indicate that NAD+ accepts electrons during glycolysis, beta-oxidation, and the citric acid cycle, becoming reduced to NADH. The NADH subsequently donates electrons to the electron transport chain, facilitating ATP production through oxidative phosphorylation.(4)

Studies examining NAD+/NADH ratios suggested that this balance serves as a critical indicator of cellular metabolic state. Research indicated that alterations in NAD+/NADH ratios may influence the activity of NAD+-dependent enzymes and impact cellular redox status, potentially affecting metabolic flux through various pathways.(4)

NAD+ and Sirtuin Activation

Research investigating sirtuin enzymes has demonstrated their dependence on NAD+ as a substrate for their deacetylase activity. Studies indicated that sirtuins remove acetyl groups from target proteins while consuming NAD+ and producing nicotinamide and O-acetyl-ADP-ribose as byproducts.(5)

Investigations examining SIRT1, the most extensively studied mammalian sirtuin, suggested its involvement in metabolic regulation, stress resistance, and longevity pathways. Research indicated that SIRT1 may deacetylate numerous substrates including PGC-1α, FOXO transcription factors, and p53, potentially influencing mitochondrial biogenesis, oxidative stress responses, and inflammatory signaling.(6)

Studies exploring mitochondrial sirtuins suggested that SIRT3, localized primarily in mitochondria, may regulate mitochondrial protein acetylation and influence oxidative metabolism. Investigations into the relationship between NAD+ availability and sirtuin activity suggested that NAD+ levels may modulate sirtuin function.(7)

NAD+ Decline with Aging

Research investigating age-related changes in NAD+ levels has consistently demonstrated declines across multiple tissues and model organisms. Studies in rodents indicated that NAD+ concentrations in liver, skeletal muscle, adipose tissue, and brain tissue decreased significantly with advancing age, with some tissues showing reductions exceeding 50% between young and old animals.(8)

Studies exploring mechanisms underlying NAD+ decline suggested multiple contributing factors. Research indicated that increased expression and activity of CD38, an NAD+-consuming enzyme, may contribute to age-related NAD+ depletion. Additional investigations suggested that decreased expression of NAD+ biosynthetic enzymes and increased NAD+ consumption by PARPs responding to accumulated DNA damage may also contribute.(9)

Research examining consequences of age-related NAD+ decline suggested associations with mitochondrial dysfunction, reduced sirtuin activity, impaired cellular stress responses, and metabolic alterations. Studies indicated that these changes may contribute to various age-associated pathological conditions.(8)

NAD+ Precursors and Biosynthetic Pathways

Research has identified multiple pathways for NAD+ biosynthesis, utilizing different precursor molecules. Investigations into salvage pathways, which recycle NAD+ breakdown products, suggested these routes represent the primary mechanism for NAD+ maintenance in most tissues. Research indicated that nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) function as key intermediates, with specific enzymes catalyzing their conversion to NAD+.(10)

Studies examining nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway from nicotinamide, suggested its critical role in maintaining NAD+ levels. Research indicated that NAMPT expression and activity may influence cellular NAD+ concentrations and downstream NAD+-dependent processes.(11)

Investigations comparing different NAD+ precursors suggested varying efficacy in raising tissue NAD+ levels. Research indicated that NMN and NR, which bypass NAMPT in the biosynthetic pathway, may effectively increase NAD+ concentrations when administered exogenously.(3)

NAD+ and Mitochondrial Function

Research examining mitochondrial NAD+ has suggested its critical importance for oxidative metabolism. Studies indicated that mitochondrial NAD+ levels may influence the activity of NAD+-dependent dehydrogenases in the citric acid cycle and beta-oxidation pathways, potentially affecting mitochondrial ATP production capacity.(12)

Studies examining NAD+ supplementation effects on mitochondrial function reported improvements in aged rodents. Research suggested that NAD+ precursor administration appeared to improve mitochondrial respiration capacity, increase mitochondrial protein content, and enhance oxidative metabolism in some tissues.(8)

NAD+ and Cardiovascular Function

Research examining NAD+ in cardiovascular tissues has suggested its involvement in cardiac metabolism and stress responses. Studies indicated that cardiac NAD+ levels may influence mitochondrial function and energy production in the metabolically demanding myocardium.(13)

Studies examining vascular function suggested that NAD+-dependent pathways may influence endothelial cell function and vascular tone. Research indicated that SIRT1 activation in endothelial cells appeared to promote nitric oxide production and reduce inflammatory responses, potentially contributing to vascular health.(14)

Investigations into age-related vascular dysfunction suggested that declining NAD+ levels might contribute to endothelial impairment. Research indicated that NAD+ precursor supplementation appeared to improve endothelial function and reduce arterial stiffness in aged animals.(15)

NAD+ and Skeletal Muscle Function

Research investigating skeletal muscle NAD+ has demonstrated its importance for muscle metabolism and function. Studies indicated that NAD+ levels in skeletal muscle decline with aging and may be reduced in various muscle pathologies.(16)

Studies exploring NAD+ supplementation effects on muscle function reported improvements in aged animals. Research suggested that NAD+ precursor administration appeared to improve muscle mitochondrial function, increase muscle mass, and enhance exercise capacity in some experimental protocols. Investigations into muscle regeneration suggested that NAD+-dependent pathways may influence satellite cell function and muscle repair, with potential benefits for muscle stem cell activation.(17)

NAD+ and Neurodegenerative Processes

Research investigating NAD+ in neuronal function has suggested its importance for neuronal energy metabolism and stress resistance. Studies indicated that neurons, with their high energy demands and limited regenerative capacity, may be particularly vulnerable to NAD+ depletion.(18)

Investigations into neurodegenerative disease models suggested potential protective effects of NAD+ restoration. Research in animal models of Alzheimer’s disease indicated that NAD+ precursor supplementation appeared to reduce pathology, improve mitochondrial function, and enhance cognitive performance in some experimental paradigms.(18)

NAD+ Supplementation Strategies

Research investigating different approaches to increase NAD+ levels has examined various precursor molecules and administration routes. Studies comparing oral supplementation with NMN, NR, nicotinamide, and nicotinic acid suggested varying efficacy in raising tissue NAD+ concentrations.(19)

Investigations into NMN supplementation indicated that oral administration appeared to increase NAD+ levels in multiple tissues in rodent studies. Research suggested that NMN may be absorbed and subsequently converted to NAD+ through tissue-specific pathways.(20)

Studies examining NR supplementation suggested its ability to increase tissue NAD+ levels following oral administration. Research indicated that NR may utilize specific transporters for cellular uptake and is subsequently phosphorylated to form NMN, which is then converted to NAD+.(10)

Investigations into human supplementation studies with NAD+ precursors have reported varying outcomes. Research indicated that NR and NMN supplementation appeared to increase blood NAD+ metabolite levels in humans, though tissue-specific effects and functional outcomes have shown variable results across studies.(19)

Available for Research Purposes Only

NAD+ and its precursors are available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering.

References

1. Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-19.

2. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213.

3. Yoshino J, Baur JA, Imai SI. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018;27(3):513-528.

4. Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008;10(2):179-206.

5. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471.

6. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138-145.

7. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-295.

8. Gomes AP, Price NL, Ling AJ, et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-1638.

9. Camacho-Pereira J, Tarragó MG, Chini CC, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016;23(6):1127-1139.

10. Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004;117(4):495-502.

11. Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 2004;279(49):50754-50763.

12. Yang Y, Sauve AA. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016;1864(12):1787-1800.

13. Diguet N, Trammell SAJ, Tannous C, et al. Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation. 2018;137(21):2256-2273.

14. Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 2007;104(37):14855-14860.

15. de Picciotto NE, Gano LB, Johnson LC, et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016;15(3):522-530.

16. Frederick DW, Loro E, Liu L, et al. Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. Cell Metab. 2016;24(2):269-282.

17. Zhang H, Ryu D, Wu Y, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443.

18. Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 2015;15:19.

19. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286.

20. Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795-806.