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Introduction

Nicotinamide adenine dinucleotide (NAD⁺) is a molecule found in every living cell, essential for cellular metabolism – the process of converting nutrients into energy.³–¹² NAD⁺ acts as a cellular battery, shuttling electrons through the mitochondria to produce ATP, the body’s core energy source.¹–³ Beyond cellular metabolism, NAD⁺ also fuels enzymes that regulate cellular repair and longevity, including sirtuins and PARPs.⁴ ⁸ ⁹

Over time, these processes use up NAD faster than it can be replenished, leading to the age-related decline in NAD+ levels associated with slower metabolism, mitochondrial dysfunction, and diminished cellular resilience.⁷–⁹ Studies suggest that restoring NAD⁺ may enhance mitochondrial performance, metabolic balance, and markers of healthy aging, making it one of the most closely studied molecules in modern longevity science.¹⁰ ¹²

NAD⁺ Fast Facts

• Full Name: Nicotinamide Adenine Dinucleotide
  
• Form: Coenzyme (oxidized form NAD⁺, reduced form NADH)
  
• Found in: All living cells (bacteria, plants, animals, humans)
  
• Primary Role: Energy metabolism, DNA repair, cellular signaling, epigenetic regulation
  
• Research Focus: Anti-aging, energy enhancement, cognitive support, mitochondrial function¹ ² ³

Chemical Structure

NAD⁺ is a dinucleotide coenzyme composed of two linked molecules — one containing adenine and the other nicotinamide, a form of vitamin B₃. This structure allows NAD⁺ to alternate between oxidized (NAD⁺) and reduced (NADH) states, transferring electrons to power metabolism.
Because it derives from niacin, NAD⁺ directly connects vitamin B₃ nutrition to cellular energy production.

Above: NAD+ Chemical Structure. Nicotinamide (top) connected to adenine (bottom) via two ribose sugars and phosphate groups (left). Note the N in the nicotinamide structure is positively charged (N+), which tells us that it is oxidized form (NAD+) and not reduced form (NADH), in which there would N bonded to a hydrogen atom.

Discovery & Research Milestones

The story of NAD⁺ begins over a century ago. Early biochemists noticed a mysterious “co-ferment” that made yeast ferment sugars more efficiently — a clue that energy transfer depended on a small, reusable molecule.
From that simple observation grew a century of research revealing NAD⁺ as one of biology’s most indispensable molecules.

Year	Study & Source	Key Finding
Early 1900s – Discovery	Harden A, Young WJ. Proc R Soc B. 1906¹	Identified an unknown “coferment” required for yeast fermentation — the first evidence of NAD⁺.
1930s – Characterization	Warburg O, Christian W. Biochem Z. 1936²	Defined NAD⁺ as a central electron carrier in cellular respiration and redox reactions.
1950s–1980s – Pathway Mapping	Preiss J, Handler P. J Biol Chem. 1958³	Traced NAD⁺ biosynthesis from niacin and described the Preiss–Handler and salvage pathways.
2000 – Enzyme Regulation	Imai S et al. Nature. 2000⁴	Linked NAD⁺ to sirtuin activation, introducing its role in gene regulation and longevity.
2004–2007 – Precursor Discovery	Bieganowski P, Brenner C. Cell. 2004⁵; Tempel W et al. PLoS Biol. 2007⁶	Identified and structurally mapped the NRK pathway, showing how nicotinamide riboside and NMN boost NAD⁺.
2010–2016 – Aging & Metabolic Decline	Houtkooper RH et al. Endocr Rev. 2010⁷; Camacho-Pereira J et al. Nat Med. 2016⁹	Demonstrated that NAD⁺ levels fall with age, contributing to mitochondrial dysfunction and metabolic disorders.
2018-2021 – Recent Research	Braidy N et al. Antioxid Redox Signal. 2018¹¹; Yoshino M et al. Science. 2021¹²	Demonstrated that NAD⁺ precursors are bioavailable and may enhance insulin sensitivity and muscle metabolism in human studies.

Summary

NAD⁺ is a universal metabolic cofactor that connects nutrition, energy metabolism, and cellular resilience. Once known only for its role in redox chemistry, it’s now recognized as a central regulator of aging and stress physiology. Ongoing studies continue to explore NAD⁺-boosting strategies to better understand how metabolism, repair, and longevity are intertwined.⁴⁵⁶⁹¹²

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References

1. Harden A, Young WJ. The alcoholic ferment of yeast-juice. Proc R Soc B. 1906;77(520):405–420. https://royalsocietypublishing.org/doi/10.1098/rspb.1906.0029
   
2. Warburg O, Christian W. Über die Wirkung von Nicotinamid und verwandten Verbindungen auf die Gärung. Biochem Z. 1936;287:291–328.
   
3. Preiss J, Handler P. Biosynthesis of diphosphopyridine nucleotide. II. Enzymatic aspects. J Biol Chem. 1958;233(2):493–500. https://pubmed.ncbi.nlm.nih.gov/13563527/
   
4. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Sir2 proteins are NAD-dependent histone deacetylases. Nature. 2000;403:795–800. https://pubmed.ncbi.nlm.nih.gov/10693811/
   
5. Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and in NAD⁺ metabolism. Cell. 2004;117(4):495–502. https://pubmed.ncbi.nlm.nih.gov/15137942/
   
6. Tempel W, et al. Nicotinamide riboside kinase structures reveal the NRK pathway to NAD⁺. PLoS Biol. 2007;5(10):e263. https://pmc.ncbi.nlm.nih.gov/articles/PMC1994991/
   
7. Houtkooper RH, Cantó C, Wanders RJ, Auwerx J. The Secret Life of NAD⁺: An old metabolite controlling new metabolic signaling pathways. Endocr Rev. 2010;31(2):194–223. https://pmc.ncbi.nlm.nih.gov/articles/PMC2852209/
   
8. Aksoy P, White TA, Thompson M, Chini EN. Regulation of intracellular NAD levels: CD38 as a major NADase. Biochem Biophys Res Commun. 2006;345(4):1386–1392. https://pubmed.ncbi.nlm.nih.gov/16730329/
   
9. Camacho-Pereira J, Tarragó MG, Chini CC, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction. Nat Med. 2016;22(10):1199–1206. https://pmc.ncbi.nlm.nih.gov/articles/PMC4911708/
   
10. Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948. https://pubmed.ncbi.nlm.nih.gov/27721479/
    
11. Braidy N, et al. Role of NAD and related precursors in health and disease. Antioxid Redox Signal. 2018;28(3):609–624. https://pmc.ncbi.nlm.nih.gov/articles/PMC6277084/
    
12. Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–1229. https://pubmed.ncbi.nlm.nih.gov/33888596/