What is the role of NAD+ (Nicotinamide Adenine Dinucleotide) in the body?

What NAD+ Does in the Body

NAD+ (Nicotinamide Adenine Dinucleotide) is a critical coenzyme involved in over 400 enzymatic reactions throughout the body, serving essential roles in energy production, DNA repair, cellular aging processes, and immune function. 1

Core Metabolic Functions

Energy Production and Cellular Metabolism

• NAD+ acts as a central cofactor in redox reactions that drive ATP production through glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle 2, 3
• Mitochondria require relatively high concentrations of NAD+ to drive ATP production and to convert reduced NADH back to NAD+ during glycolysis 4
• Low NAD+ levels trigger a "cellular energy crisis" caused by mitochondrial dysfunction, leading to decreased ATP production 4

DNA Repair and Cellular Protection

DNA Damage Response

• NAD+ serves as a cofactor for poly(ADP-ribose) polymerases (PARP), which execute DNA base excision repair in response to oxidative damage, ischemia, and excitotoxicity 4
• When DNA damage is excessive, PARP activation can deplete NAD+ stores, potentially leading to cell death 4
• High NAD+ levels protect neuronal tissue from apoptosis-inducing events, while depletion increases vulnerability to cell death 4

Aging and Longevity Regulation

Age-Related Decline

• Cellular NAD+ levels decline significantly with age in both men (correlation coefficient -0.706) and women (correlation coefficient -0.537) 1
• This age-related decline correlates with increased reactive oxygen species production, DNA damage, decreased SIRT1 activity, and impaired mitochondrial function 4, 1
• The NAD+:NADH ratio decreases with aging, consistent with increased PARP activation and decreased ATP production 4

Sirtuin Regulation

• NAD+ acts as an essential cofactor for sirtuins, which regulate deacetylation processes involved in gene expression, chromatin remodeling, and cellular senescence 2, 3
• Maintaining adequate NAD+ concentrations prevents SIRT2-mediated apoptosis 4

Immune System Function

Immunological Roles

• NAD+ plays essential roles in immunological functions and inflammatory responses 5
• CD38, a NAD+ hydrolase protein that consumes NAD+ while converting it to ADP-ribose, is extensively involved in immune responses 2
• Chronic immune activation and inflammatory cytokine production can accelerate CD38 activity, leading to NAD+ depletion 5

Cellular Signaling and Gene Expression

Epigenetic and Signaling Functions

• NAD+ participates in epigenetically modulated gene expression and intracellular calcium signaling 5
• NAD+ influences chromatin remodeling and cellular processes critical for maintaining tissue and metabolic homeostasis 3

Clinical Implications of NAD+ Deficiency

Neuromuscular Effects

• Vitamin B3 deficiency (which affects NAD+ synthesis) manifests as muscle weakness and wasting, gait and truncal ataxia, peripheral neuritis, limb areflexia, and myoclonus 4
• These neuromuscular deficits share similarities with age-related sarcopenia 4
• Sub-acute deficiency presents with non-specific symptoms including weakness, inactivity, fatigue, anxiety, irritability, and depression 4

Mitochondrial Dysfunction

• NAD+ depletion induces oxidative damage and mitochondrial instability, mirroring key processes underlying cellular senescence 4
• Mitochondrial depolarization and release of apoptosis-inducing factors occur when NAD+ levels are critically low 4

Important Caveats

Tissue-Specific Variations

• The mechanisms for NAD+ depletion may differ between sexes, with men showing increased PARP activation and women showing different patterns of SIRT1 decline 4
• Different tissues have varying NAD+ requirements, with highly glycolytic tissues like neurons and periodically active muscle tissue being particularly vulnerable to depletion 4

Supplementation Considerations

• The American College of Nutrition recommends daily niacin intake (NAD+ precursor) at 16 mg/day for adult males and 14 mg/day for adult females 1, 6
• "Supraphysiological" doses of vitamin B3 (≥500 mg/kg in experimental models) can prevent NAD+ depletion and subsequent mitochondrial dysfunction 4
• Injectable NAD+ has no FDA approval and lacks standardized safety data, with common side effects including muscle pain, nervous disorders, fatigue, and headaches 1, 7