What is the role of Nicotinamide adenine dinucleotide (NAD+) in the body?

Role of NAD+ in the Body

NAD+ (Nicotinamide adenine dinucleotide) is a critical coenzyme involved in over 400 enzymatic reactions in the body, playing essential roles in energy metabolism, DNA repair, gene expression, and stress responses, with declining levels during aging contributing to age-related physiological decline and disease.1

Key Functions of NAD+ in the Body

• NAD+ serves as a cofactor for poly (ADP-ribose) polymerases (PARPs), which carry out DNA base excision repair processes in response to oxidative damage, ischemia, and excitotoxicity 2
• NAD+ is essential for mitochondrial function and energy production (ATP), with decreased levels associated with impaired mitochondrial function 2, 1
• NAD+ acts as a cofactor for sirtuins (particularly SIRT1 and SIRT2), which regulate cellular processes including gene expression, DNA repair, and apoptosis 2
• NAD+ is involved in maintaining cellular redox balance through its reduced form NADH, supporting metabolic reactions throughout the body 3
• NAD+ participates in calcium-dependent secondary messenger signaling and has immunoregulatory roles 4

Age-Related Decline in NAD+ Levels

• Cellular NAD+ levels significantly decline with age in both men (correlation coefficient of -0.706) and women (correlation coefficient of -0.537) 2, 1
• This decline is associated with increased reactive oxygen species (ROS) production, DNA damage, decreased SIRT1 activity, and reduced ATP production 2, 1
• The age-related decline in NAD+ has been linked to various age-related diseases, including neurodegenerative conditions, metabolic disorders, and cardiovascular diseases 5, 6
• The mechanisms for NAD+ depletion may differ between sexes, with men showing increased PARP activation and women showing different patterns 2

Metabolic Pathways and NAD+ Biosynthesis

• NAD+ can be synthesized through multiple pathways, including de novo synthesis via the kynurenine pathway and salvage pathways from precursors like nicotinamide (NAM), nicotinic acid (NA), and nicotinamide riboside (NR) 4
• Vitamin B3 (niacin) is a primary dietary precursor for NAD+ synthesis 2
• NAD+ is constantly being consumed by enzymes like PARPs, SIRT1, and CD38, requiring continuous regeneration to maintain cellular levels 6
• The balance between NAD+ biosynthesis and consumption is critical for maintaining cellular health 6

Clinical Implications

• Maintaining adequate NAD+ levels may help prevent or mitigate age-related decline in cellular function 1, 7
• The American College of Nutrition recommends daily intake of niacin (NAD+ precursor) at 16 mg/day for adult males and 14 mg/day for adult females 1, 8
• Dietary sources of niacin include fortified packaged foods, meat, poultry, red fish (tuna, salmon), nuts, legumes, and seeds 8
• "Supraphysiological" doses of vitamin B3 have been shown in experimental models to prevent cellular NAD+ depletion and subsequent mitochondrial dysfunction 2

Safety Considerations

• Upper limits for supplementation are 10 mg/day for free nicotinic acid and approximately 900 mg/day for nicotinamide for adults 1, 8
• Injectable NAD+ administration is not FDA-approved and not found in clinical practice guidelines 9
• Common side effects of NAD+ supplementation may include muscle pain, nervous disorders, fatigue, sleep disturbance, and headaches 1
• Monitoring niacin status can be done through measurement of urinary metabolites 8

Cautions and Limitations

• While NAD+ supplementation shows promise in experimental models, long-term human clinical trials are still limited 4
• Potential risks of raising NAD+ levels include accumulation of toxic metabolites, tumorigenesis, and promotion of cellular senescence in certain contexts 4
• Paradoxically, some cancers have increased dependency on NAD+, suggesting caution in certain populations 3
• The bioavailability of oral NAD+ supplements varies, with precursors like NMN and NR showing better absorption profiles than NAD+ itself 7