What are the effects of Nicotinamide adenine dinucleotide (NAD) on the body?

Effects of NAD+ on the Body

NAD+ is a critical coenzyme involved in over 400 enzymatic reactions that fundamentally regulate cellular energy metabolism, DNA repair, mitochondrial function, and aging processes, with declining levels associated with age-related diseases and cellular dysfunction. 1

Core Metabolic and Cellular Functions

Energy Production and Mitochondrial Function

• NAD+ serves as an essential cofactor for mitochondrial ATP production, requiring relatively high concentrations to drive cellular energy metabolism and convert NADH back to NAD+ during glycolysis 2
• Low NAD+ levels trigger a "cellular energy crisis" through mitochondrial dysfunction, leading to mitochondrial depolarization and release of apoptosis-inducing factors 2
• The NAD+:NADH ratio is critical for maintaining proper mitochondrial function, with decreased ratios correlating with impaired ATP production 2

DNA Repair and Cellular Protection

• NAD+ functions as a cofactor for poly(ADP-ribose) polymerases (PARP), which execute DNA base excision repair in response to oxidative damage, ischemia, and excitotoxicity 2
• High NAD+ levels protect neuronal tissue from apoptosis-inducing events, while maintaining cellular NAD+ concentrations prevents SIRT2-mediated apoptosis 2
• NAD+ is necessary for proper DNA repair mechanisms, helping prevent potentially oncogenic mutations 3

Age-Related Decline and Consequences

Documented Cellular Changes with Aging

• Cellular NAD+ levels decline significantly with age in both men (correlation coefficient -0.706, P=0.001) and women (correlation coefficient -0.537, P=0.01) 2, 1
• This age-related decline associates with increased reactive oxygen species production, DNA damage, decreased SIRT1 activity (P≤0.01), increased PARP activity (P≤0.01), and decreased ATP production (P≤0.01) 2, 1
• The NAD+:NADH ratio decreases with aging (P≤0.01), consistent with impaired mitochondrial function 2

Clinical Manifestations of NAD+ Depletion

• Symptoms of vitamin B3 deficiency (which affects NAD+ synthesis) include muscle weakness and wasting, gait and truncal ataxia, peripheral neuritis, limb areflexia, and myoclonus 2
• Early manifestations include anorexia, weakness, inactivity, decline in nerve transmission velocities, fatigue, anxiety, irritability, and depression 2
• These neuromuscular deficits share similarities with age-related sarcopenia, suggesting NAD+ depletion may contribute to frailty 2

Brain and Neurological Effects

Neuroprotective Functions

• NAD+ and NADH mediate multiple brain processes including calcium homeostasis, neurotransmission, learning and memory, and may protect against ischemic brain injury 4
• NAD+ administration can markedly decrease ischemic brain damage, suggesting therapeutic potential for acute neurological injury 4
• NAD+ and NADH appear to be fundamental mediators of brain functions, brain senescence, and multiple brain diseases 4

Cardiovascular Effects

Cardiac Health and Disease

• NAD+ pools decline with obesity and hypertension, both major cardiovascular risk factors 5
• Experimental NAD+ elevation improves atherosclerosis, ischemic cardiomyopathy, diabetic cardiomyopathy, arrhythmogenic conditions, hypertrophic and dilated cardiomyopathies, and various forms of heart failure in preclinical models 5
• NAD+ replenishment reduces blood pressure and avoids metabolic syndrome in animal studies 5

Lifestyle and Metabolic Regulation

Factors Affecting NAD+ Levels

• NAD+ levels can be increased through fasting, caloric restriction, sports activity, low glucose availability, and heat exposure 6
• Implementing healthy lifestyle approaches that increase endogenous NAD+ correlates with extended life expectancy free of major chronic diseases 6
• NAD+ decline with age occurs due to inflammation, defects in NAMPT-mediated NAD+ biosynthesis, and PARP-mediated NAD+ depletion 6

Supplementation and Therapeutic Potential

Evidence for NAD+ Precursor Supplementation

• Supplementation with NAD+ precursors (nicotinamide riboside, nicotinamide mononucleotide) is safe, tolerable, and can increase NAD+ abundance in multiple tissues 7
• "Supraphysiological" doses of vitamin B3 (≥500 mg/kg) prevent cellular NAD+ depletion and subsequent mitochondrial dysfunction in experimental models 2
• NAD+ replenishment extends healthspan and has wide positive effects on metabolic health and age-associated diseases in preclinical studies 5

Important Caveats

• Injectable NAD+ administration lacks FDA approval and has no support in clinical practice guidelines, with significant safety risks including infection and unknown pharmacokinetics 8
• The American College of Nutrition recommends oral niacin intake at 16 mg/day for adult males and 14 mg/day for adult females, with upper limits of 10 mg/day for free nicotinic acid and approximately 900 mg/day for nicotinamide 1, 9
• Common side effects of NAD+ supplementation include muscle pain, nervous disorders, fatigue, sleep disturbance, and headaches 1