Key Points
- NAD+ precursors restore age-related NAD+ level depletion.
- NAD+ precursors like nicotinamide mononucleotide (NMN) improve physical performance in middle-aged and older adults.
NAD+ level reductions with age facilitate declining cellular energy production and DNA repair. These factors lead to accelerated aging and an increased incidence of chronic, age-related diseases. Indeed, throughout the course of aging and in many age-associated diseases, researchers have observed decreased NAD+ availability.
Scientific research using animal models has implied that increasing NAD+ levels during aging can extend lifespan, modulate aging processes, and even delay aging. Along those lines, raising NAD+ levels has positive effects on different diseases and conditions, including metabolic syndrome, type 2 diabetes, insulin sensitivity, cancer, cardiovascular disease, neurodegeneration, kidney function, reducing inflammation, and preventing obesity.
Increasing NAD+ with Precursor Molecules
Tryptophan, nicotinic acid, nicotinamide, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are precursors for NAD+ in mammals. Cells can generate NAD+ and reuse it via three pathways in humans: the de novo synthesis pathway from tryptophan, the Preiss-Handler pathway from nicotinic acid or nicotinic acid ribose, and the salvage pathway from nicotinamide mononucleotide, nicotinamide, and nicotinamide riboside.
As NAD+ is mainly produced via the NAD+ salvage pathway from nicotinamide, NR, and NMN, these salvage pathway molecules have the most promise as NAD+ boosters. More steps are required for nicotinic acid and tryptophan to produce NAD+, making those two molecules less attractive.
Because NAD+ levels decline as we age, their pharmacological restoration is currently under intensive investigation. Along those lines, approaches for NAD+ replacement include NAD+ precursors like NR, NMN, and nicotinic acid supplementation.
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NAD+ Precursor Clinical Trials
Nicotinamide Mononucleotide
NMN is the most direct NAD+ precursor, only one enzymatic step away from forming NAD+. Relative to the other precursors, NMN has only recently been tested in clinical trials for treating age-related deficits. One study in men showed that NMN effectively increases blood NAD+ levels. Only 125 mg of NMN was shown to nearly double blood NAD+ levels after four weeks, whereby NAD+ levels plateaued. Another study of MIB-626’s (a company founded by David Sinclair) NMN also doubled blood NAD+ levels, specifically in middle-aged and older adults.
Several studies have shown that NMN improves physical performance and sleep quality. In older adults, NMN improves sleep quality and physical performance. This dose of NMN also improved grip strength and walking speed in older men, in addition to enhancing muscle function and mobility. Other studies have also shown that NMN improves physical performance and sleep quality. Additionally, NMN improved muscle oxygen utilization and exercise performance in amateur runners.
In prediabetic, overweight or obese, postmenopausal women, NMN increased muscle and white blood cell NAD+ levels and improved insulin sensitivity, suggesting that NMN could prevent type 2 diabetes. Also in postmenopausal women, NMN improved glucose and cholesterol metabolism, hormone levels, and revered markers of skin aging.
NMN supplementation has also been shown to increase telomere length in the white blood cells of older adults. The shortening of telomeres has been associated with aging, so these findings demonstrate that NMN reverse aspects of molecular aging. In support of this, NMN has been shown to reduce the biological age of white blood cells from older adults.
A brand of NMN called Uthever was shown not to boost NAD+ levels or improve physical endurance in middle-aged and older adults, suggesting that some brands of NMN can outperform others. However, overall, it would seem that NMN can improve the physical performance and sleep quality of older adults, as well as improve skin aging and insulin sensitivity.
Nicotinamide Riboside
Along with NMN, NR is one of the more well-studied NAD+ precursors. NR can be found in milk and can be taken as a supplement.
Clinical studies have shown that NR increases whole blood and white blood cell levels of NAD+ in middle-aged and older adults, respectively. However, it didn’t increase NAD+ in the muscle of older adults, even at high doses.
While NR doesn’t seem to increase muscle NAD+ levels, it reduces blood and heart inflammatory markers. These findings suggest NR could reduce inflammation, a major contributor to aging when chronically activated.
When it comes to endurance exercise, NR only seems to benefit older adults. NR didn’t improve exercise endurance after one week of supplementation in young men. However, NR did improve exercise performance in older but not younger adults.
In obese older men, NR didn’t improve insulin sensitivity or body composition. However, in a much smaller study, NR improved the body composition of overweight or obese adults. Still in another study of overweight or obese middle-aged and older adults, NR didn’t have many effects other than increasing blood NAD+ levels. Therefore, the effect of NR on body composition in middle-aged and older adults is unclear.
Some companies have combined NR with pterostilbene, a plant-derived antioxidant. This combination has been shown to increase blood NAD+ levels, lower diastolic blood pressure, and improve physical performance in older adults. The combination also reduces inflammation in adults with nonalcoholic fatty liver disease. Furthermore, the NR and pterostilbene combination seems to slow the progression of amyotrophic lateral sclerosis (ALS).
As shown for ALS, NR has a more promising outlook pertaining to neurodegenerative diseases. When combined with antioxidant metabolism-boosting compounds, NR has been shown to improve the cognition and brain structure of Alzheiemer’s patients. Furthermore, NR alone improves the underlying defects of Parkinson’s disease. Overall, it seems that NR, especially when combined with antioxidants, can prevent neurodegeneration and improve cognition.
Niacin
Niacin can be found in foods like beef, fish, and poultry. In a human trial, patients with neuromuscular disease called mitochondrial myopathy saw a replenishment in blood and muscle NAD+ levels along with strength and performance improvements with 1000 mg of niacin.
Nicotinic acid has been used to lower cholesterol but causes flushing, leading to the use of niacin derivatives like acipimox. Acipimox has been shown to enhance energy production and mitochondrial function in the muscles of type 2 diabetes patients. Since these diabetes patients were an average of about 58 years old, niacin and its derivatives may be a good option for older adults with type 2 diabetes.
Nicotinamide
Nicotinamide can be found in various meats, legumes, and nuts. Nicotinamide has been tested for the prevention of type 1 diabetes in two human trials, one in 2004 and the other in 2006. In both trials, nicotinamide failed to prevent type 1 diabetes. More research is required to find if nicotinamide alone has the potential to counter aging in humans. Still, combined with D-ribose, nicotinamide has been shown to improve insulin sensitivity and lower cortisol levels in middle-aged adults.
Tryptophan
Tryptophan is an amino acid found in protein-rich foods like milk, chicken, and nuts. Likely, it’s the poorest of NAD+ precursors since it requires more biosynthesis steps to become NAD+. As such, a dietary intake of 34 to 86 mg of tryptophan is equivalent to 1 mg of nicotinic acid (niacin).
Choosing an NAD+ Precursor Supplement
Based on the human studies, it seems that most NAD+ precursors are safe and have little to no side effects (except for flushing in the case of unaltered niacin) for most individuals. Still, the long-term effects of these supplements in larger populations have not been tested. Also, each precursor has been tested for different age-related deficits, so it is unclear which ones are better for which deficits. NR seems to be more effective when combined with other metabolic activators, whereas NMN seems to have beneficial effects on its own.