- What Does NAD+ Do?
- Effects of Restoring NAD+ with Its Precursors
- NAD+ Precursor Clinical Trials
- Choosing and Obtaining NAD+ Precursors
The reduction of nicotinamide adenine dinucleotide (NAD+) with age leads to declining cellular energy production and increases inflammation. 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.
The NAD+ molecule plays a central role in cellular metabolism. It also plays key parts in DNA repair, the generation of the cell’s powerhouse – the mitochondria – and its energy-producing capacity. Additionally, due to its immune regenerating properties, NAD+ also helps to alleviate inflammation. As NAD+ levels fall with age, these aspects of cellular function decline.
Scientific research using animal models has implied that increasing NAD+ levels during aging can delay aging, extend lifespan, and even reverse aging to a certain extent. Along those lines, raising NAD+ levels has positive effects on different age-related conditions and diseases, including insulin insensitivity, type 2 diabetes, cardiovascular disease, neurodegeneration, and cancer.
History of NAD+ and Its Precursors
British biochemists Arthur Harden and William John Young discovered NAD+ in 1906. Through their study of yeast extracts during alcohol fermentation, they isolated NAD+. Through a long and difficult procedure, Hans von Euler-Chelpin then purified NAD+. Thirty years later, in 1936, German scientist and Nobel laureate Otto Heinrich Warburg discovered the electron exchange function of the NAD+ coenzyme at the site of cellular energy generation.
In 1938, vitamin precursors of NAD+ were identified by Conrad Elvehjem who showed nicotinamide in the liver has an “anti-black tongue effect.” In 1939, Elvehjem then provided evidence that niacin can be used to synthesize NAD+. In the early 1940s, Arthur Kornberg identified an enzyme – nicotinamide mononucleotide adenylyltransferase (NMNAT) – in NAD+’s biosynthesis pathway. In 1949, American biochemists Morris Friedkin and Albert L. Lehninger proved that NAD+ with an added hydrogen (NADH) linked metabolic pathways like the citric acid cycle with the synthesis of cellular energy in the form of adenosine triphosphate (ATP) molecules. In 1958, Jack Preiss and Philip Handler discovered intermediate precursor molecules and enzymes involved in the NAD+ biosynthesis pathway. Thus, salvage synthesis of NAD+ from nicotinic acid is termed the Preiss-Handler pathway.
NAD+’s relation to metabolism and healthy aging has remained an intense area of research in the 21st century. The discovery of sirtuins, proteins functionally dependent on NAD+ that participate in DNA repair and cellular antioxidant activity, in 2000 by Shin-Ichiro Imai and colleagues in the laboratory of Leonard P. Guarente spawned heightened interest in NAD+. Along those lines, in 2009, Imai proposed the “NAD+ World Hypothesis,” which posits that Sirtuin1 and NAD+-synthesizing enzyme nicotinamide phosphorybosiltransferase (NAMPT) regulate aging and longevity in mammals. In 2016, Imai expanded his hypothesis to “NAD+ World Hypothesis 2.0,” which postulates that NAMPT outside the cell (extracellular NAMPT) from fat tissue (adipose tissue) maintains NAD+ in the brain’s hormonal control center, the hypothalamus, to preserve skeletal muscle health against frailty during aging.
Increasing NAD+ with Precursor Molecules
Tryptophan, nicotinic acid, nicotinamide, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) 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, NR, and NMN.
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.
NMN and NR Animal Studies
NMN confers a wide array of longevity-associated benefits in rodents. These benefits include aiding against cardiovascular, metabolic, and neurological age-related diseases.
Although no studies to date have directly shown that NMN prolongs rodent lifespan, numerous studies have shown that it improves the length of disease-free life (healthspan). For example, a study from Shin-Ichiro Imai’s laboratory showed that supplementing aged mice with NMN in their water suppressed age-associated weight gain, enhanced energy metabolism, promoted physical activity, increased insulin sensitivity, and improved eye function.
As for NMN’s effects against age-related diseases, the molecule has shown promise in mouse studies of cardiovascular disease. For example, NMN has been shown to mitigate a common heart condition that occurs as we grow older, cardiac scarring (fibrosis). One study showed that NMN prevents heart enlargement and fibrosis to prevent heart disease. Another cardiovascular study with mice showed that NMN prevents blood vessel cells from entering a non-proliferative state where they emit inflammatory molecules called senescence. NMN also normalized the mice’s blood pressure, which had been high, likely through the improvement blood vessel health improvement and reducing the number of senescent blood vessel cells. These studies suggest that NMN may help preserve cardiac function during aging.
Rodent studies have also shown that NMN improves metabolism during aging. With mouse fat cells (adipocytes), researchers have shown that NMN increases metabolic activity and reduces inflammation. If these findings are translatable to humans, they suggest that NMN can promote weight loss and healthy energy metabolism.
Neurological ailments, like memory loss, occur as we age. For some, these ailments precipitate full blown neurodegenerative conditions. Some rodent studies have shown that NMN can be used to deter or slow age-related neurodegenerative diseases. Along those lines, a mouse study has shown that NMN can restore memorization abilities in mice with diabetes-induced memory impairment. In that study, NMN preserved neurons that often die from lack of nutrients in diabetes. Other studies have shown that NMN improves brain blood vessel generation to increase brain blood flow and function. These studies support that NMN helps preserve cognition and works against age-associated neurological disorders.
NR has also been shown to enhance healthspan in rodent studies. Along those lines, one NR mouse study showed that supplementing with the molecule increases running endurance in aged mice. These improvements in physical function resulted from enhanced mitochondrial health as demonstrated by NR-induced increased mitochondrial oxygen consumption rates. The same study also showed that NR increases mouse average lifespan by about 5%. These findings make NR supplementation promising for healthier aging.
NAD+ Precursor Clinical Trials
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 reverses aspects of molecular aging. In support of this, NMN has been shown to reduce the biological age of white blood cells from older adults.
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.
Along with NMN, NR is one of the more well-studied NAD+ precursors in humans. 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.
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.
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.
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. Also, each precursor has been tested for different age-related deficits, so it is unclear which ones are better for certain deficits.