Nicotinamide mononucleotide suggest an improvement to this article

Nicotinamide mononucleotide (NMN) is a precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide, or NAD+, a coenzyme that participates in the production of cellular energy and DNA repair. NAD+ can also be synthesized from other precursors including nicotinamide (NAM, also called niacinamide), nicotinic acid (NA), and nicotinamide riboside (NR), which are often collectively referred to as niacin (vitamin B3) or niacin equivalents.[1] These precursors are not equally allocated throughout the body; rather, they exhibit preferential distribution among the blood, brain, gut, and other organs. Tryptophan, an amino acid obtained from the diet, can also be converted into NAD+.

Nicotinamide mononucleotide is present in various types of food, including broccoli, avocado, and beef, but it is also an intermediate compound in the NAD+ salvage pathway, the recycling of nicotinamide into NAD+.

NAD+ acts as a cellular "sensor" to mediate energy-generating pathways and activate NAD+-consuming enzymes such as sirtuins and poly ADP-ribose polymerases (PARP).[2] [3] NAD+ depletion, which occurs with age, has been implicated in the progression of multiple age-related conditions such as metabolic dysregulation and neurodegenerative diseases. Nicotinamide mononucleotide, as well as other precursors such as NR, help maintain cellular levels of NAD+. Boosting NAD+ levels through precursors has proven to have therapeutic potential in treating aging and age-related diseases across multiple animal models. The first human phase 1 clinical trial is now underway to determine the safety and bioavailability of nicotinamide mononucleotide supplementation.[4]

Learn more about NAD+ in this overview article.

Beneficial health effects

Animal studies have shown nicotinamide mononucleotide administration to be effective in increasing NAD+ levels across multiple tissues while improving the outcome of a variety of age-related diseases in multiple rodent studies.

Obesity and type 2 diabetes

Insulin resistance is a major feature of type 2 diabetes, with obesity and aging acting as major contributors in the pathophysiology of this disease. In a study involving diet-induced diabetic mice, injection of 500 milligrams per kilogram of body weight (mg/kg/bw) of nicotinamide mononucleotide administered for seven days enhanced insulin sensitivity and improved glucose intolerance compared to that observed among mice not given nicotinamide mononucleotide.[5] These effects may be due to the ability of nicotinamide mononucleotide to elicit anti-inflammatory effects in dysfunctional pancreatic beta cells, the site of insulin synthesis and secretion.[6] Similar results were observed when female diet-induced obese mice injected with 500 mg/kg/bw of nicotinamide mononucleotide for 17 days exhibited increased NAD+ levels in the liver and muscle and improved glucose tolerance compared to mice fed an obesigenic diet alone.[7]

Cardiovascular health

Cardiovascular disease is the leading cause of death in the United States. Ischemia, the reduction of blood flow to the heart, followed by reperfusion, the restoration of blood flow, are life-threatening events. Heart damage induced by ischemia/reperfusion is an important cause of heart failure.[8] Although human trials are lacking, nicotinamide mononucleotide administration in rodent models improved cardiovascular function and provided protection against ischemia/reperfusion injury. A study in male mice found that 500 mg/kg/bw injection of nicotinamide mononucleotide administered 30 minutes before and four times after ischemia protected the heart from reperfusion injury.[9] In a study in which old mice, 26 to 28 months of age, were administered 300 mg/kg/bw of nicotinamide mononucleotide in their diet for 8 weeks, age‐associated arterial dysfunction and oxidative stress were reversed and arterial SIRT1 activity was increased.[10] In addition, in a mouse model of cardiomyopathy – a disease of the heart muscle that hinders the pumping of blood to the rest of the body – injection of 500 mg/kg/bw of nicotinamide mononucleotide twice weekly for six weeks improved cardiac contractility compared to that observed in mice not given NMN.[11]

Treatment of neurodegenerative disease

Nicotinamide mononucleotide administration has also been shown to improve cognition and memory in mouse and rat models of Alzheimer’s disease. Rats that were injected with 500 mg/kg/bw of nicotinamide mononucleotide every day for 10 days demonstrated sustained improvement in cognitive function as well as an attenuation of neuronal cell death.[12] Furthermore, nicotinamide mononucleotide administered at 100 mg/kg/bw for 28 days to mice genetically predisposed to develop Alzheimer's disease elicited substantial improvements in behavioral measures of cognitive impairment compared to mice not given NMN. Additionally, nicotinamide mononucleotide treatment significantly decreased beta-amyloid production and inflammatory responses, both of which may be mediators of Alzheimer's disease progression.[13]

Aging and longevity

Decreasing levels of NAD+ are observed with aging and are associated with the development of age-related diseases. A long-term study found that dietary administration of nicotinamide mononucleotide mitigated the age-associated physiological decline in mice during normal aging. Specifically, starting at 5 months of age, mice were fed either 100 or 300 mg/kg/bw nicotinamide mononucleotide for 12 months, which resulted in a dose-dependent reduction in body weight of 4 percent and 9 percent, respectively, compared to mice not given NMN.[14] Additionally, the mice that were fed nicotinamide mononucleotide had improved skeletal muscle mitochondrial function, increased energy expenditure, increased bone density, and decreased insulin resistance in a dose-dependent manner.[14]

DNA damage is thought to be one of the primary drivers of aging. A study in old mice demonstrated that nicotinamide mononucleotide administration can stimulate repair of DNA damage through PARP1. Specifically, after 22-month-old mice were injected with 500 mg/kg/bw of NMN every day for one week, their hepatic NAD+ concentration and PARP1 activity were increased.[15]

Mitochondrial health

Mitochondrial dysfunction is a hallmark of aging, and maintaining mitochondrial integrity and function may be a promising therapy to slow or reverse age-related conditions such as Alzheimer's disease, frailty, or heart failure. In a mouse model of Alzheimer's disease, in which mitochondrial dysfunction is commonly observed, mice that were injected with 100 mg/kg/bw of nicotinamide mononucleotide every other day for 28 days had improved brain mitochondria respiratory capacity.[16] Age-related declines in skeletal muscle mass and function contribute to frailty in older adults. However, long-term administration of nicotinamide mononucleotide in the drinking water of mice for 12 months prevented age-associated gene expression changes in peripheral tissues and enhanced mitochondrial respiratory capacity in skeletal muscle.[14] In heart failure, hyperacetylation of mitochondria is associated with disease progression. Nicotinamide mononucleotide administered at 500 mg/kg/bw once every three days for approximately five weeks in mice reversed mitochondrial protein hyperacetylation and delayed development of heart failure.[17]

Cancer concerns

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway that converts nicotinamide to nicotinamide mononucleotide. Both NAMPT and nicotinamide mononucleotide might have pro-angiogenic activity (the capacity to build blood vessels) and support the growth of some types of cancers. For example, in a mouse mammary carcinoma model, pharmacologically inhibiting NAMPT delayed tumor growth with a dose-dependent decrease in NAD+levels.[18]

Furthermore, NAMPT and nicotinamide mononucleotide have been associated with cellular senescence – the growth arrest of cells – which may lead to aging and cancer. In a mouse model of pancreatic cancer, proinflammatory senescent cells drive tumor growth. When mice were injected with 500 mg/kg/bw of nicotinamide mononucleotide for 13 days, they exhibited significant increases in precancerous and cancerous lesions in the pancreas. Conversely, treatment with a NAMPT inhibitor suppressed proinflammatory and senescent markers while decreasing precancerous and cancerous lesions.[19]

While the studies mentioned above suggest a role for NAD+ metabolism in cancer progression, more studies are needed to assess the role of NAD+ and its precursor molecules in various types of cancer. Thus, augmenting diet with supplements such as nicotinamide mononucleotide to increase NAD+ levels may need to be administered with precision to balance any anti-aging effects with potential harmful pro-tumorigenic effects.

Bioavailability

Evidence from multiple rodent studies demonstrated that nicotinamide mononucleotide delivered orally at a high dose (300 mg/kg/bw) can effectively increase levels of NAD+ across multiple tissues, including the pancreas, liver, and skeletal muscle, within 10 to 30 minutes of administration.[5] [9] [14] [20] [21] When a low dose of nicotinamide mononucleotide (50mg/kg/bw) is orally administered to animals, very little NAD+ is found in tissues other than the liver, and all of the NAD+ is derived from the salvage pathway and not directly from NMN.[22] NAD+ derived from the salvage pathway is subject to feedback inhibition by NAD+ levels.

Intravenous administration of nicotinamide mononucleotide delivered intact nicotinamide mononucleotide, which was directly converted to NAD+ into liver, kidney, and muscle tissue in a dose-dependent manner. Nicotinamide mononucleotide did not cross the blood-brain barrier but did raise brain levels of NAD+ derived from the salvage pathway. These data suggest that if nicotinamide mononucleotide is administered intravenously, it can directly form NAD+ and not be subject to feedback inhibition, possibly increasing tissue NAD+ levels to much higher levels than they otherwise would be.

Learn more about NAD+ flux in this overview article.

Supplementation

Nicotinamide mononucleotide supplements are readily available on the market. Although nicotinamide mononucleotide administration has proven to be safe and to effectively increase NAD+ levels in rodents, the safety and efficacy of NMN supplementation in humans remain unknown. However, the first phase 1 clinical trial is underway to determine the safety and bioavailability of nicotinamide mononucleotide in humans.[4]

Conclusion

NAD+ levels decrease with age and may in part drive the aging process and the development of age-related diseases. Boosting NAD+ levels through nicotinamide mononucleotide administration has proven to be effective in improving age-related diseases such as cardiovascular disease and Alzheimer's disease in rodents. The first ongoing human clinical trial should provide insight into the safety and bioavailability of nicotinamide mononucleotide supplementation in humans.

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