Nucleotides are relatively small biological molecules and are extremely important because they form the main building blocks of RNA and DNA. The human body needs an adequate amount of nucleotides. The natural formation of nucleotides is not in sufficient quantity for the body, nucleotides from the diet are obtained from the food that people eat in a daily amount that is based on what should be good health. NMN (nicotinamide mononucleotide), in addition to its properties that contribute to energy metabolism, has found itself in the public spotlight as an essential molecule in the fight against aging and a molecule that is directly related to many pathological conditions. (NMN) has created quite a sensation in the world of dietary supplements. It has been touted as a potential fountain of youth and an elixir for longevity. However, the Food and Drug Administration (FDA) has not approved this molecule as a supplement, which is a sign that more research on this remarkable molecule needs to be encouraged.
- Nicotinamide mononucleotide and nicotinamide adenine dinucleotide
Nicotinamide mononucleotide (NMN) is a bioactive nucleotide that includes a nucleoside containing nicotinamide, a sugar – ribose, and a phosphate group in its structure. In human cells, NMN is one of the main molecules that provide energy. Until recently, this molecule was only known for its activity as an intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). NMN is a molecule that acts as a precursor for the synthesis of NAD+, a molecule found in every cell in your body. In other words, NMN can be converted to nicotinamide adenine dinucleotide (NAD) in human cells. NAD is necessary for over 500 enzymatic reactions and exists in two forms: oxidized (NAD+) and reduced (NADH). NAD+ acts as a coenzyme, which is a molecule necessary for the function of enzyme proteins. NAD+ is also involved in important biological processes such as energy metabolism, gene expression, and the maintenance of proper mitochondrial function – the main energy-producing organelles.
Figure 1. NMN (left) and NAD+ (right)
A deficiency in NAD+ can compromise health and cause many health problems. The most commonly mentioned issues include metabolic disorders, decreased energy production in the mitochondria, oxidative stress, DNA damage, cognitive impairment, and inflammatory conditions leading to obesity, diabetes, depression, anxiety, heart disease, Parkinson’s disease, mental disorders, and neurodegenerative diseases. NAD+ levels naturally decline with age due to higher consumption and lower production or natural synthesis. This can increase the risk of age-related diseases such as type 2 diabetes and Alzheimer’s disease. This decline is associated with reduced energy production in the mitochondria, oxidative stress, DNA damage, cognitive impairment, and inflammatory conditions.
According to the Food and Drug Administration (FDA), NMN cannot be legally sold as a dietary supplement in the USA. However, many manufacturers ignore this regulatory framework, selling NMN and promoting its health benefits. Clinical studies on NMN in humans are limited, as most of the research so far has been conducted on animals. Nevertheless, it is undeniable that this molecule is attracting attention in a very positive way.
- NMN and NAD+ benefits
The production and consumption of NMN or NAD+ is directly related to pathological processes or conditions that may be associated with various forms of damage or disease in the body. We will cite some examples in which the level of these biological molecules affects the development or prevention of unwanted conditions.
Obesity
Obesity is associated with insulin resistance in multiple organs and is involved in the pathogenesis of many other diseases such as non-alcoholic fatty liver disease (NAFLD), atherogenic dyslipidemia, and cardiovascular diseases. Dysfunctional adipose tissue in obesity affects overall metabolic health. In studies with obese mice, NMN has shown potential in treating obesity-related metabolic disorders by improving multi-organ insulin sensitivity and positively influencing key metabolic markers. Obesity is directly linked to the development of diabetes.
Diabetes
Diabetes is an increasing global health problem, and a well-known contributing factor to this epidemic is a diet high in fats. Adaptive metabolic pathways, an evolutionary response to food scarcity, are diminished by modern high-fat diets. Among its numerous roles in energy metabolism, NAD+ activates a protein called Sirtuin 1 (SIRT1). It is known that NAD+ biosynthesis is mediated by SIRT1 and other molecules that regulate glucose-stimulated insulin secretion in pancreatic β cells. NMN has been shown to increase NAD+ concentration and lower blood glucose levels in diabetic animals.
Ischemia–Reperfusion Injury
It has been shown that NMN provides protection to the heart in ischemic and reperfusion conditions. Exogenous application of NMN can protect the heart by mimicking ischemic preconditioning (IPC) and activating the protein Sirtuin 1. When NMN is applied before ischemia or immediately before and during reperfusion, it protects the heart from these types of injuries. Additionally, NMN exerts positive effects on mitochondrial function by enhancing the antioxidant system, restoring oxidative stress, and reducing mitochondrial ROS production.
Vascular Dysfunction
NAD+ and NMN can be crucial for treating vascular dysfunction. Vascular disease is a major factor directly causing different cardiovascular diseases, which are the leading cause of mortality worldwide. It has been shown that NMN restores endothelial function and reduces oxidative stress in older mice with developed vascular disorders. Additionally, NMN improves the availability of nitric oxide (NO), which is essential for proper vascular function. NMN also increases the activity of SIRT1, which helps reduce oxidative stress and maintain vascular elasticity. Furthermore, NMN influences the accumulation of collagen and increases elastin in arterial walls, improving blood flow and reducing pressure in large arteries.
Neuroprotective and Cognitive Function
Cognitive decline can be induced by numerous pathological conditions and events. The most well-recognized form is age-related cognitive decline (i.e., Alzheimer’s disease and other forms of dementia); however, cognitive impairment resulting from acute events such as stroke or trauma can also have long-term impacts on cognitive function, as can long-term exposures such as diabetes and chemotherapy. NAD+ is involved in the repair and proper functioning of brain cells. NMN can influence the regeneration of damaged nerve fibers, which are important for signaling in the brain, which is especially crucial for older adults.
Alzheimer’s Disease (AD)
AD is a neurodegenerative disease and the most common type of dementia. Science is still lacking in treatments that demonstrate satisfactory efficacy in preventing AD progression. Mitochondrial dysfunction is a feature of many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD). AD is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and mitochondrial dysfunction in the brain. NAD+ as a cofactor is crucial for the tricarboxylic acid cycle, mitochondrial oxidative phosphorylation and enzymatic reactions associated with glycolysis, and the level of NAD+ in the cell is critical for survival. Emerging evidence suggests a vital role for NAD+ depletion and impairment of NAD+-dependent metabolic pathways involved in the pathophysiological hallmarks of AD. It has been shown that NAD+ supplementation can restore cognitive deficits in several types of AD.1–20
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