Understanding NAD +

NAD⁺ is an acronym that stands for nicotinamide adenine dinucleotide. It is a molecule that is present in all organisms, from single-cell organisms like bacteria to complex multicellular organisms like primates. Without NAD⁺, we would be on the path to death. This molecule is a linchpin to the function of the generators of cells, which are mitochondria. Not only does it assist in the conversion of food into energy, but it also plays a crucial role in maintaining the integrity of DNA and ensuring that cells function properly, which protects our bodies from the effects of aging and disease.

Mechanism of action of NAD+

Because of its function as a rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD) from nicotinamide, nicotinamide phosphoribosyltransferase (NAMPT) plays an essential part in the functioning of mammalian cells.  NAD is not only a vital redox cofactor, but it also serves as a substrate for enzymes that use NAD. It regulates many cellular activities, including DNA repair and gene expression, which are crucial for maintaining the growth and survival of tumours as well as their energy requirements.  The overexpression of NAMPT is a mechanism that is utilised by a number of different types of tumours in order to maintain NAD production.  This enzyme, however, has a second life outside of cells, where it exerts cytokine-like effects and mediates pro-inflammatory conditions by activating signalling pathways. This is in addition to the roles that NAD plays inside the cell. 

In order to carry out a wide variety of reactions and operations, NAD+ acts as a shuttle bus, moving electrons from one molecule to another contained within the cell.  In conjunction with its chemical counterpart, NADH, this essential molecule takes part in a variety of metabolic activities that are responsible for the production of energy within our blood cells.  Without adequate levels of cellular NAD, our cells would be unable to produce any energy, which would prevent them from surviving and preventing them from performing their jobs.  In addition to its other tasks, NAD+ is responsible for regulating our circadian rhythm, which is responsible for regulating our body's sleep-wake cycle.

Research Evidence

Diseases of Degeneration Associated with Ageing

Research conducted in both preclinical and clinical settings has shown that increasing NAD+ levels through supplementation with precursors such as nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) has provided encouraging outcomes.   These dietary supplements have been associated with a reduction in oxidative stress, an increase in mitochondrial activity, and an improvement in DNA repair. These factors may lead to a slowing down of the onset of age-related illnesses or even a full reversal of their effects. 

Conditions that lead to neurodegeneration

NAD+ and its metabolites are engaged in a number of key activities, including the health of the brain, synaptic plasticity, and the ability to withstand stress.  Increasing levels of NAD+ have been shown to block neurodegenerative processes in diseases such as Alzheimer's, Parkinson's, and Huntington's, which implies that this could be a potential therapeutic approach for these ailments. This has been proved through research. 

Cravings and Compulsions to Use

A growing body of research shows that the metabolism of NAD+ may have an effect on the neurobiology of addiction. This is a hypothesis that is supported by empirical evidence.  It is possible that increasing levels of NAD+ could help in the control of addictive behaviors, as well as the reduction of cravings and withdrawal symptoms in people who are addicted to substances or food. There is also the possibility that this could be beneficial in the treatment of addiction.

Research Application

The Metabolism of Energy

As a cofactor in several metabolic pathways, such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, NAD+ is an essential component for the process of energy metabolism.  In these processes, it makes the flow of electrons easier, which is necessary for the synthesis of ATP, which is the fundamental energy currency of the cell.

Replication of DNA and Expression of Genes

The enzymes that are involved in the process of DNA repair and gene expression also use NAD+ as a substrate.  Sirtuins, which belong to the family of NAD+-dependent deacetylases, are responsible for regulating gene expression and promoting genomic integrity. Poly(ADP-ribose) polymerases, also known as PARPs, are responsible for repairing DNA damage by using NAD+.  

Intercellular Communication and the Immune Response

NAD+ exerts an influence on cellular signaling pathways, including those that are mediated by calcium-dependent secondary messengers and those that play regulatory functions in the immune system.  An important role in immunological responses and cellular communication is played by enzymes such as CD38, which are responsible for the consumption of NAD+.

Low NAD levels are associated with aging and diseases that are age-related.  As people get older, their levels of NAD+ naturally decrease, which can be a contributing factor in a variety of age-related diseases, including neurodegeneration, metabolic disorders, and cardiovascular diseases [1] [4] [6].  This reduction is associated with poor mitochondrial activity, increased oxidative stress, and chronic inflammation, as discussed in the previous sentence.

Potential for Therapeutic Use

A number of recent studies have suggested that increasing levels of NAD+ can reduce the negative effects of aging and lengthen the lifetime of animal models used in these investigations.  In both preclinical and clinical research, NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have demonstrated that they have the potential to improve healthspan and treat age-related disorders.

Disease Management and the Role of NAD+

Alzheimer's disease and Parkinson's disease are two examples of neurodegenerative disorders. NAD+ has been shown to have a protective effect in these diseases.  It promotes neuronal function and resilience against stress, increasing the likelihood that it will halt the progression of disease.  

Both metabolic and cardiovascular health are dependent on NAD+, which plays an essential role in the maintenance of metabolic homeostasis.  It does this by modifying energy metabolism and redox balance, which in turn helps protect against illnesses such as metabolic syndrome, heart failure, and hypertension.

Future Perspective

Even if the therapeutic potential of NAD+ is exciting, there are still a few challenges that need to be conquered before it can be fully utilized.   It is necessary to perform additional studies in order to evaluate whether or not NAD+ supplementation is both safe and effective. There are not many clinical trials that have been conducted on people for an extended period of time so far.   There are a number of potential outcomes that could take place, including the accumulation of harmful metabolites, the development of tumors, and the promotion of cellular senescence. 

The key foci of research in the future should be on gaining an understanding of the molecular mechanisms that regulate NAD+ levels, improving supplementation strategies, and contrasting pharmaceutical therapies with lifestyle interventions like as changes in diet and exercise. 

NAD+, which is one of the most important molecules in cellular metabolism, has significant implications for the process of aging as well as illnesses that are connected with the process of aging.   Even though this therapeutic approach shows potential, there is a need for additional studies to be conducted to properly understand the benefits and risks associated with increasing NAD+ levels.   If these challenges are overcome, it may also make it possible to create novel treatments that enhance both the healthspan and the longevity of human health.

References

1. https://pubchem.ncbi.nlm.nih.gov/compound/Nicotinamide-Adenine-Dinucleotide#section=2D-Structure

2. Imai, S., & Guarente, L. (2016). NAD Metabolism and Its Roles in Cellular Processes During Aging. Annual Review of Biochemistry, 85, 245–270.

3. Trammell, S. A., & Brenner, C. (2015). Use NAD Precursors Like Nicotinamide Riboside to Boost Cellular Health in Mammalian Models. Journal of Nutritional Biochemistry, 26(8), 872–879.

4. Garten, A., Schuster, S., & Kiess, W. (2018). Nicotinamide Phosphoribosyltransferase as a Therapeutic Target in Age-Related NAD Decline. Molecular Metabolism, 14, 12–22.

5. Erdin, E. (2019). Effects of NAD on Mitochondrial NAD Levels and Aging Cell Function. Nature Reviews Molecular Cell Biology, 20(5), 287–298.

6. Braidy, N., Guillemin, G. J., & Grant, R. (2017). Vitamin B3 Supplementation to Boost NAD in Neurodegenerative Diseases. Journal of Neurochemistry, 142(5), 803–811.

7. Yang, H., & Sauve, A. A. (2016). NAD Salvage Pathways and Their Impact on Nuclear NAD Availability in Mammalian Cells. Biochemical Journal, 473(19), 2973–2985.

8. Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Strategies to Increase NAD Levels and NAD biosynthesis for Age-Related Disease Prevention. Aging Cell, 17(3), e12754.

9. Canto, C., Menzies, K. J., & Auwerx, J. (2015). Role of NAD in Cellular NAD Homeostasis and Energy Metabolism. Cell Metabolism, 22(1), 31–43.