Dr Graham Exelby May 2024
Currently being revised to incorporate the use of nicotinamide in amino acid dysfunction
Nicotinamide mononucleotide (NMN) is a molecule naturally occurring in all life forms. At the molecular level, it is a ribo-nucleotide, which is a basic structural unit of the nucleic acid RNA. NMN is the direct precursor of the essential molecule nicotinamide adenine dinucleotide (NAD+) which is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, and cell growth.(3)
NAD+ is an essential coenzyme required for life and cellular functions. Enzymes are catalysts that make biochemical reactions possible. Coenzymes are ‘helper’ molecules that enzymes need in order to function. NAD+ is the most abundant molecule in the body besides water, and without it, an organism would die. NAD+ is used by many proteins throughout the body, such as the sirtuins, which repair damaged DNA. It is also important for mitochondria, which are the powerhouses of the cell and generate the chemical energy that our bodies use. (3)
NAD+ plays an especially active role in metabolic processes, such as glycolysis, the TCA Cycle (AKA Krebs Cycle or Citric Acid cycle), and the electron transport chain, which occurs in our mitochondria and is how we obtain cellular energy. (3)
In its role as a ligand, NAD+ binds to enzymes and transfers electrons between molecules. Electrons are the atomic basis for cellular energy and by transferring them from one molecule to the next, NAD+ acts through a cellular mechanism similar to recharging a battery. A battery is depleted when electrons are expended to provide energy. Those electrons can’t return to their starting point without a boost. In cells, NAD+ serves as that booster. In this way, NAD+ can decrease or increase enzyme activity, gene expression, and cell signalling. (3)
A ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion,[1] or protein[2] which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. (Source https://en.wikipedia.org/wiki/Ligand_(biochemistry))
NAD+ Helps Control DNA Damage
As organisms grow older, they accrue DNA damage due to environmental factors such as radiation, pollution, and imprecise DNA replication. According to the current aging theory, the accumulation of DNA damage is the main cause of aging. Almost all cells contain the ‘molecular machinery’ to repair this damage. This machinery consumes NAD+ and energy molecules. Therefore, excessive DNA damage can drain valuable cellular resources. (3)
One important DNA repair protein, PARP (Poly (ADP-ribose) polymerase), depends on NAD+ to function. Older individuals experience decreased levels of NAD+. The accumulation of DNA damage as a result of the normal aging process leads to increased PARP, which causes decreased NAD+ concentration. This depletion is exacerbated by any further DNA damage in the mitochondria. (3)
Enhances Maintenance of DNA Repair- PARP1 is ‘Middleman’ of DNA Repair
The NAD+ made from NMN activates a group of proteins called sirtuins. Sirtuins are a family of enzymes, participating in cellular stress responses and damage repair, and play a key role in maintaining DNA integrity, which is constantly being bombarded by DNA altering substances (mutagens) like UV radiation. The sirtuins play a vital role in maintaining cellular health. They’re also involved in insulin secretion, and the aging processes and aging-related health conditions, such as neurodegenerative diseases and diabetes. The activation of sirtuins requires NAD+. (3)
Telomere Repair
Each time our cells divide, the DNA at the very ends of our chromosomes, the telomeres grows a tiny bit shorter. At a certain point, this begins to damage our genes. Sirtuins slow this process by stabilizing these. As David Sinclair, a Harvard geneticist and NAD researcher says we lose NAD+ as we age “and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.” He believes that increasing NAD+ levels naturally while aging may slow or reverse certain aging processes. (3)
The cell uses up NAD+ during the fight against coronavirus, weakening our body, according to a recent study that has not been peer-reviewed. NAD+ is essential for innate immune defence against viruses. The researchers of the study are trying to assess whether NAD+ boosters can help humans beat the pandemic. (3)
Increases Mitochondrial Function
Simply put, we couldn’t live without our mitochondria. These unique cellular structures, which even have their own DNA, are known as the powerhouses of the cell. Mitochondria are critical for metabolism; that is, they convert molecules from the food we eat into the energy that our cells use. (3)
The chronic fatigue that is rampant in our society is largely caused by mitochondrial dysfunction from a wide variety of causes. The ongoing research in COVID-19 has confirmed the virus causing mitochondrial dysfunction as one of the primary causes of the fatigue in Long Covid.
At the very core of metabolism is NAD+. Without NAD+, mitochondria cannot metabolize and cells will be left without energy, resulting in their death. In fact, mitochondrial anomalies caused by the loss of NAD+ may even impact degenerative neurological disorders eg Alzheimers disease.(7)
NAD+ Levels and Immune Function Drop With Age
Many aspects of immunity decline with age, and NK (Natural Killer Cells) immune cell function is no exception to this phenomenon. The age-related deterioration of immune function with age is linked to levels of nicotinamide adenine dinucleotide (NAD+), which also declines with age. Boosting NAD+ levels has been shown to improve immune function in mice. (3)
Figure 1: The natural killer (NK) immune cell cytotoxic response targets cancer and viral-infected cells. In the first step (A), the NK cell recognizes the target cell and clusters toward it. In the second step (B), the cell reorganizes its internal structure to orient towards the target cell. The third step (C) encompasses the NK cell docking and moving closer to the target cancer cell. The fourth and final step (D) entails the NK cell destroying the target cancer cell so that it bursts open.
Source: Paul, S., Lai, G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front. Immunol., 13 September 2017 | https://doi.org/10.3389/fimmu.2017.01124 (6)
The NAD+ precursor NMN helps with age-related disorders like insulin insensitivity and metabolic impairments like obesity in aged mice. Also, since boosting NAD+ levels have been shown to work against tumours in mice, it may also potentially enhance anti-tumour NK cell activity. Figuring out whether NMN has these immunity-restoring effects in NK cells is critical for determining if it is the compound we’ve been looking for to restore their cytotoxicity. (3)
Weiss (1) found NMN increases natural killer cell capabilities to destroy cancer cells (cytotoxicity) without increasing immune cell numbers. This study supports that taking NMN may be a way to rejuvenate natural killer immune cell activation to preserve tissue health during aging.(1)
Studies show that boosting NAD+ levels can extend life span in yeast, worms and mice. Animal research also indicates NAD+’s promise for improving several aspects of health. Raising levels of the molecule in old mice appears to rejuvenate mitochondria—the cell’s energy factories, which falter over time. Other mouse studies have demonstrated benefits such as improved cardiovascular function, enhanced muscle regeneration and better glucose metabolism with NAD+ supplementation.(3)
NAD Supplement as NMN
Intracellular concentrations of NAD+ decrease from aging as normal cellular functions deplete NAD+ supplies over time. Healthy levels of NAD+ are thought to be restored by supplementation with NAD+ precursors. According to research, precursors such as NMN and nicotinamide riboside (NR) are viewed as supplements of NAD+ production, increasing concentrations of NAD+. David Sinclair says, “Feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+.” (3) This means NAD+ cannot be used as a direct supplement, because it is not easily absorbed. NAD+ precursors are more easily absorbed than NAD+ and are more effective supplements.
NMN appears to be absorbed into cells through a molecular transporter embedded in the cell surface. Being smaller than NAD+, the NMN molecule may be absorbed more efficiently into cells. NAD+ cannot easily enter the body because of the barrier presented by the cell membrane. The membrane has a waterless space which prevents ions, polar molecules, and large molecules from entering without the use of transporters. It was once thought that NMN must be altered before entering cells but new evidence suggests that it can enter cells directly via an NMN-specific transporter in the cellular membrane. (3)
Currently, no side effects of nicotinamide mononucleotide have been documented in humans. Researchers have conducted the majority of studies on NMN in rodents, which revealed positive effects on metabolism, brain function, liver, skin, muscle, bone structure, heart health, reproduction, immunity, and lifespan. Long-term mice study also showed no toxicity, serious side effects, or increased mortality rate throughout the 12 month intervention period. (3)
Yi et al (8) showed that NMN supplementation is safe and well tolerated at up to 900 mg oral daily doses. NMN supplementation had a positive impact on the physical endurance and general health conditions of healthy adults as demonstrated in the significant improvement of six-minute walking test, blood biological age, and SF-36 scores. The 900 mg/day oral dose did not give significantly better efficacy than 600 mg/day dose.
No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated.(8)
Recent Concerns about safety
There is mixed information about safety of NAD+ in malignancy, so this should be excluded before NAD+, and probably NMN is used. The concerns as expressed by Dr Ibayashi (9) were published through a Pharma website, making a possible conflict of interest. While there is short-term data of NMN at doses up to 900mg/day, more studies need to be made to fully evaluate safety. (10)(11)
References:
1. Weiss, B. Study Shows NMN Enhances Activation of Cancer-Fighting Immune Cells https://www.nmn.com/news/study-shows-nmn-enhances-cancer-preventing-immune-cell-activation
2. Hong, W. et al. NMN ameliorates a number of age-related diseases by increasing NAD+ levels. 2021. Frontiers in Cell and Developmental Biology
4. Shade, C. The Science Behind NMN–A Stable, Reliable NAD+Activator and Anti-Aging Molecule. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238909/
5. Chatterjee, S. et al. CD38-NAD + Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab. 2018 Jan 9;27(1):85-100.e8. doi: 10.1016/j.cmet.2017.10.006. Epub 2017 Nov 9.
6. Paul, S., Lai, G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front. Immunol., 13 September 2017 | https://doi.org/10.3389/fimmu.2017.01124
7. Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol. 2015;15:19. Published 2015 Mar 1. doi:10.1186/s12883-015-0272-x
8. Yi, L., Maier, A.B., Tao, R. et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience (2022). https://doi.org/10.1007/s11357-022-00705-1
9. Ibayashi,Y. DOES NMN HAVE SIDE EFFECTS? A PHYSICIAN EXPLAINS ITS EFFECTIVENESS AND SAFETY. 2022. Abe Yoanda Pharma Co Ltd. https://en.corp.abeyoando.co.jp/journal/nmn-side-effect
10. Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar V. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. Geroscience. 2023 Feb;45(1):29-43. doi: 10.1007/s11357-022-00705-1. Epub 2022 Dec 8. PMID: 36482258; PMCID: PMC9735188.
11. Nadeeshani H, Li J, Ying T, Zhang B, Lu J. Nicotinamide mononucleotide (NMN) as an anti-aging health product - Promises and safety concerns. J Adv Res. 2021 Aug 11;37:267-278. doi: 10.1016/j.jare.2021.08.003. PMID: 35499054; PMCID: PMC9039735.
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