Nicotinamide Riboside

Nicotinamide Riboside (NR) is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide (NAD+) (1). Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra (1).

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

History

NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

Structure

Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety. 1-(B-D-Ribofuranosyl)nicotinamide Molecular formula C11H15N205 Molar mass of 255.25g/mol

Biosynthesis

NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

Functions

A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

Research

The use of oral NR supplementation to treat an array of conditions is currently underway.

Clinical trials timeline

November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

References

(1)https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside

(2)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(3)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(4) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(5)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(6)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(7) https://www.chromadex.com/ingredient/niagen/

(8) https://www.beilstein-journals.org/bjoc/articles/15/36

(9) https://pubmed.ncbi.nlm.nih.gov/27052539/

(10) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(11) https://pubmed.ncbi.nlm.nih.gov/24071780/

(12) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(18) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4