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Nicotinamide riboside: A booster of NAD+

Article
August 14, 2022
By
Ehab Naim, MBA.

Nicotinamide riboside is among the safest precursors of NAD+ - a longevity compound that plays an important role in modulating sirtuins activity.

Nicotinamide riboside: A booster of NAD+Compound description

Nicotinamide riboside (NR), a form of vitamin B3, is a widely studied precursor of nicotinamide adenine dinucleotide (NAD+). NAD+ is a coenzyme involved in oxidation-reduction (redox) reactions that plays a key role in energy metabolism (1, 2). In redox reactions, NAD+ acts as an electron carrier transferring them from one reaction to the other (3). Also, the compound acts as a cofactor for NAD+-dependent enzymes, like sirtuins and poly(ADP-ribose) polymerases (PARPs) (1). These enzymes play a crucial role in aging, longevity, and cellular functions. NAD+ levels could be boosted by supplying precursors, like those found in supplements (like NR) or food (meat, fish, and dairy products) (2, 4).

Properties

NR converts to NAD+ through the salvage pathway, which involves the conversion of NR to nicotinamide mononucleotide and then to NAD+ (2). Due to its extensive involvement in many reactions and processes, NAD+ has a variety of functions and properties. For example, its deficiency contributes to many conditions, namely metabolic diseases, cancer, aging, and neurodegenerative disorders (5). Also, NAD+ activities impact energy metabolism, DNA repair, epigenetic modifications, stress resistance, and inflammation.

Research indicates that NAD+ plays an important role in modulating sirtuins activity. Sirtuins represent a family of proteins (SIRT1-SIRT7) that influence several processes in the body, like circadian rhythm and aging (1, 2). According to the literature, a rise in NAD+ levels strongly correlates with sirtuins activation.

Also, NAD+ acts as a fuel for the PARP family of proteins (PARP1-17). In this context, research shows that PARP1, a protein involved in DNA repair, is one of the major consumers of NAD+. It is important to note that the latter occurs under normal and pathological conditions (1, 5). Preclinical studies have shown that PARP1 inhibition or NAD+ supplementation promoted longevity and ameliorated the negative consequences associated with PARP1 hyperactivation (1).

In addition to the above, research shows that NAD+ fuels the activity of over 300 enzymes (1). Collectively, these enzymes play crucial roles related to redox homeostasis, DNA maintenance and repair, chromatin remodeling, and autophagy.

With age, NAD+ levels decline, disrupting many of the said activities and developing age-related disorders (1). On the contrary, boosting NAD+ levels potentially leads to many health benefits. Examples include improved brain function and protection from neurodegenerative diseases, improved liver function, reduced muscular atrophy, decreased lipidemia, and enhanced pancreas functions (1, 2). Also, it positively influences immune function and reduces inflammation.

 

Use as a supplement

The value of NR as an NAD+ precursor has been explored in preclinical and clinical settings for decades (2, 6). As mentioned earlier, NAD+ plays a central role in metabolism. In this context, research shows that an increase in NAD+ levels can potentially ameliorate metabolic disorders like type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (2). In preclinical settings, NAD+ boosting using NR led to improved glucose tolerance, enhanced insulin sensitivity, reduced weight gain, and neuron protection in diabetic neuropathy. In clinical studies, evidence suggests that boosting NAD+ could improve the lipid profile, exercise capacity, and muscle fiber composition in individuals with a sedentary lifestyle (6). It is important to note that clinical results are not confirmatory, and further research is needed (6, 7).

NAD+ has been found to play an important role in cardiac health, and its depletion was associated with hypertrophy and heart failure (2). Based on the results from preclinical models, the literature suggests that NAD+ could possibly confer protection against adverse cardiac remodeling via multiple mechanisms. Examples include SIRT1 activation, which was found to protect against cardiac inflammation and hypertrophy in mice models (2). In humans, there are currently studies investigating the effect of NR in addressing systolic heart failure, blood pressure, and arterial stiffness, but no results have been produced yet (6, 7).

The value of NAD+ has also been explored in neurodegenerative disorders. In this context, research shows that NAD+ depletion was found to be a risk factor for Alzheimer’s disease and Parkinson’s disease (2). Many preclinical study models have proved the value of boosting NAD+ using NR in addressing these neurodegenerative disorders and conferring neuroprotective effects (2). In clinical settings, studies investigating the value of NR in multiple neurodegenerative disorders are currently taking place (6, 7). Results are yet to be published.

In addition to the above, NR can potentially promote longevity by increasing NAD+ levels (2). Currently, clinical studies investigating the potential of NR in reducing age-related muscle wasting, improving aging and recovery, and decreasing frailty are taking place (7).

NR doses used in clinical studies ranged from 100mg to 1200mg (1, 7, 8). In our Marketplace under the vendor DoNotAge, you can find nicotinamide riboside as capsules (Pure NR). Pure NR provides the body with 700mg of the bioactive molecule per serving (one serving is two capsules). 

Side effects

The literature indicates that NR is among the safest NAD+ precursors (2). In this context, it has been shown that, unlike other NAD+ precursors, it does not cause flushing, pruritus, hyperglycemia, or increased liver enzyme activity. Also, NR chloride has been given GRAS (generally regarded as safe) designation (2, 8). GRAS is a status granted by the Food and Drug Administration for chemicals and substances that have been reviewed by experts and were proven not to cause harm when used as intended. It is recommended not to mix NR with blood pressure medications. Before using this supplement, consult a licensed healthcare professional, like a physician or pharmacist.

References

1.            Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing. Nature reviews Molecular cell biology. 2021;22(2):119-41.

2.            Mehmel M, Jovanović N, Spitz U. Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Nutrients. 2020;12(6):1616.

3.            Nicotinamide adenine dinucleotide 2022 [updated 11-06-2022; cited 2022 06-12]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/.

4.            Poljsak B, Kovač V, Milisav I. Healthy Lifestyle Recommendations: Do the Beneficial Effects Originate from NAD(+) Amount at the Cellular Level? Oxidative medicine and cellular longevity. 2020;2020:8819627-.

5.            Xie N, Zhang L, Gao W, Huang C, Huber PE, Zhou X, et al. NAD(+) metabolism: pathophysiologic mechanisms and therapeutic potential. Signal transduction and targeted therapy. 2020;5(1):227-.

6.            Radenkovic D, Reason, Verdin E. Clinical Evidence for Targeting NAD Therapeutically. Pharmaceuticals (Basel, Switzerland). 2020;13(9):247.

7.            Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mechanisms of Ageing and Development. 2021;199:111567.

8.       Conze D, Brenner C, Kruger CL. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Scientific reports. 2019 Jul 5;9(1):1-3.

 

Nicotinamide riboside: A booster of NAD+Compound description

Nicotinamide riboside (NR), a form of vitamin B3, is a widely studied precursor of nicotinamide adenine dinucleotide (NAD+). NAD+ is a coenzyme involved in oxidation-reduction (redox) reactions that plays a key role in energy metabolism (1, 2). In redox reactions, NAD+ acts as an electron carrier transferring them from one reaction to the other (3). Also, the compound acts as a cofactor for NAD+-dependent enzymes, like sirtuins and poly(ADP-ribose) polymerases (PARPs) (1). These enzymes play a crucial role in aging, longevity, and cellular functions. NAD+ levels could be boosted by supplying precursors, like those found in supplements (like NR) or food (meat, fish, and dairy products) (2, 4).

Properties

NR converts to NAD+ through the salvage pathway, which involves the conversion of NR to nicotinamide mononucleotide and then to NAD+ (2). Due to its extensive involvement in many reactions and processes, NAD+ has a variety of functions and properties. For example, its deficiency contributes to many conditions, namely metabolic diseases, cancer, aging, and neurodegenerative disorders (5). Also, NAD+ activities impact energy metabolism, DNA repair, epigenetic modifications, stress resistance, and inflammation.

Research indicates that NAD+ plays an important role in modulating sirtuins activity. Sirtuins represent a family of proteins (SIRT1-SIRT7) that influence several processes in the body, like circadian rhythm and aging (1, 2). According to the literature, a rise in NAD+ levels strongly correlates with sirtuins activation.

Also, NAD+ acts as a fuel for the PARP family of proteins (PARP1-17). In this context, research shows that PARP1, a protein involved in DNA repair, is one of the major consumers of NAD+. It is important to note that the latter occurs under normal and pathological conditions (1, 5). Preclinical studies have shown that PARP1 inhibition or NAD+ supplementation promoted longevity and ameliorated the negative consequences associated with PARP1 hyperactivation (1).

In addition to the above, research shows that NAD+ fuels the activity of over 300 enzymes (1). Collectively, these enzymes play crucial roles related to redox homeostasis, DNA maintenance and repair, chromatin remodeling, and autophagy.

With age, NAD+ levels decline, disrupting many of the said activities and developing age-related disorders (1). On the contrary, boosting NAD+ levels potentially leads to many health benefits. Examples include improved brain function and protection from neurodegenerative diseases, improved liver function, reduced muscular atrophy, decreased lipidemia, and enhanced pancreas functions (1, 2). Also, it positively influences immune function and reduces inflammation.

 

Use as a supplement

The value of NR as an NAD+ precursor has been explored in preclinical and clinical settings for decades (2, 6). As mentioned earlier, NAD+ plays a central role in metabolism. In this context, research shows that an increase in NAD+ levels can potentially ameliorate metabolic disorders like type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (2). In preclinical settings, NAD+ boosting using NR led to improved glucose tolerance, enhanced insulin sensitivity, reduced weight gain, and neuron protection in diabetic neuropathy. In clinical studies, evidence suggests that boosting NAD+ could improve the lipid profile, exercise capacity, and muscle fiber composition in individuals with a sedentary lifestyle (6). It is important to note that clinical results are not confirmatory, and further research is needed (6, 7).

NAD+ has been found to play an important role in cardiac health, and its depletion was associated with hypertrophy and heart failure (2). Based on the results from preclinical models, the literature suggests that NAD+ could possibly confer protection against adverse cardiac remodeling via multiple mechanisms. Examples include SIRT1 activation, which was found to protect against cardiac inflammation and hypertrophy in mice models (2). In humans, there are currently studies investigating the effect of NR in addressing systolic heart failure, blood pressure, and arterial stiffness, but no results have been produced yet (6, 7).

The value of NAD+ has also been explored in neurodegenerative disorders. In this context, research shows that NAD+ depletion was found to be a risk factor for Alzheimer’s disease and Parkinson’s disease (2). Many preclinical study models have proved the value of boosting NAD+ using NR in addressing these neurodegenerative disorders and conferring neuroprotective effects (2). In clinical settings, studies investigating the value of NR in multiple neurodegenerative disorders are currently taking place (6, 7). Results are yet to be published.

In addition to the above, NR can potentially promote longevity by increasing NAD+ levels (2). Currently, clinical studies investigating the potential of NR in reducing age-related muscle wasting, improving aging and recovery, and decreasing frailty are taking place (7).

NR doses used in clinical studies ranged from 100mg to 1200mg (1, 7, 8). In our Marketplace under the vendor DoNotAge, you can find nicotinamide riboside as capsules (Pure NR). Pure NR provides the body with 700mg of the bioactive molecule per serving (one serving is two capsules). 

Side effects

The literature indicates that NR is among the safest NAD+ precursors (2). In this context, it has been shown that, unlike other NAD+ precursors, it does not cause flushing, pruritus, hyperglycemia, or increased liver enzyme activity. Also, NR chloride has been given GRAS (generally regarded as safe) designation (2, 8). GRAS is a status granted by the Food and Drug Administration for chemicals and substances that have been reviewed by experts and were proven not to cause harm when used as intended. It is recommended not to mix NR with blood pressure medications. Before using this supplement, consult a licensed healthcare professional, like a physician or pharmacist.

References

1.            Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing. Nature reviews Molecular cell biology. 2021;22(2):119-41.

2.            Mehmel M, Jovanović N, Spitz U. Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Nutrients. 2020;12(6):1616.

3.            Nicotinamide adenine dinucleotide 2022 [updated 11-06-2022; cited 2022 06-12]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/.

4.            Poljsak B, Kovač V, Milisav I. Healthy Lifestyle Recommendations: Do the Beneficial Effects Originate from NAD(+) Amount at the Cellular Level? Oxidative medicine and cellular longevity. 2020;2020:8819627-.

5.            Xie N, Zhang L, Gao W, Huang C, Huber PE, Zhou X, et al. NAD(+) metabolism: pathophysiologic mechanisms and therapeutic potential. Signal transduction and targeted therapy. 2020;5(1):227-.

6.            Radenkovic D, Reason, Verdin E. Clinical Evidence for Targeting NAD Therapeutically. Pharmaceuticals (Basel, Switzerland). 2020;13(9):247.

7.            Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mechanisms of Ageing and Development. 2021;199:111567.

8.       Conze D, Brenner C, Kruger CL. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Scientific reports. 2019 Jul 5;9(1):1-3.

 

Article reviewed by
Dr. Ana Baroni MD. Ph.D.
SCIENTIFIC & MEDICAL ADVISOR
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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
Quality Garant

Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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