What is NR? Benefits, Dosage, and Risks
Introduction | What is Nicotinamide Riboside (NR)? | Overview of Potential Health Benefits and Risks | How Does NR Work? | What Foods Naturally Contain NR? | NR Supplements and Dosage | Potential Health Benefits of NR | Potential Side Effects and Drug Interactions | Conclusion: NR is a Potentially Potent Weapon in the Fight Against Aging
Nicotinamide riboside (NR) is backed by clinical trials supporting its ability to increase NAD+ levels by up to 90% in ageing adults. By boosting this critical enzyme, NR has been shown to promote cellular health and protect against age-related disease in cell, animal, and human trials. Learn more about NR, one of the most exciting and promising compounds currently studied by longevity science.
What is Nicotinamide Riboside (NR)?
In the field of longevity science, few molecules have generated more buzz than Nicotinamide Riboside. Often referred to as NR or Niagen, this fascinating compound is a crucial building block for cellular function, maintenance, and ageing. Interest in the health benefits of NR has exploded in recent years, with some of the most brilliant minds in longevity science– including eight Nobel laureates– focusing on the research and development of safe and effective NR supplements.
NR is a form of B vitamin and perhaps most similar to B3, also called niacin. There are eight known variations of B vitamins. As a family, they help other enzymes perform various important tasks within the body, including food metabolism, oxygen transport, and disease prevention. Though comparable to niacin, NR has a unique chemical structure that has been shown to have profoundly positive health impacts in the cell, animal, and human studies. Research indicates NR is a potent anti-ageing molecule, helping to promote cellular longevity, protect DNA, and even prevent the development of certain diseases like Alzheimer’s, amyotrophic sclerosis (ALS), and Parkinson’s (for more information, see Potential Health Benefits of NR below).
Trace amounts of NR may be found in some foods, particularly certain meats and milk. However, research indicates that longevity benefits are most likely achieved through supplements that yield much higher concentrations than what can be attained through a well-rounded diet of fruits, vegetables, meats, and dairy products. NR supplements are generally well-tolerated, and they are commonly manufactured with nicotinamide riboside chloride– an NR chloride salt that the U.S. Food and Drug Administration labels as “Generally Recognized as Safe” (GRAS).
Overview of Potential Health Benefits and Risks
Disclaimer: Always consult your health care professional prior to making changes in your diet or exercise regimen, including whether to use supplements containing nicotinamide riboside (NR). Pregnant women, women who are nursing, and children especially must always consult a physician prior to taking supplements or medications.
Overview of potential NR health benefits:
- Increases NAD+ and promotes mitochondrial health
- Promotes cellular longevity
- May reduce risk of heart disease
- May protect against neurodegenerative disease
- May promote muscle stem cells and regeneration
- May promote weight loss and management
Overview of potential risks and side effects:
- NR is known to be generally well-tolerated
Mild to moderate side effects might include nausea, headache, fatigue, and GI discomfort (typically limited to stomachache, diarrhea, and indigestion)
How Does NR Work?
Nicotinamide riboside (NR) has two primary mechanisms of action. First, it appears to boost natural levels of the enzyme nicotinamide adenine dinucleotide, or NAD+. This has been demonstrated in several studies observing cell cultures, animals, and human subjects. Second, NR appears to play a key role in healthy aging by activating the body’s sirtuin pathways. These powerful networks are known to protect the human genome, assisting with DNA repair, stability, and longevity.
Promotes NAD+, a Crucial Enzyme for Energy and Longevity
Nicotinamide adenine dinucleotide, or NAD+, is among the most vital and versatile of all enzymes in the human body. As a co-enzyme, NAD+ acts as a catalyst that makes chemical reactions happen. Specifically, it plays a key role in converting food molecules into chemical energy that can be used at the cellular level. Interestingly, NAD+ achieves this by acting as a catalyst that drives the exchange of electrons from one atom to another.
A common analogy compares NAD+ to a rechargeable battery. Just as a battery relies on a jolt of electricity to activate the flow of electrons from one end to the other, cells rely on the enzymatic power of NAD+ to facilitate the electron exchanges that ultimately create life-sustaining chemical energy.
The importance of NAD+ cannot be understated. Because NAD+ plays such a central role in catalyzing chemical reactions, it also has the ability to increase or decrease global enzyme activity, gene expression, and cell signalling. Revisiting the rechargeable battery analogy, NAD+ does more than enable the creation of chemical energy. It also affects the quality and longevity of that energy as it is distributed through the system it is powering.
So, how does the body ensure it always has ample amounts of NAD+? Scientists have observed three primary means through which this vital enzyme is created and utilized. Understanding each process helps illustrate why supplementing with NR appears to have such profound anti-ageing effects. These processes include:
- De-novo (from scratch): NAD+ is synthesized from dietary tryptophan
- Preiss-Handler pathway: NAD+ is synthesized from dietary B3 vitamins
- Nicotinate salvage pathway: NAD+ is synthesized by “scavenging” existing molecules and recycling them
First, NAD+ can be synthesized do-novo, or from scratch from dietary tryptophan. Tryptophan is an essential amino acid, meaning the body cannot produce it on its own. Instead, this amino acid must be acquired through foods like oats, bananas, chicken, turkey and dairy products like milk and cheese (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908021). This is a multi-stage and energy-intensive means of synthesizing NAD+, as it requires food ingestion, digestion, and a host of subsequent chemical reactions.
NAD+ may also be synthesized via the Preiss-Handler pathway. Like the do-novo process described above, this pathway requires ingestion, digestion, and several subsequent chemical reactions. Unlike the do-novo process, the Preiss-Handler pathway utilizes dietary vitamin B3 as the raw material from which NAD+ is ultimately created.
Finally, NAD+ can be created through the nicotinate salvage pathway. This is the most efficient method, and it is generally known to be the “main source of NAD+” in cells. The salvage pathway process is like a built-in recycling network that gathers up existing chemicals– which are often the byproduct of previous NAD+ reactions– then uses them to create additional chemical precursors for new NAD+ molecules. In humans, this elegantly circular process works as follows:
- NAD+ is synthesized, or broken down, for use in various cellular functions, like metabolism and DNA repair
- One of the leftover byproducts of NAD+ synthesis is a molecule called nicotinamide, or NAM
- NAM “enters” the salvage pathway
- NAM is converted to nicotinamide mononucleotide or NMN
- NMN is catalyzed to form NAD+
- NAD+ is synthesized and utilized again, which produces NAM as a byproduct
- NAM enters the salvage pathway, acting as the precursor for additional NMN and NAD+
- The cycle goes on, continuously recycling NAM to form NMN and NAD+
To summarize: NAM creates NMN, which then creates NAD+. So, where does NR come in?
Interestingly, NR uses the same salvage pathway described above. Once catalyzed, NR forms NMN, which goes on to form NAD+ as normal. In this way, NR is referred to as an NAD+ “booster” for its ability to enter the pathway, increase the prevalence of NMN, and cause a corresponding rise in NAD+ (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352172/). By increasing NAD+ levels, NR causes several downstream benefits as well. Perhaps most important is sirtuin network activation.
Activates Sirtuin Networks to Promote Healthy Lifespan
In addition to playing a vital role in energy metabolism, NAD+ also acts as a key substrate in a powerful group of proteins called sirtuins. In an article published by the peer-reviewed journal Annual Review of Pathology, Marcia Haigis and Dr. David Sinclair provide a helpful summary of this new and exciting group of anti-ageing enzyme networks:
- there are seven known sirtuin pathways
- as a family, sirtuin networks regulate gene expression and protect cells during times of stress
- a helpful analogy is to imagine sirtuin pathways as a team of managers who sit in a control center that monitors and responds to cellular systems, globally and in real time
- in the absence of stress, sirtuin networks are primarily responsible for controlling cellular reproduction and DNA repair
- in times of stress, they shift focus to life-preserving functions like preventing cell death, increasing mitochondrial function, and fighting chronic inflammation
- sirtuins are a recent discovery, and more research is needed understand each of the 7 known networks
Leading research has established a clear link between NAD+ and sirtuins. Increasing levels of NAD+ provide more substrate material for these vital longevity networks, which causes a corresponding increase in global sirtuin activity (1 , 2). However, the opposite is also true.
Notably, NAD+ levels decrease dramatically as humans age. This decrease, along with subsequent down-regulation of the sirtuin pathways, is now thought to be the leading cause of ageing and age-related disease.
By increasing NAD+ through fasting, exercise, and supplements like NR, longevity researchers believe this core cause of ageing can be avoided– and perhaps reversed entirely (for more, see Potential Health Benefits of NR below).
What Foods Naturally Contain NR?
A healthy, well-rounded diet is unlikely to provide therapeutic doses of NR associated with the longevity benefits explored in this article. However, small amounts of NR exist in some health foods. According to a 2020 paper published by the journal Oxidative Medicine and Cellular Longevity, trace amounts of nicotinamide riboside can be found in the following:
- Immature soybeans
- Cow’s milk, cheese, butter, and other dairy products
Interestingly, the article also explains that certain eating and lifestyle behaviours may impede the body’s ability to synthesize NAD+ naturally. These include:
- Diets high in fat and sugar may cause “energy overload” and decrease the production of NAD+
- A sedentary lifestyle (inactivity) may lead to inefficient electron flow, energy imbalance, and reduced production of NAD+
Thus, individuals interested in using NR as an NAD+ booster may benefit from adopting an active lifestyle and eating a balanced diet that limits fat, processed foods, and sugar. The Harvard Healthy Eating Plate is one such protocol. Additionally, individuals are always advised to consult their primary care physician or seek the guidance of a licensed nutritionist prior to making diet or lifestyle changes.
NR Supplements and Dosage
Disclaimer: Always consult your health care professional prior to making changes in your diet or exercise regimen, including whether to use supplements like nicotinamide riboside (NR).
NR supplements are generally well-tolerated in adults. Although more clinical trials are needed, NR has been observed to be safe at doses of up to 2,000 milligrams daily (1 , 2). At the time of this writing, commercially available supplements contain much lower doses. Commonly, such supplements:
- Provide 200-500mg NR per serving
- Are taken daily
- It can be taken with food or on an empty stomach
- Should be taken at the same time each day to maintain consistent NR levels over time
Importantly, nicotinamide riboside chloride– a chloride salt formulation of NR– is labelled Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration. This ingredient is commonly listed as Niagen on supplement labels, and it is among the very first formulations of NR to be commercially available in the United States.
Mild side effects may occur when supplementing with NR, although they appear to be rare. These include headaches and GI disturbances (for more information, see Potential Side Effects and Drug Interactions below). Notably, NR is not known to cause skin irritation or flushing despite being chemically similar to niacin.
Potential Health Benefits of NR
Increases NAD+ and promotes mitochondrial health
Mitochondria are energy producers. Without these tiny organelles, individual cells would cease to exist (as would the organism as a whole). Mitochondria rely on NAD+ to create chemical energy for everything from metabolism to cell signalling and DNA repair, as detailed in the above section, How Does NR Work?
Unfortunately, NAD+ levels steadily decline as humans age. Alarmingly, this decline is made worse by a corresponding decline in mitochondrial health and function, and when mitochondria suffer, disease follows. It is estimated that well over 40 major diseases are related to mitochondrial dysfunction, including type 2 diabetes, cancer, and neurodegenerative diseases like Alzheimer’s (1 , 2, 3 , 4).
NR has been shown to improve mitochondrial health by increasing systemic levels of its most vital enzyme, NAD+. As described above, this is achieved through NR’s primary mechanism of action: Entering the nicotinate salvage pathway to form NMN, which is then synthesized into NAD+. This has been demonstrated in at least two clinical studies in which participants were supplemented with 100-500mg of NR daily. In one of the trials– a randomized, double-blind, and placebo-controlled study– 120 adults taking 250mg of NR experienced a 40% increase in NAD+, while those taking 500mg experienced an increase of 90% (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701244/).
Promotes cellular longevity
Declining NAD+ affects more than just mitochondria, however. This downward trend sends a shockwave through any network that relies on NAD+ to facilitate enzymatic reactions. When it comes to health and longevity, few are more important than the sirtuins.
Sirtuins are a family of enzymes found in human cells. Because enzymes act as catalysts for chemical reactions, these families are often described as “networks” to illustrate their ability to communicate with one another. Sirtuin networks are primarily responsible for regulating cell cycles, DNA repair, and energy metabolism. These vital processes require NAD+ as a co-substrate, leading many longevity experts to theorize that declining NAD+ levels ultimately drive the cause of human ageing. Sirtuin networks fire less often– and less efficiently– as the body produces less of this vital enzyme (https://pubmed.ncbi.nlm.nih.gov/23995787/). According to this theory, cellular ageing, dysfunction, cancer, and death are the result of such networks growing quieter over time.
Since NR has been clinically proven to increase NAD+ levels by up to 90%, researchers believe it may also drive sirtuin activation downstream. In a 2011 research review published by the Handbook of Experimental Pharmacology, molecules like NR are referred to as “sirtuin-activating compounds” that represent a “promising” means of promoting sirtuin activity— and thus longevity– over time. Evidence of such activity can be seen in a 2020 article published in the peer-reviewed journal NeuroToxicology, in which the results of an animal trial showed NR to reduce neuroinflammation by way of SIRT1 activation. Further evidence of the NR-sirtuin relationship is seen in at least two pre-clinical studies in which NR supplementation stimulated sirtuin activity and yielded positive outcomes in models for both metabolic syndrome and cardiomyopathy.
May reduce the risk of heart disease
Heart disease is the leading cause of death worldwide, accounting for nearly 18 million fatalities in 2019 alone. Generally, three main factors contribute to this condition. Many conditions contribute to heart disease, and three significant ones include arterial stiffness, high blood pressure, and oxidative stress.
Arterial stiffness is a natural phenomenon that involves cardiac tissues– specifically arteries and veins– becoming stiff and less malleable over time. The condition is particularly dangerous when it occurs in the aorta, the body’s largest artery responsible for channelling blood from the heart to the circulatory system. Called aortic stiffening, this specific type of arterial stiffness has been named a “hallmark for ageing” that indicates a high risk for other cardiovascular diseases and complications. NR intervention may help, according to a 2017 paper published by Artery Research. In the study, adults given 500mg of NR twice daily for six weeks showed significant improvements in aortic stiffness, as measured by carotid-femoral pulse wave velocity.
Like arterial stiffness, high blood pressure typically develops over time and is the result of lifestyle choices, genetic predispositions, and the presence of other co-morbidities. For example, obesity and diabetes are two common conditions known to contribute to high blood pressure. NR may help to reduce high blood pressure and the risk of associated diseases, according to a 2022 article published by the peer-reviewed journal Frontiers in Cardiovascular Medicine.
Finally, oxidative stress occurs when free radicals accumulate within cardiac tissues. This type of cellular stress has been named an important contributing factor to not only cardiac disease but also heart failure specifically. In animal models, NMN supplementation has been shown to reduce oxidative stress by increasing NAD+ and corresponding SIRT1 activation. These findings indicate NR supplements may achieve similar results, as NR is known to synthesize NMN and increase NAD+ levels systemically. However, more research is needed to understand better the role of NR in reducing oxidative stress in human cardiac tissues.
May protect against neurodegenerative disease
A slow deterioration of central nervous system cells characterises the neurodegenerative disease. This may cause severe loss of mobility, speech, cognitive function, and even death. Such diseases come in many forms, and the two most prevalent are Alzheimer’s and Parkinson’s disease. It is estimated more than 7 million Americans live with such conditions, with millions more battling neurodegenerative diseases globally.
Research is ongoing to understand better the mechanisms underlying such diseases, as well as interventions that may help. The latest research indicates that two significant contributing factors include mitochondrial dysfunction and oxidative stress (1 , 2 , 3).
In cell culture studies, NR has shown efficacy in treating Parkinson’s disease. As described in a 2018 paper published by the peer-reviewed journal Cell Reports, NR treatment appears to increase NAD+ levels and “significantly ameliorate” mitochondrial function in stem cells from patients with Parkinson’s.
When it comes to treating Alzheimer’s disease, results are similarly promising. In an animal study published by the peer-reviewed journal Neurobiology of Aging, NR was shown to increase NAD+ levels in the brain while also increasing the production of a unique protein, PGC-1-alpha, that may help protect brain cells from oxidative stress. As the study drew to a close, researchers noted that mice treated with NR also demonstrated improved cognitive abilities when given memory-based tasks.
Perhaps most exciting is the potential for NR to slow the progression of amyotrophic lateral sclerosis, or ALS. In a double-blind, randomized, placebo-controlled pilot study, a patented formulation of NR and pterostilbene produced “significant improvements” in pulmonary function, muscular strength, and participants’ scores on the ALS functional rating scale.
May promote muscle stem cells and regeneration
Most people think of stem cells as “raw materials” from which other body cells are built. That’s only partly true, however. Stem cells are also capable of fixing damaged tissue, and researchers believe they may someday be used to treat serious degenerative conditions like paralysis and Alzheimer’s.
NR may help. In at least one animal model, the supplement altered DNA expression to increase the production of a special type of “prohibition protein” that delayed the death of muscle stem cells. The study was conducted on mice with muscular dystrophy, a serious degenerative condition characterized by gradual loss of muscle size, strength, and function. Published by the peer-reviewed journal Science, the article notes that NR not only delayed stem cell death but also increased life span. More research is needed to see if similar results might be seen in humans. However, researchers are optimistic NR may someday help persons with degenerative conditions significantly improve strength, mobility, and quality of life.
May promote weight loss and management
Obesity is a multifaceted disease that involves a variety of factors, including an individual’s hereditary disposition to weight gain and lifestyle choices. Although the cause of obesity can be complex, the solution is clearer. In general, it is generally accepted that reductions in body weight require individuals to maintain a caloric deficit for a prolonged period of time.
The impact of this “calories in versus calories out” approach is best illustrated in a 2020 meta-analysis published by the peer-reviewed journal Nutrients. In it, researchers found calorie deficits of about 10% lead to weight loss and reduced risk of age-related disease (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468870/). In practice, a 10% deficit for an individual who needs 2,000 daily calories to maintain their body weight would mean cutting to 1,800 (a 10% deficit).
Maintaining a calorie deficit is difficult, in part because it demands the mental discipline and emotional stability to accept persistent feelings of hunger. In these situations, it is generally accepted that increasing one’s calorie requirements will help. Revisiting the example above, imagine the same individual increases their calorie requirement to 2,220 but maintains their normal eating behaviours and consumes just 2,000. In this scenario, the individual eats 2,000 calories as normal and also creates a 10% caloric deficit because their body’s requirement increased to 2,220.
In simple terms, this is what happens when individuals adopt an exercise routine without changing their eating behaviours. The added exercise requires more calories, which creates a deficit if the individual does not change their calorie intake.
NR may help individuals increase their body’s natural calorie requirements– and thus, more easily lose or maintain a healthy weight– through two primary mechanisms: Increasing metabolism and increasing muscle tissue.
In one study, NR supplementation increased basal metabolism in mice. Researchers observed reductions in abdominal visceral fat as a result, further illustrating the potential efficacy of NR as a weight loss aid. In another study, researchers found NR supplementation to improve skeletal muscle composition in mice. Specifically, researchers noted increases in non-fat body mass, which includes things like organs, muscles, and tendons. This phenomenon may confer an indirect weight loss benefit, as increased muscle mass is known to increase basal caloric requirements.
Potential Side Effects and Drug Interactions
At the time of this writing, nicotinamide riboside (NR) is reported to be generally well-tolerated at doses ranging from 500mg to 2,000mg daily. Mild to moderate side effects might include nausea, headache, fatigue, and GI discomfort (typically limited to stomachache, diarrhoea, and indigestion).
Moreover, the ingredient nicotinamide riboside chloride is labelled Generally Recognized as Safe(GRAS) by the U.S. Food and Drug Administration.
Conclusion: NR is a Potentially Potent Weapon in the Fight Against Aging
Nicotinamide riboside (NR) is a unique form of B vitamin clinically proven to increase the production of NAD+ by an astonishing 90% in ageing adults. Because NAD+ declines with age, supplementing with NR may help to “boost” levels of this critical enzyme later in life. Cell and animal studies are promising, indicating NR may improve cellular health, function, and longevity. Its role in boosting NAD+, coupled with its ability to promote sirtuin activity, makes NR a potentially powerful weapon in the fight against ageing and disease.
- NRNicotinamide Riboside, or NR, is a compound that acts as a precursor to NAD+, a coenzyme which may increase longevity, protect cells from age-related diseases, and support healthy ageing.£49.00 — or subscribe and save 5%
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