Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have taken the longevity and anti-aging world by storm. With animal studies showing exciting results including reversal of age-related diseases, these supplements are an exciting glimpse into the future of reversing aging.
This article digs into the science of how NR and NMN work, the research that has been done on NR and NMN, and then explains the connections with sirtuins, PARPs, and aging. Also included is information on the genetic variants that impact the body’s production of NAD+ and the relation to sirtuin gene variants.
What is NAD+?
NAD+ (nicotinamide adenine dinucleotide) is an important molecule that all plants and animals produce and use. It is a niacin derivative used in all living cells for a bunch of different purposes. It is one of those ‘can’t live without it‘ types of molecules!
NAD+ in cellular energy production:
A quick overview of cellular energy production for those for whom high school biology is but a distant memory…
In cellular metabolism, NAD+ is an essential part of energy production.
When you eat food, your body converts it into the components needed by the cells for producing energy. For example, carbohydrates break down into their simple components such as glucose. The glucose can then be directly used in cells to produce ATP, which is the molecule your body uses for energy.
During cellular energy production, glycolysis uses glucose to produce a little ATP (net of 2 ATP molecules) and acetyl-CoA. Then, the acetyl-CoA can be used in the mitochondria to produce more ATP via the Krebs cycle. Additionally, your body can convert fatty acids into acetyl-CoA when in ketosis, thus providing an alternative fuel source for the mitochondria.
NAD+ comes into play within the Krebs cycle, with electrons shuttling between NAD+ and NADH.
Next up in energy production within the mitochondria is oxidative phosphorylation (electron transport chain). Within the inner membrane of the mitochondria, oxidative phosphorylation takes those intermediates of the citric acid cycle and cranks out a bunch of ATP (energy molecules). It is your body’s main way of producing energy when enough oxygen is present.
An essential step in this process uses NAD+ for the transfer of electrons.
In addition to ATP production, NAD+ is needed for:
While using NAD+ for cellular energy production is completely fundamental to life as we know it, this molecule is also used in numerous other reactions in the body.
ADP-ribose transfer reactions consume NAD+. Examples of this include processes such as the repair of DNA and in the maintenance of telomeres, the end caps of DNA that are important in cellular aging.
Reactions involving sirtuins also use NAD+. Sirtuins are a family of proteins (SIRT1 through SIRT7) essential for turning on and off the translation of genes within a cell. It is foundational for the control of cellular functions. (More on sirtuins to come…)
Additionally, NAD+ is involved in cell signaling processes both within and outside of cells.
Yep – I’ve used the words essential, foundational, and fundamental here, but these words seem almost too weak to explain the necessity of NAD+ in your body.
Let’s get a little more technical here, delving into SIRTs and PARPs and acronyms galore…
NAD+ and Aging:
As we age, there are a lot of physiological changes that take place. We all know this: hearing loss and hair loss; your muscle mass declines and wrinkles increase; weight tends to rise, along with blood glucose levels. Eventually, you end up with heart problems or diabetes, and then everything goes downhill from there.
NAD+ levels decrease with aging and are likely at the heart of some of the age-related declines we face.
- For example, NAD+ is important in DNA repair, and this process is so important for preventing cellular death – or cancer.[ref]
- Mitochondrial energy production decreasing as we age is another big part of why everything goes downhill. NAD+ is essential in energy production.
Sirtuins and Aging:
I mentioned above that sirtuins rely on NAD+, which is important in gene expression. Let me explain this further…
Sirtuins are a family of genes (SIRT1 through SIRT7) involved in regulating gene expression. The sirtuins cause the DNA in the cell nucleus to either be accessible or inaccessible for a gene to be transcribed.
The ability for the regulation of genes to be transcribed into proteins is fundamental to cell function. Every cell contains the same DNA in the nucleus. The differences between a liver cell and a muscle cell are due to the regulation of which genes are transcribed. Thus, disrupting the sirtuins can lead to mucked-up cell function and the symptoms of aging.
Lifespan extension studies: In the initial studies on the sirtuin genes in yeast, adding in additional copies of the gene increased lifespan by 30%.[ref] This discovery led to research showing how important sirtuins are in human healthspan.
The SIRTs all have specific functions:
- SIRT1 encodes the sirtuin 1 protein. It involves sensing nutrient availability and is thus linked to problems with insulin resistance. Studies show animals with insulin resistance have decreased SIRT1 levels. When researchers increase SIRT1 in animals, they are resistant to the problems of obesity and insulin resistance that a high-fat diet induces in them.[ref][ref] Researchers recently discovered that SIRT1 is also important in developing the egg cell.[ref]
- SIRT2 codes for the sirtuin 2 protein that is located in the cytosol of the cell. This important enzyme arranges the chromosomes for cell division in mitosis.
- SIRT3, 4, and 5, found in the mitochondria, are important for oxidative stress and fat metabolism.[ref]
- SIRT6 is important in the gene expression for metabolic regulation, telomere maintenance, and mitochondrial respiration. Reducing Sirt6 in the liver causes animals to develop fatty liver disease, and knocking out Sirt6 altogether causes animals to die within a few weeks due to severely accelerated aging.[ref]
Sirtuins use NAD+ to complete their cellular activity, and through that, the NAD+ levels may be a sensor for how much energy is available in an organism.[ref]
PARPs and NAD+
Another enzyme group that utilizes NAD+ in their reactions is PARPs, which stands for poly(ADP-ribose) polymerase.
PARPs are another family of proteins that are important in DNA repair and genomic stability. They detect broken DNA and signal for it to be repaired. Additionally, when DNA isn’t able to be repaired, cell death is initiated. Again, these are vital cellular functions, especially in aging.[ref]
PPAR1 uses up a lot of NAD+ in the process, causing a decrease in ATP production for the cell. When a cell hasn’t replicated the DNA properly, the DNA damage signaling response is enacted.[ref] Cell death is necessary in the right context, but excessive cell death, especially in the brain, is not good.
Excessive DNA breakage can lead to a lot of PARP activation, thus depleting NAD+. What causes DNA breakage? UV light, reactive oxygen species (oxidative stress), lipid peroxidation, and a lot of different environmental toxicants. DNA damage occurs all the time in the normal course of cell replication, but in aging, oxidative stress causes an increase in PPAR1 and a subsequent decrease in NAD+.
PARP1 can initiate cellular repair for single-strand DNA breaks. This is important for longevity.
Inhibiting PARP is a way to mitigate the decreased NAD+ and ATP levels and decrease cell death. It doesn’t fix the cause (DNA breakage), but it puts a bandaid on the downstream effects of PARP activation.
Atherosclerosis and congestive heart failure are two diseases in which PARP inhibitors might be used. The inflammation within the vascular cells causes PARP1 activation and the subsequent decrease in NAD+ and cellular energy. Inhibiting PARP then slows the inflammatory response and preserves the ATP and NAD+ in the heart cells.[ref]
The positive side of inhibiting PARP would be to have plenty of NAD+ available for the rest of the heart cells. Animal studies using a mouse model of sepsis show that, indeed, giving nicotinamide riboside, which increases NAD+, protected the heart and lungs from injury and decreased death due to sepsis.[ref]
Creating NAD+ in the body:
We’ve covered a lot of what NAD+ does, but you may be wondering, how do we create it?
Precursors of NAD+ include different forms of niacin (vitamin B3) and tryptophan. The different forms of niacin, whether from food or supplements, are nicotinamide (aka niacinamide) and nicotinic acid (niacin). The nicotinic acid form (niacin) is the one that can cause flushing when taken as a supplement.
Foods high in niacin include tuna, chicken, beef liver, salmon, and pork. Non-meat sources of niacin include brown rice, peanuts, and potatoes.
What doesn’t have niacin? Corn that hasn’t been nixtamalized (processed with lime water). A lack of niacin causes a disease state known as pellagra. Thus, in the late 1800s and early 1900s when people in the US South were dependent on corn for most of their calories, there was an epidemic of pellagra. Symptoms of pellagra include dementia, diarrhea, and a skin rash.
Tryptophan, found in a lot of protein-containing foods, is an essential amino acid. Your body can also convert tryptophan into niacin through the kynurenine pathway. However, this pathway to form niacin isn’t utilized by the body as much as obtaining niacin from foods that contain it.
Another way to create more NAD+ is by converting nicotinic acid. The first step in converting nicotinic acid to NA mononucleotide (NAM) uses the NAPRT enzyme coded for by the NAPRT gene.[ref][ref]
NR and NMN:
Both nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are essential in creating and recycling NAD+.
NMN, synthesized from nicotinamide (niacinamide) and PRPP (5’-phosphoribosyl-pyrophosphate), uses the enzyme NAMPT.[ref] (More on NAMPT in the Genetic Variants section below.)
Nicotinamide riboside (NR) is another precursor of NAD+ and intermediate in the NAD salvage pathway. It can be found at low levels in foods, particularly in milk, and it is available as a supplement.
NAD+ doesn’t have to be synthesized continually from the precursors — it can be recycled through the “NAD Salvage Pathways”. Reusing the components of NAD+, specifically nicotinamide, is your body’s main way of having enough NAD+ available in all cells. This salvage pathway uses the supplemental NR and NMN in the body.
Studies on NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide):
Enough background science – let’s get into the fascinating research on supplemental nicotinamide riboside and nicotinamide mononucleotide.
Animal studies on NR and NMN:
Below are some of the animal studies on NAD+ precursors (NR or NMN):
- Alzheimer’s: In a mouse model of Alzheimer’s disease, NMN shows the restoration of mitochondrial function in the brain. The oxygen consumption deficits in the brain mitochondria, found in Alzheimer’s, showed a reversal. Again, this is a mouse study… but pretty cool.[ref]
- Fertility: Several studies have shown that NMN or NAD+ precursors restore fertility at the end of an animal’s normal reproductive age. It seems to do this through rejuvenating egg quality.[ref][ref]
- Hemorrhagic shock: In a rodent model of hemorrhagic shock, those receiving NMN had less inflammation and better cellular metabolism. Both of which increase survival in hemorrhagic shock.[ref]
- Aging: Nicotinamide riboside (NR) was fed to old mice for three months. The NR decreased several of the signs of aging in mice, such as altered fat mass, cholesterol levels, and liver enzymes. [ref]
- Fatty Liver Disease: Quite a few studies show that NR can reverse fatty liver disease.[ref][ref][ref]
- Cognitive Function: Another mouse study showed that NR could improve cognitive function in a mouse model of diabetes. Not only was cognitive function improved, but inflammatory markers in the brain were reduced, as was amyloid-beta.[ref]
- Hearing Loss: NR was shown to protect mice from age-related noise-induced hearing loss. It was achieved through increasing SIRT3 expression.[ref]
- Retinal Degeneration: NR helps to prevent retinal degeneration and inflammation in the retina. [ref]
- Offspring: For postpartum mouse moms, NR was beneficial. It increased lactation, nursing behavior, and transmission of micronutrients to the mouse babies. Those offspring grew up to have advantages “in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis”.[ref]
- Mitochondrial Function: A mouse study also found that NMN could dampen the DNA damage response and improve mitochondrial function. It also helped with liver damage.[ref]
- Increased Lifespan: A small increase in lifespan (about 4%) has been shown in mice fed NR starting at old age.[ref]
- Restored SIRT1 Levels: Middle-aged mice fed NMN showed increased Sirt1 levels, similar to younger mice.[ref]
Human studies on NR and NMN:
Safety first! So far, studies show that NR and NMN are safe for most people. (Talk with your doctor if you have questions on supplements.)
- A study looked at the safety of nicotinamide riboside (TruNiagen brand) in healthy men and women over the course of 8 weeks. They used doses ranging from 100 to 1000 mg. All doses increased NAD+ metabolites within two weeks, which was dose-dependent (high doses= high NAD+). Most importantly, there were no differences in adverse events between the NR groups and the placebo group. This study also noted that the NR did not mess up methylation.[ref]
- Another trial found that 2,000 mg/day of NR in obese, sedentary men aged 40 – 70 was safe and well tolerated in a 12-week study. But, it didn’t show any miraculous effects on insulin sensitivity, glucose disposal, or resting energy expenditure.[ref] Note that 2,000 mg/day is more than most people take (or can afford to take).
Does it work to boost NAD+?
A clinical trial examined the effects of NR on healthy volunteers for 9 days. The study participants took 250 mg for the first two days and then titrated up to 1000 mg. On day 9, NAD+ levels had increased by 100%. No side effects were reported for the NR supplement. Interestingly, most of the individual response curves were similar in percentage increase, but a couple of participants had a much bigger response.[ref – open access]
A study of ‘aged men’ looked at the effects of supplementing with 1,000 mg of NR per day for three weeks. The results showed an elevation of NAD+ in the muscles and a decrease in inflammatory cytokine levels.[ref]
A study that included 30 middle-aged and older men and women looked at the effect of NR vs placebo for six weeks. Oral NR supplementation (1,000mg/day ) raised NAD+ levels by 60% compared to placebo. NR lowered blood pressure and aortic stiffness (a little). Notably, participants who had stage one hypertension to begin with, had a 10-point drop in systolic blood pressure.[ref]
A small clinical trial in patients with heart failure showed that oral nicotinamide riboside decreased proinflammatory cytokines. The researchers concluded that NR may improve mitochondrial respiration and attenuate inflammation in heart failure.[ref]
Skeletal muscle metabolism:
A recent study found: “NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate.”[ref]
A clinical trial found that people recovered more quickly from COVID-19 when given supplemental NR, N-acetyl-cysteine, and l-carnitine. The phase II and phase III clinical trials found that recovery was 3-4 days faster with the supplement.[ref]
Nicotinamide riboside absorption:
A recent (2021) animal study found that oral nicotinamide riboside is absorbed in a two-phase fashion. The initial absorption in the small intestines raises NAD+ levels quickly. But not all NR is absorbed in the small intestines. The part that reaches the large intestines goes through several transformations, and research now shows that BST1 (also known as CD157) plays an essential role in the later phase of absorption. From the study: “Thus, we concluded that NR metabolism is more complicated than originally thought, and it is important to consider the role of BST1 in NR supplementation therapy to protect from aging and aging-related diseases.”[ref]
So what is BST1? Also known as CD157, the molecule catalyzes NAD+ hydrolysis. It is important in immune system reactions, including in the brain. Research ties variants in BST1 to Parkinson’s disease and REM sleep disorder. Studies also find BST1 variants to impact autism risk related to the regulation of brain development.[ref]
Interestingly, researchers have found in animal studies that BST1 (CD157) is important in oxytocin levels in the brain. The study was specifically looking at how low oxytocin relates to autism spectrum behaviors. Giving nicotinamide riboside to mice that lack BST1 corrected the behavioral deficits in the animals.[ref] Adding to this, a recent study in children with autism found that nicotinamide riboside levels (along with 7 other metabolites) are lower in autism spectrum disorder compared to healthy controls.[ref]
Obviously, a lot more research is needed here to determine if the animal studies are a good model for human behavior changes in autism. But the mechanism of action with BST1 playing an important role in NAD+ reactions in the brain is fascinating.
Nicotinamide Riboside, NAD+ pathway, and SARS-CoV-2:
Viruses replicate inside cells using specific enzymes, and in the case of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp) is essential for viral replication. Molecular docking studies show that nicotinamide riboside ” is expected to have therapeutic effects on COVID-19 due to its super close structural similarity to the proven RdRp inhibitors.”[ref]
When someone is ill with COVID-19, the PARP genes are over-expressed, and NAD levels decrease. In addition to responding to DNA damage, PARPs are also part of cellular antiviral responses.
Researchers find that in COVID-19, PARPs are increased, the NAD+ salvage pathway is activated, and NAD biosynthesis (e.g., niacin creation) is decreased. One study concludes “These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.”[ref]
Circadian Rhythm and NAD+
Circadian rhythm is a theme that runs throughout genetics and health. There’s no escaping the fact that the circadian rhythm controls so much of what goes on in our bodies. The cycle of sunlight and darkness governs all living organisms…
The core molecular circadian clock is driven by the rising and falling levels of four genes: CLOCK and BMAL1 rise and then are suppressed as PER and CRY accumulate. The CLOCK gene expression is controlled by a sirtuin (SIRT1), which, in turn, is dependent on NAD+ levels.[ref]
I know – you all are thinking, “holy crap! mind blown!” right now. Or you are wondering how deep in the weeds this article will wander:-)
Let me connect a few dots… NAD+ levels are needed for the sirtuins to work. The sirtuin family of proteins controls whether a portion of the DNA is available to be transcribed – or not. Like a light switch turning on or off.
SIRT1, important for the core circadian clock gene (aptly named CLOCK) to function correctly, rises and falls cyclically over 24 hours.
A connection exists between the disruption of the core clock genes and the various chronic disease states associated with aging, such as diabetes, heart disease, obesity, metabolic syndrome, and Alzheimer’s disease.
Thus, one mechanism by which low NAD+ levels impact us as we age is through altered CLOCK gene expression.
SIRT6 has also been shown to control the liver’s clock – separately from SIRT1. It leads to the control of lipid metabolism in the liver.[ref]
NAD+ Genotype Report:
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NAMPT gene: encodes an enzyme used in the synthesis of NMN by the body. NAMPT is also called visfatin in studies.
Check your genetic data for rs61330082 (23andMe v5; AncestryDNA):
- G/G: typical NAMPT production
- A/G: decreased NAMPT production
- A/A: decreased NAMPT production[ref]
Members: Your genotype for rs61330082 is —.
Check your genetic data for rs9770242 (23andMe v4; AncestryDNA):
- A/A: most common genotype,
- A/C: typical
- C/C: lower risk of heart disease[ref], lower fasting glucose levels, and lower fasting plasma insulin levels[ref]
Members: Your genotype for rs9770242 is —.
SIRTUINS: The sirtuins use up NAD+ in the cells. Genetic variants in this family of genes impact disease risk for many diseases associated with aging and low NAD+. The genetic variants listed here are just a few of the SIRT gene variants chosen because they are included in common genetic testing.
Check your genetic data for rs3758391(23andMe v5; AncestryDNA):
- C/C: typical
- C/T: lower cardiovascular disease mortality, better cognitive function in aging
- T/T: lower cardiovascular disease mortality, better cognitive function in aging[ref], elevated SIRT1 expression[ref]
Members: Your genotype for rs3758391 is —.
Check your genetic data for rs12778366 (23andMe v4, v5; AncestryDNA):
- C/C: reduced risk of diabetes complications[ref]; 30% reduced mortality risk in aging population, better glucose tolerance[ref]
- C/T: reduced risk of diabetes complications, somewhat reduced mortality risk
- T/T: typical
Members: Your genotype for rs12778366 is —.
Check your genetic data for rs511744 (23andMe v4; AncestryDNA):
- T/T: increased lifespan (avg. of 1.3 years in this study)[ref]
- C/T: typical lifespan
- C/C: typical lifespan
Members: Your genotype for rs511744 is —.
SIRT6 gene: important in metabolic regulation, telomere maintenance, and mitochondrial respiration.
Check your genetic data for rs352493 (23andMe v4, v5; AncestryDNA):
- T/T: typical
- C/T: risk of increased severity in CAD
- C/C: increased risk of more severe coronary artery disease[ref]
Members: Your genotype for rs352493 is —.
BST1 gene: bone-marrow stromal cell antigen 1 (BST1 or CD157) hydrolyzes nicotinamide riboside to NAM in the colon (later phase of oral absorption of NR)[ref] Genome-wide association studies have identified BST1 as a risk factor for Parkinson’s disease. It is also important in the immune response. Recent research has also identified BST1 rare variants as important in REM sleep disorder.[ref]
Check your genetic data for rs4698412 (23andMe v4, v5; AncestryDNA):
- A/A: slightly increased risk of Parkinson’s, more likely to have gait problems in PD[ref]
- A/G: slightly increased risk of Parkinson’s
- G/G: typical
Members: Your genotype for rs4698412 is —.
Niacin, NR, or NMN from food:
Niacin can be formed in the body from a pathway that starts with tryptophan. Abundant in most protein-containing foods, tryptophan is an essential amino acid that can either be converted into kynurenine (and eventually niacin) or serotonin.
Some studies indicate that 20mg/day of niacin can meet our need for NAD+ biosynthesis. The US RDA is 16mg/day.[ref]
NMN is found in trace amounts in foods:
- Broccoli and cabbage contain up to 1mg/ 100 gm of NMN.
- Avocados and tomatoes have also been shown to contain NMN in the .36 to 1.6 mg/100 grams range.
- While food can be a minor source of NMN, it is mainly synthesized in the body.
Tryptophan, the precursor amino acid for niacin, can also eventually be converted to NAD+. But, it takes 60 times the amount of tryptophan compared to niacin. Tryptophan can help to prevent pellagra (niacin deficiency disease), but it isn’t the main source for most people today.[ref]
Related article: Tryptophan and the kynurenine pathway genes
Supplements to boost NAD+
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Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.