Nicotinamide Riboside and NMN: Boosting NAD+ in Aging

Key takeaways:
~NAD+ is a critical coenzyme, utilized in every living cell and essential for numerous cellular functions.
~ NAD+ levels decrease with aging, and this is thought to be one of the key reasons for many age-related declines.
~ Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as supplements and increase NAD+ levels.
~ Genetic variants impact the body’s production of NAD+ and related genes.

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 aging of sirtuins, PARPs, and CD38 or CD157.

What is NAD+?

NAD+ (nicotinamide adenine dinucleotide) is an important molecule that all plants and animals produce and use in cellular processes. It is a niacin derivative indispensable for multiple cellular functions, earning its reputation as a molecule essential for life.

First, let’s look at NAD+ in ATP production and then touch on the many other roles.

NAD+ in cellular energy production:

A quick overview of the basics of cellular energy production…

In cellular metabolism, NAD+ is an essential part of energy production. When we eat food, it’s converted into the components needed by the cells to produce ATP for energy. For example, carbohydrates break down into glucose, which can then be directly used in cells to produce ATP, the molecule your body uses for energy storage.

During cellular energy production, the majority of ATP production comes from processes in the mitochondria (the powerhouse of the cell). This is where NAD+ is essential.

Two ways ATP is made in mitochondria – and both involve NAD+:

• Within the Krebs cycle (a.k.a. citric acid cycle), electrons shuttle between NAD+ and NADH.
• Within the inner membrane of the mitochondria, the electron transport chain uses NAD+ for the transfer of electrons. This is your body’s main way of producing energy when enough oxygen is present.

Here’s what this looks  like:

Other essential roles of NAD+:

Beyond energy production, NAD+ is also used in numerous other reactions in the body.

1) ADP-ribose transfer reactions consume NAD+. ADP-ribose transfer reactions  include:

• the repair of DNA
• the maintenance of telomeres
• PARP and CD38/CD157 reactions

2) CD38/CD157: Immune system and NAD+
Two very similar and related enzymes, CD157 and CD38, are responsible for using up a lot of NAD+ in the body.

• CD157 acts both as an enzyme and as a cellular receptor on immune cells. It is important in immune system reactions, including in the brain. Research ties variants in CD157 to Parkinson’s disease and REM sleep disorder. Studies also find CD157 variants to impact autism risk related to the regulation of brain development.[ref]
• Interestingly, researchers have found in animal studies that CD157 (also called BST1) is important in oxytocin levels in the brain. The study was specifically looking at how low oxytocin relates to autism spectrum behaviors. Giving NR to mice that lack CD157/BST1 corrected the behavioral deficits in the animals.[ref] 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]
• CD38 is a very similar molecule to CD157 and acts in much the same way in different cell types. Both molecules use up NAD+ by acting as enzymes that catalyze the degradation of NAD+ to use the metabolites as messenger molecules.
• CD157 and CD38 also play an important role in the immune system and are found as surface receptors on immune cells. Both are also involved in the immune response and neuroinflammation in the brain.[ref]

3) Sirtuins:
Sirtuins are a family of proteins (SIRT1 through SIRT7) essential for turning on and off the translation of genes within a cell. For instance, SIRT1 is linked to nutrient sensing and insulin resistance, and its enhancement can resist obesity-related problems. Other sirtuins, like SIRT6, play roles in metabolic regulation and mitochondrial function. All sirtuins depend on NAD+ for their activity, linking NAD+ levels to energy availability in organisms.

4) Cell signaling processes:
Additionally, NAD+ is involved in cell signaling processes both within and outside of cells.

The decline of NAD+ in aging:

As we age, there are a lot of physiological changes that take place. We all know the signs of aging: hearing loss and hair loss; your muscle mass declines and wrinkles increase; weight tends to rise, along with blood glucose levels. Eventually, everything seems to go downhill…  And a lack of  NAD+ is part of the problem.

CD38 and Aging:

Research shows that CD38 is a key part of the decline of NAD+ in aging. Knocking out the CD38 gene can prevent NAD+ declines in aging.

In aging, increased inflammation causes increased CD38, which uses up more NAD+ causing a parallel decline in NAD+ levels. Increased cellular senescence in aging also causes increased CD38 (and decreased NAD+).[ref]

Should we all just block CD38 to prevent the decline in NAD+ levels? Well, I don’t think so… CD38 does a lot, including regulating calcium ions and neurotransmitter release. It’s also important in the activation of T cells. So while it isn’t as simple as just shutting down all CD38 activity, I”ll include some ways to decrease CD38 activity a little bit in the Lifehacks section. (More on CD38 and CD157 in the Genotype report section)

NAD+ levels interact with the immune response in Covid patients in a couple of ways:

• When someone is ill with COVID-19, the PARP genes are over-expressed, and NAD levels decrease.
• 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]
• CD38 levels are broadly upregulated in Covid patients, which further depletes NAD+ levels.[ref]
• A 2023 study showed that the gene expression of multiple NAD-consuming enzymes was increased (PARPs, CD38) while SIRT1 expression was downregulated. This leads to a significant decrease in NAD+ levels (which are already decreased in aging).  Animal models clearly showed that boosting NAD+ could improve recovery from Covid.[ref]

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][ref]
• SIRT2 codes for the sirtuin 2 protein which 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 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] (More on the SIRTs in the Genotype section below)

PARPs and NAD+ in aging:

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]

PARP1 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][ref]

Creating NAD+ in the body:

Precursors of NAD+ include different forms of niacin (vitamin B3) and tryptophan.

The different forms of niacin, whether from food or supplements, are nicotinamide (also called niacinamide) and nicotinic acid (called niacin). The nicotinic acid form (niacin) is the one that can cause flushing when taken as a supplement.

What happens if you don’t get enough niacin from food? A lack of niacin causes a disease state known as pellagra. In the early 1900s when people in the US South were dependent on corn (no niacin) for most of their calories, there was an epidemic of pellagra. Symptoms of pellagra include dementia, diarrhea, and a skin rash.

Tryptophan 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 usually enough to meet the body’s needs, and thus you also need to get niacin from food.

In addition to using niacin from tryptophan, another way cells 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 (Nicotinamide Riboside) and NMN (Nicotinamide Mononucleotide):

Both nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are essential in creating and recycling NAD+.  Plus, both are available as supplements. Let’s look at how they come into play in the NAD+ pathway – and why supplemental NR or NMN may be important in aging.

NMN, synthesized from nicotinamide (niacinamide) and PRPP (5’-phosphoribosyl-pyrophosphate), uses the enzyme NAMPT.[ref] (More on NAMPT in the Genotype 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.

This salvage pathway is where supplemental NR and NMN come into play — boosting NAD+ levels. This salvage process hinges on a key enzyme, NAMPT.

Research studies on supplemental NR and NMN:

Enough background science – let’s get into the research on supplemental nicotinamide riboside and nicotinamide mononucleotide and how they can affect the diseases of aging.

Clinical trials (in humans) using NR and NMN:

Animal studies are great for showing the mechanism of action, but human clinical trials give us a better picture of what happens at different doses, ages, and health conditions.

Circadian rhythm depends on NAD+

Circadian rhythm is the 24-hour biological rhythm that controls many cellular functions. It is estimated that about 40% of cell functions fluctuate over the course of a day – based on circadian clock gene expression.

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 – this article is getting a bit deep in the science, but stick with me. 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 gene, CLOCK, to function correctly, rises and falls cyclically over 24 hours. SIRT1 relies on NAD+ availability.[ref]

The disruption of the core clock genes is causally linked to chronic diseases of aging, such as diabetes, heart disease, obesity, metabolic syndrome, and Alzheimer’s disease.[ref]

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, which ties circadian rhythm, NAD+, and metabolic health together.[ref]

Lifehacks:

NAD+ levels decline with aging, and reversing this decline has been shown in numerous studies (mostly animal studies) to help with overall health in aging.

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, and avocados and tomatoes also have trace amounts. 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+:

There are multiple ways to boost NAD+ levels with supplements, from directly supplying NR or NMN to decreasing the breakdown of NAD in cells. Additionally, you need to take into account your age in considering whether you even need to worry about NAD+ levels. Please talk with your doctor if you have any questions on whether a supplement is right for you.

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