NAD+ has many important roles for health, including stimulating anti-aging activities of Sirtuins and the DNA damage repair enzymes.
High NAD+ is necessary for healthy metabolism and mitochondria. In addition, low NAD+ can contribute to fatigue and several diseases. Read this post to learn more about NAD+ and factors that increase or decrease it.
- Introduction: What is NAD+?
- Production of NAD+
- The Roles of NAD+
- NAD+ as a Coenzyme that Stimulates Enzyme Activity
- Harmful Effects of Low NAD+
- 1) Low NAD+ Means Aging
- 2) Low NAD+ Can Suffocate the Cells (Hypoxia)
- 3) Low NAD+ Increases Sunburn and Skin Cancer
- 4) Low NAD+ is Associated with Fatigue
- 5) Low NAD+ May Worsen Weight Gain and Metabolic Syndrome
- 6) Low NAD+ May Worsen Cardiovascular Diseases
- 7) Low NAD+ May Contribute to Multiple Sclerosis (MS)
- Other Roles of NAD+
- Factors that Increase NAD+
- Factors that Decrease NAD+
- Genes that Affect NAD+ Levels (SelfDecode)
- Caveats and Negative Effects of NAD+
Introduction: What is NAD+?
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells which consists of two nucleotides (adenine and nicotinamide).
NAD exists in two forms: NAD+ and NADH respectively. NADH contains 2 more electrons than NAD+.
Production of NAD+
NAD+ and the Electron Transport Chain in the Mitochondria
This 2-minute video demonstrates the process of oxidative phosphorylation, which converts NADH into NAD+, which generates 3 ATP molecules for each NADH used.
When our cells break down carbohydrates and fat for energy, the energy is stored by creating ATP and NADH. The energy stored in the 2 more electrons of NADH can then be converted to ATP via a process called “oxidative phosphorylation” or “cellular respiration” in the mitochondria.
In the presence of food abundance or when our bodies break down (metabolize) more carbohydrates and fats, NADH levels increase, while NAD+ levels decrease.
When electrons go through your mitochondrial electron chain, energy is produced. NADH is the most significant carrier of these electrons and it becomes NAD+ when it gives away those electrons. The body gets energy from food via electrons contained in that food.
When you have the ingredients to use those electrons, you will feel vital and healthy and when you don’t have the proper inputs you will be sick and weak.
The cell uses levels of NAD+ to know if we need to increase metabolism or energy utilization because relatively higher levels of NAD+ means we’ve been using electrons up.
Different pathways that produce and break down NAD+, source: https://www.ncbi.nlm.nih.gov/pubmed/24988458
The following are precursors (raw materials) from which NAD+ can be produced:
- Tryptophan (L-Trp)
- Nicotinic Acid (NA, Vitamin B3)
- Nicotinamide (NAM, also called no flush Niacin)
- Nicotinamide Riboside (NR)
- Nicotinamide Mononucleotide (NMN)
Generally, supplementation with NAD+ precursors in the salvage pathways, i.e. NR and NMN, is more effective at increasing cellular levels of NAD+ than those in the de novo pathway because the enzyme NAMPT is a rate-limiting step (bottleneck) in NAD+ production (R, R2).
Not every cell is capable of converting every one of the above precursors at all times because these precursors also have other roles in the cells (R, R2). The following biochemical conversion or pathways happen in these cells:
- Tryptophan into NAD+: liver, neuronal, and immune cells
- Nicotinamide into nicotinic acid: gut bacteria
- Nicotinic acid (B3) into NAD+: Liver, kidney, heart, and intestinal cells
- Salvage pathway: heart and skeletal muscles
Therefore, supporting each of these pathways may increase NAD+ specifically in these tissues or organs than others, and depending on factors like stress levels, inflammation, and circadian rhythm entrainment
The Roles of NAD+
NAD+ as a Coenzyme that Stimulates Enzyme Activity
NAD+ is a coenzyme that activates enzymes that catalyze redox reactions (electron transfer) in the body. These enzymes include Sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38 (R). These enzymes that use NAD+ also break down NAD+.
NAD+ Activates Sirtuins
Sirtuins are enzymes that use NAD+ to pluck off acetyl groups (deacetylate) from proteins to modify them (R).
Sirt1, when activated by NAD+, then activates:
- PGC-1alpha (R), which stimulates mitochondrial biogenesis (creation of new mitochondria) and increased fatty acid oxidation
- FOXO1 (R), part of the insulin signaling pathway. FOXO1 activation reduces adipogenesis (production of new fat cells) by inhibiting PPAR-gamma
- p53, a tumor-suppressor (anti-cancer) gene that prevents cells with DNA damage from growing into cancers
- SREBP1c, which controls blood sugar, fatty acid, and fat production in response to insulin. It also controls cholesterol levels.
- PPAR-gamma, which increases insulin sensitivity and insulin secretion (R). It is an inflammatory gene (R).
- Genes that control circadian rhythm (R, R2)
Sirt3, when activated by NAD+, which leads these changes in the mitochondria (R):
- Activation of SOD2, a mitochondrial antioxidant enzyme
- Activation of Mitochondria enzymes responsible for breaking down fatty acid and carbohydrate for energy in, including LCAD, SDH, and AceCS2.
- Deactivation of HIF-1alpha, a protein that is produced when oxygen is low.
NAD+ Activates PARP, an Enzyme That Repairs Damaged DNA
When there is a significant amount of DNA damage in the cell, inhibiting PARP can cause the cells to undergo apoptosis. Therefore PARP inhibitors are being tested as anti-cancer therapy (R).
Mice without PARP have increased NAD+, Sirt1 activity and experience some metabolic benefits (R).
Harmful Effects of Low NAD+
1) Low NAD+ Means Aging
In mitochondria of young people, NADH can readily donate its electrons to generate NAD+. During the aging process, increased DNA damage reduces NAD+, leading to reduced SIRT1 activity and reduced mitochondrial function (R).
The more NAD+ levels increase, the more SIRT1 is active (on the other hand, Nicotinamide blocks SIRT1 activity) (R).
Low NAD+ reduces Sirt1 activity, which ages the body.
In addition, during aging, the decline in function of genes that control circadian rhythm can reduce NAD+ levels (R).
2) Low NAD+ Can Suffocate the Cells (Hypoxia)
When you have low oxygen (hypoxia), your mitochondria don’t work as well and for good reason. Oxygen needs to be there to accept electrons in the mitochondria. When you have low oxygen, it can’t accept electrons, so your body wants to slow mitochondrial function down.
When you have low oxygen, your body responds by slowing the conversion of NADH to NAD+ (less oxidation). Therefore, you have a buildup of NADH and a relative reduction of NAD+.
3) Low NAD+ Increases Sunburn and Skin Cancer
4) Low NAD+ is Associated with Fatigue
Fatigue, low physical and mental energy are also signs of lower NAD+/SIRT1.
Levels of NAD+ largely control the “redox potential” because NAD+ has the ability to acquire electrons.
The higher the redox potential of the cell, the better the mitochondria work and the more it can fight infections and function the way a cell is supposed to function.
5) Low NAD+ May Worsen Weight Gain and Metabolic Syndrome
NAD+ activation of Sirtuins clearly turn on genes that improve metabolism, help with weight loss, and reduce LDL cholesterol. In addition, niacin and other NAD+ precursors are being tested as treatments for cardiovascular disease.
In a mouse study, supplementation with nicotinamide riboside (a precursor of NAD+) can protect against diet-induced obesity (R). These animals can also better burn fat, burn more calories, and become more insulin sensitive.
6) Low NAD+ May Worsen Cardiovascular Diseases
The heart muscles heavily uses the mitochondria, and the mitochondria activity requires Sirt3 (R).
NAD+ levels also drop in the case of ischemia-reperfusion injury (damage to the heart from lack of blood flow) (R).
7) Low NAD+ May Contribute to Multiple Sclerosis (MS)
During chronic nervous system inflammation, activation of Th1-derived cytokines by CD38 (an enzyme that uses NAD+) can reduce available NAD+ outside the cells (R). Overall, in MS patients, NAD+ increases in the immune system and decreases in the nervous system (R).
NAD+ deficient neurons are more vulnerable to degeneration like in MS (R).
In animal models of MS, NAD+ levels are elevated in the CNS because of the changes in the immune system (R).
Increasing NAD+ by supplementation with NAD+ precursors or fasting can help with MS in animals (R), but administration of tryptophan seems to increase numbers of lymphocytes and making MS worse (R, R2).
Other Roles of NAD+
8) NAD+ Increases Cellular Antioxidants
NAD+ increases activities of SOD2 through Sirt3 (R).
9) NAD+ Increases Metabolism Along with Thyroid Hormones
10) NAD+ Helps with Brain Function
The brain has a high energy demand, so neurons contain a lot of mitochondria. Mitochondria dysfunction also contributes to many mental health and neurodegenerative diseases.
This is also why a lot of my clients claim to do better with niacin/nicotinamide in the short term: because it increases NAD+ (R).
So we see that lower levels of NAD+ will decrease brain energy and dopamine, and people will start to need stimulants to keep up.
11) NAD+ Helps Balance Immune Function and Reduce Inflammation
Sick people often have chronic infections that they can’t get rid of and chronic inflammation.
Increasing NAD+ in animal models reverses autoimmune disease through various means, which demonstrates that low NAD+ is one cause of a deregulated immune system and why autoimmune conditions often coexist with chronic fatigue and brain fog.
SIRT1/NAD+ is important for the immune system to clear pathogens in part via MHC II activation. Hypoxia or low oxygen prevents MHC II from activating by decreasing SIRT1 activity (oxidized LDL also decreased SIRT1 in macrophages) (R).
NAD+ (and by extension SIRT1) seems like one of those molecules that creates an optimal and balanced environment for your immune system to fight infections, while also dampening inflammation.
Factors that Increase NAD+
1) Fasting or Caloric Restriction Increases NAD+
Your body senses the ratio of NAD+ and NADH and if you have low NAD+ relative to NADH, it’s a signal that you have an excess of energy either by ingesting too much energy/calories or expending too little energy. It can also be a signal for too little oxygen.
When you have high NAD+ levels, it means you likely have been using your energy up and have a negative energy balance – you’re expending more calories than you’re consuming.
When the cells have more carbohydrate to burn, this results in an accumulation of NADH. Carbohydrate and nutrient depletion allows NADH to get used up so that NAD+ build up. Therefore, fasting and caloric restriction results in higher NAD+ and Sirtuin activation (R).
2) Ketosis/Beta-Hydroxybutyrate Increases NAD+
Fat-burning states such as in ketosis can increase NAD+ (R).
3) Exercise Increases NAD+
Energy stress created by exercise cause the cells to burn NADH for energy, thus generating more NAD+ (R). NAMPT levels also increase with exercise (R).
4) Having More Body Fat Increases NAD+
Being fat of having more adipose tissue can increase NAMPT enzyme levels and leads to higher levels of systemic and hypothalamic NAD+ levels (R). Although being overweight has a bunch of negative health consequences, having higher NAD+ levels is a benefit, which may be one reason why thin people often do worse with chronic health issues.
5) Saunas and Heat shock.
Saunas are also considered a panacea and have been a part of every historical culture. We think it’s because we’re sweating out toxins, and that might have something to do with it, but saunas and heat shocks also increase NAD+ levels (R).
6) Fermented Foods and Kombucha
8) AMPK Activation
9) NAD+ Intermediates
- Niacinamide– low doses (R).
- Tryptophan and Aspartic acid are a fuel for NAD+ (R), but we usually get enough dietary amino acids if you eat adequate protein.
- Nicotinamide Riboside (NR) (R)
- Nicotinamide Mononucleotide (NMN) (R)
Although NR and NMN have been shown to be a great strategy to mitigate aging, their efficacy in humans still need to be further tested.
Mice NR and NMN doses are around 400 – 500 mg/kg per day, which are really high for human use (R).
- Oxaloacetate (R)
- Malic acid (R)
- Resveratrol (R)
- Apigenin (R)
- Leucine (R)
- Niacinamide- low doses (R).
- Lithium inhibits mir-34a, which inhibits NAMPT, the enzyme that makes NAD+ (R, R2) So lithium should technically increase NAMPT and NAD+ by taking the breaks away from its production.
- Succinic acid – to a lower degree than malate (R)
Factors that Decrease NAD+
1) Chronic Inflammation
The relationship between circadian rhythm and NAD+ levels, and some of the ways that chronic inflammation can affect NAD+ levels. Source: https://www.ncbi.nlm.nih.gov/pubmed/24786309
2) Disrupted Circadian Rhythm
The ebb and flow of cellular production due to circadian rhythm will result in the ebb and flow of NAD+ levels.
With aging, there will be lessor of this ebb and flow, which may explain why NAD+ declines with age.
Because NAMPT is involved in the conversion of nicotinamide to NAD+, in the presence of inflammation or disrupted circadian rhythm, it is more effective to increase NAD+ by supplementation with other NAD+ precursors that don’t require NAMPT, such as nicotinamide riboside or nicotinamide mononucleotide.
3) DNA Damage (PARP Activation)
Massive amounts of DNA damage means that more PARP molecules will be at work on damaged DNA and use up the NAD+. This decline in NAD+ can reduce Sirtuin activity (R).
4) Reduced Sirtuin Activity
Although NAD+ controls Sirtuin activity, there are many ways low Sirtuin levels can decrease NAD+ levels, including:
- Sirtuin controls circadian rhythm (R), so low sirtuin levels may disrupt the circadian ebb and flow and thus reduce NAD+ levels.
- Reduced sirtuin activity can reduce mitochondrial function through PGC-1alpha and several other mitochondrial enzymes.
6) High Blood Sugar and Insulin Levels
Genes that Affect NAD+ Levels (SelfDecode)
NAMPT Produces NAD+ from Other Precursors
If you are not producing the enzyme NAMPT as well, you may be more susceptible to low NAD+ from other lifestyle factors. Also, if you have these SNPs, you may need to supplement more nicotinamide riboside to get the effects.
PPAR-alpha Stimulates Conversion of Tryptophan to NAD+
SNPs inside of PPAR-alpha
ACMSD Converts Tryptophan to KYN
ACMSD converts tryptophan to quinolinic acid and kynurenine before conversion to NAD+ (R)
NADH: ubiquinone oxidoreductase (Complex I) Converts NADH to NAD+
These are genes that make enzymes which convert NADH to NAD+ in the mitochondria.
- RS11548670 (NDUFS1)
- RS1156044 (NDUFV2)
- RS11663316 (NDUFV2)
- RS12457810 (NDUFV2)
- RS7407664 (NDUFV2)
- RS7637404 (NDUFV2)
- RS906807 (NDUFV2)
- RS1142530 (NDUFS7)
- RS11666067 (NDUFS7)
- RS7258846 (NDUFS7)
Caveats and Negative Effects of NAD+
The Big Picture – Increasing NAD+ in People with Fatigue
When people deal with fatigue both from hypoglycemia and low NAD+, fasting to increase NAD+ is not a good idea because not eating will also make you tired from hypoglycemia.
Blood sugar (from eating) dose-dependently worsens (increases) your NADH/NAD+ ratio in the same way as low oxygen. When you combine excess carbs/sugar and low oxygen, you start getting fatigued and have low energy.
This is one of the most significant reasons why sugar/carbs make people with health issues feel worse.
In fact, you might feel worse after eating anything because eating decreases NAD+ levels and fasting increases it. This is especially true in a high fat+/high sugar diet (R).
Fasting, calorie restriction, and interval exercise help people because they all raise NAD+ levels (R). There are other reasons why these help, but increasing NAD+ is perhaps the most significant reason.
Some people do worse in the short term from fasting because skipping meals cause hypoglycemia. When I was in a bad state, I’d feel like crap if I skipped meals. And then I’d eat a meal and crash because there weren’t enough energy-related molecules (ATP levels) in my lateral hypothalamus from fasting, which shuts orexin down.
Although exercise increases NAD+, people who have chronic issues can also do worse from exercise because exercise can be inflammatory and cause oxidative stress – but this is only a problem if your system can’t buffer it. Each person needs to find the right dosage for them.
Low NAD+ May Stop Cancer Growth
Most cancer cells rely on carbohydrates as energy sources. In addition, these cells also have a lot of DNA damage, which means that PARPs are activated. Therefore, cancer cells typically have low NAD+, but low NAD+ actually slows cancer growth. This is counterintuitive because NAD+ can shift metabolism towards fat burning.
Inhibiting NAMPT can reduce NAD+ levels, which can (R):
- reduce cancer growth
- sensitize the cancer cells to chemotherapy
- increases apoptosis
- inhibits glycolysis (carbohydrate burning for energy)
The use of NAD+ precursors therefore may not be beneficial in cancer patients, but this depends on the type and metabolic properties of the tumors (R).
NR Supplementation May Lower Exercise Performance
In mice, NR supplementation worsens exercise performance. They had a lower physical performance compared to the control group (R).
“The NR group showed a tendency towards worse physical performance by 35% compared to the control group at the final 10% load (P = 0.071)”(R).