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.
What is NAD+?
Nicotinamide adenine dinucleotide (NAD) is a coenzyme that consists of adenine and nicotinamide, it is found in all living cells.
NAD exists in two forms: NAD+ and NADH respectively. NADH contains 2 more electrons than NAD+.
Genetic variations in the genes that interact with NAD can influence how we process this essential molecule.
The Science: How NAD+ is Naturally Produced by the Body
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 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.
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:
- Nicotinamide Riboside (NR)
- Tryptophan (L-Trp)
- Nicotinic Acid (NA, Vitamin B3)
- Nicotinamide (NAM, also called no-flush Niacin)
- Nicotinamide Mononucleotide (NMN)
Generally, supplementation with NAD+ precursors in the salvage pathways, i.e. Nicotinamide Riboside and NMN, is more effective at increasing cellular levels of NAD+ than those in the de novo pathway because the enzyme NAMPT is the bottleneck in NAD+ production [1, 2].
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 [3, 4]. 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
11 Harmful Effects of Low NAD+
First, it’s important to know why having low NAD+ is a problem. That information will motivate you to increase this molecule.
1) Quickens 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 .
The more NAD+ levels increase, the more SIRT1 is active (on the other hand, Nicotinamide blocks SIRT1 activity) .
Low NAD+ reduces Sirt1 activity, which ages the body.
In addition, during aging, the decline in the function of genes that control circadian rhythm can reduce NAD+ levels .
2) 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+.
Having low oxygen in your cells also results in higher NADH and lower NAD+. Low NAD+ decreases SIRT1, which then causes higher Hypoxia Inducible Factor .
3) Increases Sunburn and Skin Cancer
People who I would suspect to have low NAD+ levels tend to burn easily from the sun. This indicates low MSH and/or low NAD+.
4) 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) May Worsen Weight Gain and Metabolic Syndrome
NAD+ activation of Sirtuins clearly turns 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+) protected against diet-induced obesity . These animals can also better burn fat, burn more calories, and become more insulin sensitive.
Sirtuins improve glucose levels and glucose homeostasis by increasing insulin levels .
6) May Worsen Cardiovascular Diseases
NAD+ Depletion, typically caused by DNA damage in failing hearts, can accelerate heart failure in experimental animals .
7) 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 . Overall, in MS patients, NAD+ increases in the immune system and decreases in the nervous system .
NAD+ deficient neurons are more vulnerable to degeneration like in MS .
In animal models of MS, NAD+ levels are elevated in the central nervous system because of the changes in the immune system .
Increasing NAD+ by supplementation with NAD+ precursors or fasting can help with MS in animals , but administrating tryptophan seems to increase numbers of lymphocytes and making MS worse [29, 30].
8) Decreases Cellular Antioxidants
SOD2 is an important factor in reducing cellular oxidative stress.
9) Decreases Metabolism Along with Thyroid Hormones
10) Can Impair 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.
In rats, NAD+ administration through the nose may decrease brain damage from oxygen deprivation (e.g. due to stroke) .
This is also why a lot of my clients claim to do better with niacin/nicotinamide in the short term: because it increases NAD+ .
When rats were given niacinamide to increase NAD+ levels, the negative changes caused by amphetamines were reduced .
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) Harms Immune Balance/Function and Increases Inflammation
Sick people often have chronic infections and inflammation that they can’t get rid of.
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) .
NAMPT, which makes NAD+, also increases MHC II activation. However, by activating other Sirtuins, it reduces pro-inflammatory cytokines and regulates the immune system .
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.
2 Surprising Negative Effects of NAD+
1) Low Levels 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 genes involved in DNA repair 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 :
- 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 .
2) Nicotinamide Riboside Supplementation May Lower Exercise Performance
“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)” .
Ways to Increase NAD+
Top 9 Ways to Increase NAD+
Factors that make the mitochondria more efficient and activates Sirtuins typically increase NAD+, including fasting, caloric restriction, and ketosis.
1) Fasting or Caloric Restriction
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+ builds up. Therefore, fasting and caloric restriction results in higher NAD+ and Sirtuin activation .
Fat-burning states such as in ketosis can increase NAD+ .
Ketogenic diets can help you enter this state without having to fast.
Energy stress created by exercise causes the cells to burn NADH for energy, thus generating more NAD+. NAMPT levels also increase with exercise .
Interval training is the optimal method of creating time efficient energy stress through exercise. Aerobic exercise is another method and provides the benefit of sustaining energy stress for a prolonged time.
4) Having More Body Fat
Being fat or having more adipose tissue can increase NAMPT enzyme levels and leads to higher levels of systemic and hypothalamic NAD+ levels . 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 .
Since infrared also increases SIRT1 , infrared Saunas are ideal.
6) Fermented Foods and Kombucha
Fermented foods and beverages such as kombucha contain NAD+, which is one reason why it energizes me. Fermentation uses NADH to produce lactate, and the byproduct is NAD+.
Fructose can increase Sirt1 function and activate the enzyme that converts NADH to NAD+ in the mitochondria .
Honey and fruit are good natural sources of fructose.
8) Nicotinamide Riboside
Nicotinamide riboside (NR) is the best supplement to increase NAD+.
Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with positive effects on energy metabolism and neuroprotection. These work by increasing NAD+ .
In a study published in Nature, human blood NAD+ can rise as much as 2.7-fold with a single oral dose of Nicotinamide Riboside in a pilot study of one individual .
The study also mentioned that there’s a “distinct and superior” effect compared to nicotinic acid and nicotinamide .
Mice that consume NR also have elevated liver NAD+ levels .
Doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in blood NAD+ .
In the cell, oxaloacetate and NADH produce malate and NAD+.
Supplements to Increase NAD+
- Nicotinamide Riboside
- Oxaloacetate 
- Malic acid 
- Resveratrol 
- Apigenin 
- Leucine 
- Niacinamide – low doses 
- Lithium inhibits mir-34a, which inhibits NAMPT, the enzyme that makes NAD+  So lithium should technically increase NAMPT and NAD+ by taking the breaks away from its production.
- Succinic acid – to a lower degree than malate .
- Niacinamide – low doses 
- Tryptophan and Aspartic acid are fuel for NAD+ , but we usually get enough dietary amino acids if you eat adequate protein.
- Nicotinamide Riboside (NR) 
- Nicotinamide Mononucleotide (NMN) 
Although NR and NMN have been shown to be a great strategy to mitigate aging, their efficacy in humans still needs to be further tested.
AMPK Activation Increases NAD+
AMPK increases SIRT1 activity by increasing cellular NAD+levels (increases NAMPT ). SIRT1 activation also stimulates fatty acid oxidation and indirectly activates AMPK.
7 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
Chronic inflammation reduces NAD+ levels by inhibiting the NAMPT enzyme and circadian rhythm genes .
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 lesser 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.
Having low oxygen in your cells also results in higher NADH and lower NAD+. Low NAD+ decreases SIRT1, which then causes higher Hypoxia Inducible Factor .
4) High Blood Sugar and Insulin Levels
The chronic fatigue syndrome sufferers that I coach do very poorly with alcohol since alcohol decreases NAD+ [66, 67].
Alcohol has many negative effects, but they don’t explain how fast people start to feel worse from it. NAD+ explains the almost instant effects.
6) DNA Damage (PARP Activation)
7) Reduced Sirtuin Activity
Although NAD+ controls Sirtuin activity, there are many ways low Sirtuin levels can decrease NAD+ levels, including:
- Sirtuin controls circadian rhythm , 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.
The Mechanisms by Which NAD+ Benefits Our Health
NAD+ is a coenzyme that activates enzymes that support redox reactions (electron transfer) in the body. These enzymes include Sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38 . These enzymes that use NAD+ also break down NAD+.
Typically, increased activity of other enzymes that use NAD+ can reduce available NAD+. This reduced levels of NAD+ can inhibit Sirtuins .
Sirtuin enzymes turn off certain genes that promote aging, such as those involved in inflammation, fat synthesis and storage, and blood sugar management.
Humans have 7 different Sirtuin enzymes, but Sirt1 and Sirt3 are of interest in this post.
Sirtuins are enzymes that use NAD+ to pluck off acetyl groups (deacetylate) from proteins to modify them.
The more NAD+ levels increase, the more active Sirtuins are (on the other hand, Nicotinamide blocks Sirt1 activity) .
Sirt1, when activated by NAD+, then activates:
- PGC-1alpha , which stimulates mitochondrial biogenesis (creation of new mitochondria) and increased fatty acid oxidation
- FOXO1 , 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. It is an inflammatory gene .
- Genes that control circadian rhythm [11, 12]
Sirt3, when activated by NAD+, which leads these changes in the mitochondria :
- 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.
Activates PARP, an Enzyme That Repairs Damaged DNA
NAD+ is needed for PARP (Poly ADP ribose polymerase) activity. PARP is an enzyme that repairs DNA in response to damage or cellular stress.
PARP activity correlates with maximum lifespan across 13 mammalian species. For example, humans have 5X times the PARP activity as rats. People who live to 100 also have higher PARP activity.
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 .
Mice without PARP have increased NAD+, Sirt1 activity and experience some metabolic benefits .
The Big Picture – Increasing NAD+ in People with Fatigue
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.
NAD+ is one of the most significant reasons why consuming sugar or carbs can make people with health issues feel worse. Also, low NAD+ can contribute to fatigue after meals.
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 .
Fasting, calorie restriction, and interval exercise help people because they all raise NAD+ levels . There are other reasons why these practices help, but increasing NAD+ is perhaps the most significant reason.
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.
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