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.

Contents

Introduction: What is NAD+?

The chemical structures of NAD and NAD+.
The chemical structures of NAD and 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. Go to SelfDecode to learn how you can have your own genetic makeup analyzed for NAD-related factors.

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.

NAD+ Synthesis

Different pathways that produce NAD+, source: https://www.ncbi.nlm.nih.gov/pubmed/24988458

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:

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 (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

NAMPT activity may be reduced by circadian rhythm misregulation and inflammation, and increased by exercise (R, R2R3).

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) Low NAD+ 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 (R).

Therefore, NAD+ levels decline with age and oxidative stress over time (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).

In turn, SIRT1 also plays a massive role in circadian gene expression, which again plays a huge role in all of our cells (R, R2).

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+.

Low NAD+ is called “pseudohypoxia” because the body sets in motion some of the same responses to low NAD+ that’s caused by low oxygen, even if you have adequate oxygen levels (R, R2).

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 (R).

3) Low NAD+ Increases Sunburn and Skin Cancer

NAD+ and NADH protect you from damaging/burning your skin in the sun and skin cancer (R, R2).  NAD+ absorbs mainly the UVB spectrum and NADH absorbs mainly UVA spectrum.

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) Low NAD+ is Associated with Fatigue

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.

Supplementation of NADH, NAD+ or its cofactors helps with chronic fatigue syndrome and fibromyalgia (R, R2).

5) Low NAD+ 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 (R). 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 (R).

Metabolic syndrome is strongly linked to depression. This low Sirtuin activity, together with lowered NAD+ from inflammation, and lowered tryptophan availability, may worsen the depression (R).

6) Low NAD+ May Worsen Cardiovascular Diseases

The heart muscles heavily uses the mitochondria, and the mitochondria activity requires Sirt3 (R).

NAD+ Depletion, typically caused by DNA damage in failing hearts, can accelerate heart failure in experimental animals (R).

NAD+ levels also drop in the case of ischemiareperfusion injury (damage to the heart from lack of blood flow) (R).

Ways to increase NAD+ and activate Sirtuins have therefore been proposed as treatments or supplemental treatments for heart diseases (R, R2).

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).

In MS patients, NAD+ increases in the immune system but neurons are NAD+ deficient (R). In addition, MS patients have less serum tryptophan available to make more NAD+ inside neurons (R).

NAD+ deficient neurons are more vulnerable to degeneration like in MS (R).

In animal models of MS, NAD+ levels are elevated in the central nervous system 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).

8) Low NAD+ Decreases Cellular Antioxidants

NAD+ increases activities of the antioxidant enzyme SOD2 through Sirt3 (R).

SOD2 is an important factor in reducing cellular oxidative stress.

9) Low NAD+ Decreases Metabolism Along with Thyroid Hormones

NAD+ controls metabolism (along with hormones like T3) and lower levels of NAD+ and T3 will make you feel cold due to a lowered metabolism.  In frog cells, NAD+ increases free T3 (R).

10) Low NAD+ Can Impair Brain Function

bigstock-Human-Brain-120459878-min

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.

Treatment with NADH improves cognitive function of Alzheimer’s disease patients (R).

In a mouse model of Alzheimer’s disease, increasing NAD+ by supplementing with nicotinamide riboside restores cognitive function by increasing PGC-1alpha levels (R).

NADH has been used to treat Parkinson’s as NADH may increase the bioavailability of levodopa, the medication for Parkinson’s (R, R2).

In rats, NAD+ administration through the nose may decrease brain damage from oxygen deprivation (e.g. due to stroke) (R).

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).

My clients often claim to do better with amphetamine usage as well in the short term.  Amphetamines use up energy, ATP and also deplete dopamine in certain parts of the brain (striatum in rats) (R).

When rats were given niacinamide to increase NAD+ levels, the negative changes caused by amphetamines were reduced (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) Low NAD+ 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.

NAD+ reverses autoimmunity by increasing an anti-inflammatory variety of Th1 and Th17 cells (which are usually bad, but NAD+ changes them to increase TGF-b and IL-10) (R).

What we see is that we can make generalizations about the immune system, but nuance is often critical.  So NAD+ levels can turn Th1 dominance from being bad to being good (R).

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).

NAMPT, which makes NAD+, also increases MHC II activation. However, by activating other Sirtuins, it reduces pro-inflammatory cytokines and regulates the immune system (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.

2 Surprising Negative Effects of NAD+

1) 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 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 (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).

2) Nicotinamide Riboside Supplementation May Lower Exercise Performance

In mice, Nicotinamide Riboside supplementation, which increases NAD+, worsens exercise performance. The mice 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).

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 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+ builds up. Therefore, fasting and caloric restriction results in higher NAD+ and Sirtuin activation (R).

2) Ketosis/Beta-Hydroxybutyrate Increases NAD+

ketogenic-diet

Fat-burning states such as in ketosis can increase NAD+ (R).

Ketogenic diets can help you enter this state without having to fast.

3) Exercise Increases NAD+

Energy stress created by exercise cause the cells to burn NADH for energy, thus generating more NAD+. NAMPT levels also increase with exercise (R).

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 Increases NAD+

Being fat or 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).

Since infrared also increases SIRT1 (R), infrared Saunas are ideal.

6) Fermented Foods and Kombucha

bigstock-a-sampler-of-fermented-food-gr-148127186-min

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+ (R).

7) Fructose

Fructose can increase Sirt1 function and activate the enzyme that converts NADH to NAD+ in the mitochondria (R).

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+ (R).

In a study published in Nature, human blood NADcan rise as much as 2.7-fold with a single oral dose of Nicotinamide Riboside in a pilot study of one individual (R).

The study also mentioned that there’s a “distinct and superior” effect compared to nicotinic acid and nicotinamide (R).

Mice that consume NR also have elevated liver NAD+ levels (R).

Doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in blood NAD+ (R).

9) Oxaloacetate

In the cell, oxaloacetate and NADH produce malate and NAD+.

Figure-8-The-malate-oxaloacetate-shuttle-exchanging-cytosolic-NADH-for-mitochondrial

source: https://www.ncbi.nlm.nih.gov/pubmed/11152939

Supplements to Increase NAD+

  1. Nicotinamide Riboside
  2. Oxaloacetate
  3. Malic acid (R)
  4. Resveratrol (R)
  5. Apigenin (R)
  6. Leucine (R)
  7. Niacinamide – low doses (R).
  8. Lithium inhibits mir-34a, which inhibits NAMPT, the enzyme that makes NAD+ (R)  So lithium should technically increase NAMPT and NAD+ by taking the breaks away from its production.
  9. Succinic acid – to a lower degree than malate (R)

NAD+ Intermediates

Supplementation with NAD+ intermediates readily increases cellular and mitochondrial NAD+, and reverse many aging or disease processes associated with low NAD+ (R, R2)

  • 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 needs to be further tested.

AMPK Activation Increases NAD+

AMPK increases SIRT1 activity by increasing cellular NAD+levels (increases NAMPT (R)) (R). SIRT1 activation also stimulates fatty acid oxidation and indirectly activates AMPK (R).

Read this post for information on how to increase 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 (R).

2) Disrupted Circadian Rhythm

The circadian clock genes BMAL1 and CLOCK control the production of the NAMPT enzyme which is the final step in the production of NAD+ (R).

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) Overeating

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 (R).

4) High Blood Sugar and Insulin Levels

Having high blood sugar levels results in higher NADH and lower NAD+ (R). Insulin also increases the NADH/NAD+ ratio (R).

5) Alcohol

The chronic fatigue syndrome sufferers that I coach do very poorly with alcohol since alcohol decreases NAD+ (R, R2).

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)

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).

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 (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.

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 (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.

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.

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 (R). 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 (R).

NAD+ Activates Sirtuins

Sirtuin enzymes turn off certain genes that promote aging, such as those involved in inflammation, fat synthesis and storage, and blood sugar management (R).

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) (R).

Source: https://www.ncbi.nlm.nih.gov/pubmed/23071150Source: https://www.ncbi.nlm.nih.gov/pubmed/23071150

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

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 (R).

Mice without PARP have increased NAD+, Sirt1 activity and experience some metabolic benefits (R).

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.

  1. RS1319501
  2. RS9770242

NAD(+) level decrease in aged mice and humans, which is a result of lower NAMPT (R).

PPAR-alpha Stimulates Conversion of Tryptophan to NAD+

PPARs, especially PPAR-alpha, stimulate the conversion of Tryptophan to NAD+ (R).

SNPs inside of PPAR-alpha

  1. RS135551
  2. RS1800206
  3. RS4253623
  4. RS4253655
  5. RS4253728
  6. RS4253772
  7. RS4823613
  8. RS9615264

ACMSD Converts Tryptophan to KYN

ACMSD converts tryptophan to quinolinic acid and kynurenine before conversion to NAD+ (R)

  1. RS10198552
  2. RS4954192
  3. RS6430538
  4. RS6430553
  5. RS6710823

NADH: ubiquinone oxidoreductase (Complex I) Converts NADH to NAD+

These are genes that make enzymes which convert NADH to NAD+ in the mitochondria.

  1. RS11548670 (NDUFS1)
  2. RS1156044 (NDUFV2)
  3. RS11663316 (NDUFV2)
  4. RS12457810 (NDUFV2)
  5. RS7407664 (NDUFV2)
  6. RS7637404 (NDUFV2)
  7. RS906807 (NDUFV2)
  8. RS1142530 (NDUFS7)
  9. RS11666067 (NDUFS7)
  10. RS7258846 (NDUFS7)

SelfDecode has these genes and SNPs. If you would like to learn about your SNPs, get a 23andme DNA test and upload your raw data to SelfDecode.

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25 COMMENTS

  • twhite48

    What about the similarity of superficial and possibly metabolic effects of beta-alanine, niacin/nicotinic acid and this NAD+ booster?

  • Mohamad

    Can i use nad in alzheimer treatment

  • Austin Enty

    Don’t you guys think it is interesting that the Keto Diet is also used for reversing diabetes in some early conditions and it also promotes NAD+? It makes you think that maybe everything we thought about nutrition is wrong.

    1. Austin Enty

      Also, after doing a bit of research on products I really found that this one worked pretty well for most people so I did a review on it. Let me know what you think.

      [NADforeveryoung]

    2. Peter Rutkiewicz

      Ketosis is the default and natural condition that uses fats as the principle energy source and not glycogen or carbohydrates. We have very little carbohydrate stores in our bodies and extra carbs (easily exceeded in a single meal) gets converted and stored as fats. Fats are nature’s storehouse for energy under the most demanding conditions (Whales, bears, deer, seals, penguins and birds demonstrate this with monster migration patterns and long periods of fasting). The second storehouse is the amino acids in the muscles. Ketosis uses fats while amino acids are gradually introduced to supplement as fats stores are depleted. When the fat stores become very low, catabolism deepens and muscles rapidly give up their stores. If arrested soon enough, it is relatively without harm. If it continues, the catabolism can threaten the health of the organism. This can be observed with the outcome of imposed starvation so common in World War 2: the wasting away of the muscles followed by internal organ damage.

      Three square meals a day is a creation of the food industry and a political policy to help consume the surplus of food that the United States easily produces. We really don’t need all those calories but nutritionally, several RDA recommendations are too low, particularly in vitamin D and vitamin B12, and to a lesser degree in A, C and certain B vitamins. This is demonstrated by the fact that nutrient rich diets and supplementation improves the health issues of many patients. Some diseases are related both directly and indirectly to deficiencies because some individuals simply require a lot more than the RDA to have optimal health.

  • Sam

    As good as it may sound, this supplement has not been tested on humans. (now resveratrol is useless according to the studies, not 10 years ago people raved about it….http://www.health.harvard.edu/blog/diet-rich-resveratrol-offers-health-boost-201405157153

    Further, NAD+ may increase some forms of cancers, just like telomeraze, you want to have balance

    According to J Chem Inf Model. 2016 May 23;56(5):843-53, “NAD concentrations are known to be significantly increased in several cancers, particularly in glioma, consistent with the observation of up-regulation of several enzymes of the network. “

    1. Nattha Wannissorn

      You are right. It’s not a panacea and there are tradeoffs to increasing it. Upregulating NAD+ in cancer cells is different from throughout the body, though.

    2. Peter Rutkiewicz

      I have seen and read of anecdotal evidence of resveratrol being used daily for decades and prolonging the life of patients. Since it was oncologists making the claim that resveratrol is helpful to people with terminal cancer, it makes logical sense not to wait for “test results” and proceed with supplementation. Moreover, in the matter of cancer and all disease prevention, medical experts (doctors) at the cutting edge have criticized the RDA of 400 IU of vitamin D as woefully inadequate and recommend vitamin D3 at the rate of 2000 to 5000 IU PER DAY since it has been found in studies that lower levels of vitamin D shut down certain genes that are concerned with the immune system, particularly those involved with tumor suppression. Haven’t read of a single case of vitamin D causing anyone a problem yet and I’ve been at the 2000-5000 IU level for 3 years. Nasal congestion for a few days is the most I’ve experienced. I don’t get flu or pneumonia shots and with 7 school age grandchildren that I see several times a week, I’m pretty exposed.

  • Dan B

    Can you elaborate on this: “on the other hand, Nicotinamide blocks Sirt1 activity) (R).”

    So is it a bad idea or not to take NR?

    1. Nattha Wannissorn

      Nicotinamide is a different thing from NR.

  • Josh Fitzgibbon

    Hi Selfhacked, I have noticed you mention positive effects of fructose a lot however there is evidence it causes advanced glycation end products. Quite conflicting!

    1. Nattha Wannissorn

      There are pros and cons to everything.

  • twhite48

    Good source of information with leads and clues to learn more.
    My impression is that for most people hypoglycemia is a short term consequence of hyperglycemia but in “ketogenic” adapted people fasting does not cause hypoglycemia.
    What about HMB effects relative to NAD+ etc.

  • Ev

    This sounds like a creating a gradient or ratio of Nadh to nad plus based on your personal needs and genetics. Is there a rule that you always have to have a greater nad plus level to be maximal or efficient.

  • Tara Smith

    Tons of good information on here!! I work with The NAD Treatment Center in San Diego, and they are using NAD to detox addicts along with other chronic conditions. Supplementing with stabilized NADH and NAD precursors can be effective depending on the situation, but it just doesn’t compare IV NAD.

    1. Harris Willams

      Tara if you notice NO where on this page does it state to take NAD directly now does it? I’ve talked to several Ph.D biochemist who state taking NAD supplement via IV does NOT enter the mitochondria to increase ATP. You IV clinics are spin offs from the Quack William Hitt who ran to Mexico because the state of Texas busted him for fraud. Also tell me do you NAD IV clinics measure NAD levels or neurotransmitters BEFORE and AFTER treatment or are you just relying on what the Junkies say how they feel? Do you measure CoQ10 levels at all? But yet you charge $1000-1300 a day!

      “California attorney Jenelle C Prins, who has investigated Hitt, reports that “William Hitt does not have any undergraduate or medical degrees. In 1987 he was sued by the State of Texas, Case No 87 27882, for fraudulent practices. In sworn documents filed with the court, he admitted that he had no degrees of any type (except for one from what Hitt called ‘a paper mill’, known as Walden College).” Prins reports that the University of Colorado, where Hitt once claimed to have been awarded an MD in 1952, “has no record of him”.
      And what of that Nobel Prize? Hitt claims to have won the Nobel Peace Prize while a member of the International Physicians for the Prevention of Nuclear War. This is false, she says.
      The International Physicians for the Prevention of Nuclear War corresponded with me and stated that Hitt had never been a member. Hitt has recently changed his story to say he was a member of the Mexican delegation to the International Physicians et al, but I checked this claim as well and it is also false.”

      Hitt claims to have won a “prestigious Eli Lily Award and several other awards. “I called Eli Lily and spoke with a woman there who researched Hitt’s claim,” says Prins. “First, Eli Lilly does not give out a prize. They do, however, provide grants, but no grant was ever awarded to Hitt.”
      “We learnt of his falsity when one of my clients returned from treatment for Hepatitis C in Mexico,” says Prins. “When she went to her regular doctor to check her viral load, her levels were higher than when she went to Mexico.” Prins says that in this and several other cases, “Hitt doctored test results”…”

      The James Randi Educational Foundation

  • Sam

    Hi Joe,

    from your references on Malic Acid, it states:”Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction.”

    What do you take from it?

  • ravstr

    thanks for this. is there a way to measure NAD+ (or Nicotinamide) via blood test?

    1. Nattha Wannissorn

      You can technically measure it in the blood but most of it is in the cells and mitochondria.

      1. ravstr

        gotcha, thanks. If I can follow up – what would be your recommendation on how to go about testing NAD+? been wanting to check nad levels for sometime now, no luck so far.

        1. Nattha Wannissorn

          There is no way to test it directly because their levels are different in various parts of the brain. It’s very tricky unless you want to use radioactive stuff. If you run an organic acids test (e.g. with Genova), you might be able to see how well the mitochondria is functioning from the metabolites and that’s a good surrogate marker for NAD+ levels in combination with the symptoms.

        2. Harris Willams

          This Doctor in the UK does mitochondrial testing

    2. Harris Willams

      The South Africans have been testing blood levels for years but like Nattha states what’s in the blood really isn’t the issues it’s what’s in the mitochrondria that counts. So if it’s true that NAD supplements do NOT cross the inner membrane of the mitochondria then measuring blood levels would be irrelevant now wouldn’t it?

      “All of this could be assessed just after birth by two simple blood tests (the biochemical indicators of NED): the lactate and pyruvate tests and the lactate/pyruvate ratio. NED can be successfully addressed by NAD therapy and the nutriceutical supplements involved.

      NAD Levels can be Measured.

      “Measured enzymatically in blood or CSF as an index of impaired pyruvate metabolism due to defects of glucose oxidation (fed state) or gluconeogenesis (fasted). The ratio of lactate to pyruvate reflects the NAD/NADH ratio and is useful in distinguishing primary defects of pyruvate metabolism from defects of electron transport (or oxidation)”. (The Center for Inherited Disorders of Energy Metabolism (CIDEM) at Case Western Reserve University (CWRU) School of Medicine, Cleveland, Ohio, is a group of inter-disciplinary, specialized laboratories which focus on disorders of mitochondrial function).

      The Lactate and Pyruvate blood tests are available from most Labs.

      The formula to calculate the patient’s NAD Level is as follows: (Pyruvate test value x 1000) divided by the Lactate test value. A result of 100+ indicates a Normal NAD Level. The Average NAD Energy Block of diabetic patients is 64 instead of 100+. The average were calculated based on the results of a substantial number of blood tests done independently by major South African Labs Ampath and Lancet. “

  • Adam Rummler

    Would you supplement with both NAD+ and NADH?

  • T

    Ozone also increases nad+, no?

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