NAD FAQ’s – Frequently Asked Questions about NAD+

Research

NMN was able to mitigate most age-associated physiological declines in mice Treatment of old mice with NMN reversed all of these biochemical aspects of aging

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (mills, 2016)

Raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

Restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

DNA Repair

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation

The cells of old mice were indistinguishable from young mice after just one week of treatment.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

WEIGHT

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

Administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NAD(+) levels were increased significantly both in muscle and liver by NMN

NMN-supplementation can induce similar reversal of the glucose intolerance

NMN intervention is likely to be increased catabolism of fats NMN-supplementation does mimic exercise

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN reduces vascular oxidative stress

NMN treatment normalizes aortic stiffness in old mice

NMN represents a novel strategy for combating arterial aging

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

ENERGY

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

Restoration of cardiac function and energy metabolism upon NMN supplementation

Remarkable decrease in whole-body EE and cardiac energy wasting

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

VISION

Exogenous NMN prevents photoreceptor degeneration and restores vision

NMN rescues retinal dysfunction in light-induced degeneration

 

NAMPT-mediated NAD+ biosynthesis is essential for vision in mice (lin, 2016)

Clinical Studies with NMN

Completed and pending publication

Beginning 2018

  • 2018 Sinclair Metrobio study – Phase 2

The Phase 1 study by Dr Sinclair has been completed, and they are ready to go forward with the Phase 2 study, so we can conclude there were positive results, and no negative side effects, else they would have to publish those immediately.

In the University of Washington study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

  • change in beta-cell function
  • works to control blood sugar
  • blood vessels dilate
  • effects of NMN on blood lipids
  • effects of NMN on body fat
  • markers of cardiovascular and metabolic health

The active supplementation portion of this study has ended, but testing of metabolic parameters will continue for 2 years after supplementation has ended.  So researchers know the immediate effects and  preliminary results are expected to be announced in 2018, with  final results expected in 2020.
 

  • Are there any studies with Humans and NMN yet?
  • There have been at least 2 studies with humans completed. 1 in Japan, an 1 by Dr Sinclair at Boston university. It takes an average of 18 months to get results published from human trials, so we don’t yet have those results. But we know Dr Sinclair has already began Phase 2 testing with NMN. It would not be possible to fund, or get approval, for Phase 2 testing unless the Phase 1 testing was successful. There has been no phase 2 testing of NR yet, so NMN is moving ahead now.

  • Now that we know the Slc12a8 protein has recently been shown as a dedicated transporter to carry NMN across cell membrane – mostly in small intestine and liver, why do we benefit from taking NMN by Sublingual?
  • NMN doesn’t require Slc12a8 to enter cells. That is an alternate pathway that is specific for NMN and most prevalent in small intestine, liver, and pancreas.

    In some cells, NMN needs to lose a phosphate (be converted to NR) to enter. However, that does not impede it from entering.

    NMN uses a protein it finds readily available at the cell membrane to discard the phosphate.

    It is not really an impassible barrier to entry that Chromadex likes to portray, but more like a checkpoint. Maybe like you are at a friends house, and need to remove your shoes before entering.

    In a test tube, NR is faster to enter cells. But in vivo, it’s not. Taking in water or garage, they raise NAD+ in the liver nearly the same amount at the same speed.

    Taking either NR or NMN by sublingual dosage will be faster.

    Taking NMN sublingual puts 30% or so in the blood in minutes, where it can enter cells throughout the body. If you swallow a capsule of NR , it takes and hour or more to go thru liver before some very small % can reach the bloodstream.

    Any NMN that makes its way to the bloodstream from sublingual use is available to cells throughout the body to take up. The liver constantly filters blood, and will soon remove NMN from the blood, to convert to NAD, just as if it was from a capsule of NMN (or NR). So that portion of NMN will be taking a shortcut to the liver to be used there for NAD+, having avoided being digested to NAM in the GI tract.

    Now we know that with Slc12a8, some % of NMN can be converted to NAD+ in the small intestine, much quicker than NR from the liver. But we don’t know what % that is, and likely HUGE variation in it.

    The sublingual NMN gets the 30% to blood almost immediately, with some of the remainder as NAD in small intestine, and some eventually to the liver where we know it has no problem converting to NAD at nearly the same rate as NR.

    So in older people with active Slc12a8, you get 30% NMN in blood in minutes, x% in small intestine fairly quick, and the remainder ends up converting to NAD+ at similar or faster rate as NR.

    Read more here

  • Whats the difference in ingredients between powder and tablets
  • Thanks for your interest. We feel the powder is a bit more effective as it absorbed instantly, with none spreading out to other parts of the mouth and being swallowed.

    The tablets are more convenient to carry around and take throughout the day.

    We believe many doses throughout the day are key to achieving the best/fastest results, so the convenience of the tablets is important for some people.
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    If you will only take it a few times a day while at home, the convenience isn’t as important and the jars of powder are better.

    Actually, for most people the best answer is both. Powder in the morning, before bed, and whenever at home. Carrying the tablets for whenever you will be away from home for several hours.

  • Why 4-8 tablets instead of 2-4 like you used to recommend?
  • Sublingual tablets bypass the digestive system so more NMN can be absorbed optimally and deliver a lot more NMN directly to the bloodstream and on to other cells and tissues throughout the body. This delivery method is also more advantageous regarding your investment.

    NMN is an expensive product and cost will often be a factor in how much a user chooses to take. There is no required minimum dosage.

    2 sublingual tablets a day will provide more benefit than from 2 Capsules that are swallowed and digested in the GI tract, and is a good choice for cost effectiveness.

    We recommend what we feel is the maximum useful dosage so people can experience the maximum benefit – not a minimal dosage to make the product seem more affordable.

    We previously recommended a lower dosage as we weren’t sure how higher dosages were utilized by the body and did not want to encourage users to incur more expense than necessary for maximum effect.

    Now, more experience with sublingual usage has shown that smaller, more frequent dosages are more effective.

    Users find 4 dosages are noticeably better than the 2 times a day we previously recommended.

    Most users also find even more benefit from 8 times a day.

    So we encourage customers to try 4-8 dosages a day, but twice a day is a reasonable choice for cost effectiveness.

  • What is homeostasis – how does it effect NAD+ ?
  • The Trammel thesis, and Elysium study shows homeostasis limits the long term increase of NAD+ in the liver.

    In Trammel, Dr Brenner consumed 1000 mg of NR. At day 1, his liver NAD+ was increased by 270%.

    The Elysium study used 250 or 500 mg of NR per day (plus pterostilbene). Liver NAD+ was increased by 40 or 90% at 30 days, and dropped to 40 or 55% at 60 days.

    The authors of the Elysium study believe that homeostasis limits the maximum increase in Liver NAD+ that can be sustained over the long term.

    So, when taking capsules, 500 mg a day can increase liver NAD+ around 50%, and is about the maximum useful dosage.

    While 50% increase is helpful, keep in mind that as we age, our NAD+ levels drop in half. So if you have half the NAD+ as when you were young, a 50% increase would take you up to 75% of your youthful levels.

    We know that supplying NMN or NAD+ directly to the bloodstream bypasses the liver, so homeostasis that limits liver NAD+, does not limit the NAD+ levels in the bloodstream.

  • What happens if I stop taking a NAD+ booster?
  • As we age, we have increasing damage to our cells. Our bodies constantly repair the damage, but it is a constant battle. One analogy I use is that NAD+ are like the workers that repair roads and structures in a city.

    When we are young, we have plenty of NAD+, and the city is new, so there is no problem keeping up with the repairs.

    As we age, the roads and buildings deteriorate, and the limited number of workers (NAD+), fall behind in maintenance. Lower priority problems get skipped. More and more problems (disease) develop.

    You don’t get old in a day, week, or month. Having insufficient NAD+ levels over years leads to slow deterioration.

    Restoring NAD+ levels is like hiring more workers for your city. The most critical needs are addressed first. After that, lower priority tasks get done.

    Any repairs your body can make due to having more NAD+ do not disappear overnight, just as you don’t age in one day.

    You will probably find the increased energy levels you have from taking a NAD+ booster fade away over some days or weeks. Other benefits will take longer to disappear.

  • Why take some days off (cycle) NAD+ precursors?
  • 3 reasons we recommend this in our protocol:

    1. Homeostasis – The body adapts to everything and attempts to reach a balance. Taking precursors to boost your NAD+ levels higher may cause your body to slow down the recycling process.
    2. Downstream NAD+ metabolites – NAM and MeNam result from NAD+ consumption. The liver/kidneys will process them and get rid of excess amounts of both in the urine, but we think it is helpful to take a break to avoid buildup.
    3. Rest – Many users report greatly increased energy and endurance with NMN, and find they exercise a lot more. Some report getting a bit tired after a few weeks of such increased activity. This may be due to overtraining, or just getting less sleep. Stopping the NMN for a few days each week avoids this.

  • Why would I take NMN vs NAD+ or some other NAD+ precursor?
  • There are several other precursors the body can use to make NAD, such as NR, NAM, Niacin, and Tryptophan. Normally, they would all go through the liver and depend on the body normal process to manufacture NAD. That is the process that has not been able to keep up with the demand as we age.

    You can try to encourage the liver to produce more NAD, which is what oral supplementation of NMN, NR, and all other precursors do. But that route does bump up against homeostasis, which limits how much you can get outside the liver.

    The Liu study shows that CD38 breaks down NAD in the liver, and ONLY excretes NAM to the rest of the body (when using 50 mg/kg in mice). So it is very limited in ability to reach outside the liver.

    So the whole point is to take a shortcut around that process and supply NAD directly to more cells throughout the body.

    Providing NMN direct to the bloodstream via sublingual delivery is not the same as providing NAD+ direct to the bloodstream via sublingual delivery. They both can have an affect on some tissues, but perhaps not all. There is surely some overlap in their effect, but also some differences. It is surely different than dumping NAM, Niacen, NR, NMN, or NAD into the liver.

    The short answer is, NAD for brain, NMN for the body.

  • Why are you selling both NMN and NAD+ supplements?
  • If we KNEW that one was clearly superior for all health challenges, we would only offer that one, and nothing else.

    In 2017, we were by far the biggest seller of NMN capsules, but stopped selling that product because we believe sublingual delivery is 10x more effective and did not want to sell an inferior product, even though we could have made a lot of money by selling both.

    We are offering NMN and NAD+ now, because we believe they both will have unique benefits. We will have a more detailed article on the differences soon, but we’ll repeat the short answer here – NAD for brain, NMN for the body.

  • What about NADH – can I take that in place of NAD+ ?
  • NAD+ levels drop as we age. NADH levels do not. The ratio of NAD+ to NADH is the key, and benefits come from increasing that ratio.

    Increasing levels of NADH in the body are the exact opposite of what you want for health.

    It is easier to produce, so became popular over the last few years.

    It can provide an effect on mood, which is why some people take NADH, but is not good for your health – it is the opposite of what you want.

  • What about risk of faster cancer growth with NAD+ increase
  • Researchers have theorized that increased availability of NAD+ may aid growth of cancer cells.

    Of the hundreds of studies that supplied NR/NMN/NAD+ to mice, none yet have shown an increased incidence of cancer.

    Below are 2 recent studies that some people have pointed to that seem to show a possible link, along with our interpretation.

    Pathway linked to slower aging also fuels brain cancer

    This research showed that NAMPT is increased in that form of brain cancer, and that inhibiting NAMPT helps kill the cancer cells. They are not supplying NR/NMN/NAD+ to the bloodstream and seeing increased cancer/tumor growth.

    Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells

    High NMN and NAD+ concentrations were needed to counter the effect of syrosingopine-metformin treatment

    The observation that ATP levels can be partly restored by exogenous NAD+ or the NAD precursor NMN suggests that the cause of synthetic lethality is NAD+ depletion. This rescue requires supra-physiological concentrations of NAD+ and NMN

    This study used a combination of Metformin and syrosingopine to induce cancer cell death, and found lower NAD+ levels as a result. When they added massive quantity of NMN or NAD+, the drug combination was less effective at killing the cancer cells.

    This was not in the body, but in test tubes, and using quantities not found in the bloodstream.

  • Is your NMN or NAD+ FDA approved?
  • Our product are classified as dietary supplements, as are most other vitamins and supplements. In this category, the FDA will make sure the product is safe and manufactured in a safe way, but will not comment on efficacy, that’s up for the consumer to decide. So technically, “no”, but it’s not really a black-and-white issue like most people think.

    All of our products are manufactured in an FDA regulated facility and made in the USA. We have multiple tests at third party labs to ensure our product is the best quality. We take great pride in making the most safe and effective products possible. Products that are classified as dietary supplements cannot get FDA approval because they do not have claims. Rather, their production is overseen by the FDA.

  • What if I take NR, NAD+ and NMN ?
  • NR is not currently available in a sublingual form. NR capsules will go through the liver and use the bodies normal salvage pathway to produce NAD in the liver, and some will make it to the rest of the body.

    If you also take NAD+ and NMN sublingually, perhaps 30% of that sublingual NAD and NAM will make it direct to the bloodstream and be taken up by cells throughout the body, with different affinities for different tissues than what is supplied from the liver.

    We believe that NR, NMN, and NAD all have overlapping benefits. We also believe each have specific benefit for different parts of the body.

    The short answer is, NMN for the body, and NAD+ for the brain.

    One might provide more benefit to more tissues throughout the body, but you might also benefit from another NAD+ booster that reaches a different tissue more effectively.

    If you are looking for what is the “most bang for the buck”, we currently believe that is sublingual NMN.

    If your funds are not limited, it might be helpful to take all 3.

  • I have read that NR is the largest molecule that can cross the cell membrane, and both NMN and NAD+ must be degraded back to NR to enter cells directly – is this true?

  • – SEE BELOW – or full article here

     

    NAD+ DOES CROSS THE BLOOD BRAIN BARRIER AND ENTERS CELLS INTACT

     

    There are claims that both NMN and NAD+ are “TOO LARGE”, and cannot enter cells directly, but must first be broken down to NR.

    We recently wrote this article refuting that theory.

    On September 1 2018, more proof was published proving that NAD+ crosses the blood brain barrier, enters the hypothalamus INTACT, and raises NAD+ levels.

    Even better, just 1 Mg/kg a day decreased hunger, increased energy expenditure and fat burning for up to 24 hours after dosage.

    For reference, most research providing mice with NMN or NR in drinking water uses 300 to 400 Mg/kg a day.

    This study found both IV and IP injections had similar results. The results with 1-3 Mg/Kg by IP is extremely promising, as we note that sublingual delivery can be even more effective than IP delivery.