Researchers have found that using supplementation with NMN, NR and NAD+ to restore levels of NAD+ in mice make them look and behave like they did when young and extends their lifespan significantly.
Although they have similar effect in some organs, it seems there are differences in the effect they have in other tissues throughout the body.
NAD+ crosses the blood brain barrier to increase NAD+ in the hypothalamus to increase energy expenditure and decrease hunger. (more below).
Administration of LABELED NAD+ by IP and IV injection of just 1 mg/kg a day demonstrated that exogenous NAD+ crosses the blood brain barrier to enter the hypothalamus INTACT, reduces hunger and weight gain, and increases energy expenditure and fat burning in mice.
They also show that NR and NMN can not utilize the cd43 gap to cross the blood brain barrier.
This might explain why In humans, NAD+ clinics have found success treating addictions and other brain imbalances, but NR and NMN have not been used in similar fashion.
Below are some of the disease and illnesses that we believe NAD+ supplementation is more effective for than NMN.
- Chronic fatigue
- Weight control
- Mood disorders
- Alcohol and drug addiction
Research has also shown NAD+ supplementation to be effective for the following conditions (more here).
- Protects against liver damage
- Multiple Sclerosis autoimmune-related neurodegeneration
- Heart disease
- Heart damage from stroke
- Brain damage from injury
NMN shows a particular ability to restore vascular growth and benefit tissues such as muscle and heart that haven’t been replicated in studies with NR or NAD+.
Below are the three studies that made the biggest splash’s about the potential for reversing aging by restoring NAD+ to youthful levels that have ALL been accomplished using NMN
After 6 days of NMN, 22 month old mice had the muscle capacity, endurance and metabolism of 6 month old mice (2013 Sinclair study)
NMN effectively mitigates age-associated physiological decline in mice (2016 Mills Long Term study)
“The old mice became as fit and strong as young mice” (Sinclair, 2018)
The third study identifies the key cellular mechanisms behind vascular aging and the critical role it plays on muscle health.
Dr Sinclairs team fed NMN to old mice. After two months, the mice had increased muscular blood flow, enhanced physical performance and endurance and the old mice became as fit and strong as young mice.
NEW BLOOD VESSELS sprouted within the skeletal muscles, capillary density increased and matched the capillary growth of young mice.
- NMN restored the vascular system of old mice to that of young mice.
- Mice treated with NMN had had nearly 100% increased endurance.
Renewed capillary growth and increased blood flow may help reverse heart and neurological problems in addition to sarcopenia.
According to Dr. Sinclair, the same mechanism could spur the creation of blood vessels in the brain, where “the lack of oxygen and buildup of waste products sets off a downward spiral of disease and disability,” such as Parkinson’s and Alzheimer’s.
Poor Bioavailability from Capsules
NAD+ not effective in drinking water or in capsule form
The NAD+ molecule is twice as large as NR or NMN, and is totally degraded in the Gastro-Intestinal tract, so researchers do not use NAD+ in drinking water of mice and it is not sold in capsule form for humans.
NAD+ in IV or IP injections
Research has been successful using NAD+ injections in mice.
In humans, clinics that provide NAD+ by IV are exploding in popularity, even though they charge over $1,000 a day and require the patient to be hooked up to a drip IV for 8 hours.
NMN and NR poor bioavailability in capsules
NMN and NR capsules are only partially digested in the stomach, but are almost totally metabolized in the liver and excreted as NAM (Liu, 2018).
Sublingual delivery solves the bioavailability problem
Molecules like NMN, NR and NAD+ that have low molecular weight and are hydrophilic can be absorbed through the capillaries under the tongue directly into the bloodstream. This is called Sublingual (under the tongue) delivery.
This solves the bioavailability problem of capsules that get digested in the stomach, so NAD+ can be used instead of NAD+ precursors. It also greatly improves the effectiveness of NMN.
Why no sublingual NR?
NR is not stable by itself (see below) , so Chromadex adds Chloride to make it stable.
ALL NR sold is actually Nicotinamide Riboside CHLORIDE
Unfortunately, the taste is not acceptable for sublingual use.
So NR is only available in capsule form, which much pass through the stomach and liver where it is metabolized to the less effective Nicotinamide (Liu, 2018) .
NR is NOT STABLE and not found in blood plasma
In both mice and humans, studies repeatedly failed to find any NR in the blood plasma at any time, even after very high dosages of NR (97, 98, 99) NR has been found at trace levels in inside blood cells.
The following quote from this Dr Brenner study also did not find NR in bloodstream after oral supplements, but was found in trace amounts after Injection.
NR varied and displayed no response to NR administration… but was detected after IP of double labeled NR.
When added to blood plasma in the lab, NR is unstable and quickly deteriorates to NAM (Canto,Brenner 2016).
∼10% of NR degraded after 10 min and ∼66% degraded after 1 h (Fig. 8e), which is further illustrated by gradual increase in NAM abundance in the samples (Fig. 8g).
NR is quickly taken up by cells and elevates NAD+ in the liver, but is not found outside the liver in blood plasma. This implies much of the overlapping benefits of NR with NMN and NAD+ are due to the increased NAD+ created in the liver.NR increase in NAD+ limited by HOMEOSTASIS
The Liver is the “engine” that supplies the great majority of NAD+ to the rest of the body (Liu,2018).
In the Trammel thesis, Dr Brenner consumed 1000 mg of NR. At day 1, his NAD+ was increased by 270%.
The Elysium study used 500 mg of NR per day (plus pterostilbene). NAD+ was increased in blood plasma by 90% at 30 days, and dropped to 55% at 60 days.
The authors of the Elysium study believe that homeostasis limits the maximum increase in NAD+ that can be sustained over the long term.
High levels of NAD+ can induce homeostatic mechanisms to restrain further increases.
This may explain why those taking NR capsules often report increased energy, which seems to fade after some time. Homeostasis has brought their NAD+ levels back down and the hypothalamus isn’t getting the message to increase metabolism as it did back on day 1.
While 50% increase is helpful, keep in mind that as we age, our NAD+ levels drop in half. So the average person would need to DOUBLE their NAD+ levels – a 100% increase – to reach the levels they have in youth.
- Sublingual delivery is required for all NAD+ metabolites and precursors to avoid digestion in the stomach and liver.
- NAD+ clinics use slow drip IV of NAD+ to avoid the stomach and liver. They are exploding in popularity, but the extreme cost and time required for treatment severely limit their application for the general public.
- Sublingual NAD+ delivery solves the bioavailability problem and mimics the slow drip delivery used successfully by NAD+ IV clinics.
- Sublingual NAD+ is not subject to the homeostasis that limits NAD+ increase with NR (and perhaps NMN), as it is supplied directly to the bloodstream.
- We believe the ability of NAD+ to increase metabolism through the hypothalamus has a great impact on the entire body. This is accomplished directly from increased NAD+ circulating in blood plasma, and not from NMN or NR.
- Other organs such as heart, liver, kidney, and lungs also clearly benefit from increased circulating NAD+, but there is evidence NR an NMN may have similar effectiveness.
- Exogenous NR increases circulating NAD+ levels, but after several weeks, that increase is severely limited by homeostasis.
- Exogenous NMN elevates NAD+ levels similar to NR, but seems to be less limited by homeostasis. Publication of recently completed research should shed more light on that question.
NMN demonstrates a remarkable ability to rapidly restore vascular growth that has not been shown with use of NR or NAD+.
Sublingual NAD+ will lead to a greater increase in circulating NAD+ than NR or NMN supplements.