In 2012, Research published by Dr Sinclair of Harvard stunned researchers by showing that short term supplementation with Nicotinamide Mono-Nucleotide (NMN) reversed many aspects of aging, making the cells of old mice resemble those of much younger mice, and greatly improving their health.
“treatment of old mice with NMN reversed all of these biochemical aspects of aging”
NMN was able to achieve this remarkable transformation because it is a “precursor” to the Co-enzyme Nicotinamide Adenine Dinucleotide (NAD+) which is in every cell of our bodies, and is crucial for proper functioning of the mitochondria that power all activity in our cells.
“raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse”
As we age our levels of NAD+ drop significantly in multiple organs, such as pancreas, adipose tissue, skeletal muscle, liver, skin, and brain (1), which is thought to be a major factor in many age related diseases, and perhaps even a key factor in why we age (2)
LONG TERM STUDY DEMONSTRATES MORE BENEFITS WITH NMN
This study published October 27, 2016 is the first to measure the effects of long term supplementation with NMN to increase NAD+.
Researchers treated regular wild-type mice for 12 months with two different doses of Nicotinamide Mononucleotide (NMN) supplied in their drinking water and compared various markers of health vs those of mice in a control group.
Testing revealed that NMN does indeed prevent physiological decline in mice, noting these changes:
- Decreased body weight and fat
- Increased lean muscle mass
- Increased energy and mobility
- Increased oxygen consumption and respiratory capacity
- Improved insulin sensitivity and blood plasma lipid profile
- Improved visual acuity
- Improved bone density
- Is well-tolerated with no obvious bad side effects
Based on this and prior research, the authors concluded that supplementation to increase NAD+ may also be an effective anti-aging treatment in humans as well.
According to the FDA guidelines, the dosages used would equate to 560 or 1700 mg daily for a 70kg human.
ORAL SUPPLEMENTATION OF NMN RESULTS IN QUICK SPIKE IN NAD+
Prior to the long term testing, researchers carried out single dosage experiments. Mice were given NMN in water by oral gavage at dosage of 300 mg/kg of body weight, after which levels of NMN in blood plasma and liver were measured at 2.5, 5, 10, 15, and 30 minutes.
NMN level in blood showed a rapid rise at 2.5 minutes to 10 minutes, then back down by 15 minutes.
Levels of NAD+ in liver showed a more gradual increase between 15 and 30 minutes.
These test confirm that oral NMN supplements are absorbed and quickly converted to NAD+ in blood and major tissues.
LOWER FAT AND INCREASED LEAN MUSCLE MASS
Researchers assessed a variety of physiological, biochemical, and molecular parameters in control and NMN administered mice.
They found that NMN administration significantly and dose dependently suppressed age-associated body weight gain (Figures 2A and 2B).
The average numbers of percent body weight reduction normalized to control mice were 4% and 9% in 100 and 300 mg/kg/day groups, respectively.
This suppressive effect of NMN on age-associated body weight gain became more evident by plotting body weight gain in each group (Figure 2B).
At 12 months, the 300 mg/kg/day group tended to have a decreased fat mass and an increased lean mass compared to controls (Figure S1F).
NMN-administered and control mice did not show any recognizable difference in body length (Figure S2A). Interestingly, when mice became older, NMN-administered mice were able to maintain higher levels of food and water consumption in a dose-dependent manner compared to control mice (Figures 2C and 2D).
These results confirm that the effect of NMN on body weight was not due to a growth defect or loss of appetite.
Furthermore, analyses of blood cell counts (Figures S2B–S2E), blood chemistry panels (Figures S2F–S2W), and urine (Figure S2X) did not detect any sign of obvious toxicity from NMN at either dose.
No statistical difference was detected by the log-rank test in survival of mice over the entire intervention period between control, 100 and 300 mg/kg/day NMN-administered mouse cohorts.
No obvious differences were observed for the causes of death, which included urinary tract obstruction, thrombosis, and myocardial infarction, between control and NMN-adminis-tered mice (Figure S3A).
These results suggest that NMN administration can significantly suppress age-associated body weight gain in a dose-dependent manner in regular chow-fed mice, without showing any serious side effects during the entire 12-month intervention period.
INCREASED OXYGEN CONSUMPTION AND RESPIRATORY CAPACITY
Oxygen consumption, energy expenditure, and respiratory quotient were measured at the 6- and 12-month time points for control, 100, and 300 mg/kg/day NMN-administered mice (Figures 3A–3E).
Oxygen consumption significantly increased in both 100 and 300 mg/kg/day groups during both light and dark periods (Figure 3A). Energy expenditure also showed significant increases through 24 hr in the 100 mg/kg/ day group and during the light period in the 300 mg/kg/day group (Figure 3B).
Respiratory quotient significantly decreased in both groups during both light and dark periods (Figure 3C), suggesting that NMN-administered mice switched their main energy source from glucose to fatty acids. Body temperature did not significantly change, although NMN-administered mice occasionally showed a tendency of higher body temperatures (Figure S3B).
Interestingly, whereas oxygen consumption and energy expenditure significantly decreased, particularly during the dark period, from 6 months to 12 months in control mice, mice treated with NMN for 12 months were able to maintain both oxygen consumption and energy expenditure close to those of control mice at 6 months after NMN administration (Figures 3D and 3E).
Taken together, these results strongly suggest that NMN has significant preventive effects against age associated impairment in energy metabolism in regular chow-fed wild-type mice.
INCREASED ENERGY AND ACTIVITY LEVELS
General locomotor activity in control and NMN-administered mice were measured at 12–15 months of age. Ambulations (whole-body movements) and rearing (vertical activity) were measured (Charts F and G).
Compared to control mice, mice administered with 100 mg/kg/day NMN showed significantly higher hourly ambulations during the dark period, whereas mice administered with 300 mg/kg/day NMN showed slightly lower ambulations (Chart F).
In rearing activity, there was no significant difference between control and 100 mg/kg/ day groups. However, the 300 mg/kg/day group exhibited decreases in rearing activity throughout the dark period. (chart G)
NMN administration can stimulate energy metabolism and general locomotor activity in aged mice, however the lower dose appears to have been more effective.
There were conflicting indications on the most effective dosage in this research.
300 mg/kg/day was more effective for body weight gain, insulin sensitivity, tear production, and bone mineral density.
100 mg/kg/ day improved oxygen consumption, energy expenditure, and physical activity more.
It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period, suggesting the long-term safety of NMN.
NMN SUPPLEMENTATION VS NR
DAMAGED CARDIOVASCULAR SYSTEMS TO NORMAL WITH NMN, BUT NOT NR
“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “
“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”
REPAIRS DNA DAMAGE
Dr Sinclairs team also published research in Mar 2017 that 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.”
NMN vs NICOTINAMIDE RIBOSIDE FOR BOOSTING NAD+
Both NMN and Nicotinamide Riboside (Niagen) are being investigated for their ability to increase NAD+ levels and provide a wide range of health benefits.
The long term NMN study detailed here along with others demonstrating positive results for humans and animals with NMN and NR clearly indicate the importance of NAD+ decrease as a common trigger of age-associated physiological decline, and the likelihood that supplementation to increase NAD+ can ameliorate some of this decline.
They are both precursors to NAD+, and also to each other. NR is phosphorylated to NMN (r), then NMN is converted into NAD by NMNAT1-3 in the bloodstream, as well as inside the mitochondria in our cells.
The case for NR
Nicotinamide Riboside has been sold commercially since 2014 as Niagen.
Chromadex has bought 7 patents related to the production and usage of NR from Universities and tightly controls the supply of Niagen. They fund most of the research on NR.
Dr Charles Brenner discovered Nicotinamide Riboside back in 2005, and is one of the leading researchers evaluating NR as a supplement for boosting NAD+ in humans. He is an advisor to Chromadex and owner of the retail brand Chromadex uses to market NR.
As depicted in the image, it is NMN > NR (enter cell) > NMN > NAD+. This would SEEM to favor NR, but we do not have a good consensus on this question, and Dr Brenner clearly has reason to prefer NR over NMN.
The Trammel PHD work on NR and NAD+ that Dr Brenner oversaw seems to show NR is more effective at raising NAD+ levels comparing mg per mg of NMN.
Both NMN and NR have had numerous studies with mice demonstrating benefits.
For NR, there have been 2 completed and soon to be published studies with humans, and 3 more ongoing.
The case for NMN
Dr Sinclair has favored NMN for use in raising NAD+ levels in his research, but he has been careful to mention both compounds as potentially useful(r).
NMN is not patented, and does not have a publicly traded company like Chromadex funding research on it, which may be why the commercial market for it has been slower to develop thus far.
In late 2016, NMN first became available as a commercial product but was prohibitively expensive as it is difficult to manufacture. It is rapidly coming down in price now and likely to be similar to NR pricing soon, or possibly even lower as it is not patent protected.
Fans of NMN such as Dr Sinclair claim that since NR must first be converted to NMN, it is more efficient to supplement with NMN as it is only 1 step away from NAD+.
The studies on Freidrichs Ataxia mentioned above seem to favor NMN, as it was able to restore cardiac function, whereas NR did not work in a similar experiment.
2 studies exploring the benefits of NMN on human subjects are just now getting started.
However, NR and NMK are two distinct NAD+ precursors and additional research may find that effective interventions for age-associated physiological decline include some combination of NMN and NR.
CONCLUSION – WHAT WE KNOW NOW
I believe bringing NAD+ levels back up to what they were in our youth can reverse many age related health problems.
We don’t yet know how much can be achieved thru taking one or more supplements to raise NAD+.
It’s quite likely NMN and NR will be part of the answer, along with other supplements to lower the inflammation that consumes more and more NAD+ as we age.
It’s also likely that other supplements to stimulate AMPK and NAMPT production, which increases production of NAD+, will also be a complementary therapy.
We DO KNOW, that exercise (particularly HIIT) stimulates AMPK and increases NAD+.
We DO KNOW that lowering glucose and insulins levels lowers inflammation and increases NAD+.
We DO KNOW that a Ketogenic Diet is particularly effective at lowering inflammation and increasing NAD+
We DO KNOW that intermittent fasting is very effective at lowering inflammation and increasing NAD+
We DO KNOW that exercise while fasting is even more effective that either one alone at increasing NAD+.
So, yes, we believe NMN is effective at raising NAD+ levels, but is far more effective when combined with Ketogenic Diet and HIIT.