NMN boosts NAD+ and prevents physiological decline in Mice

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This study published October 27 is the first to measure the effects of long term supplementation to increase NAD+.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

Researchers treated regular chow-fed wild-type mice for 12 months with two different doses of Nicotinamide Mononucleotide (NMN).

NMN was supplied in the drinking water, which is sipped throughout the day at dosages of 100 or 300mg/kg of bodyweight per day (vs control group).

According to the FDA guidelines  dosages would equate to 560 or 1700 mg daily for a 70kg human.

Testing several different measures of physical performance and health of subjects as they aged showed 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 authors concluded that supplementation to increase NAD+ may also be an effective anti-aging treatment in humans as well.

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ABOUT NAD+

Nicotinamide Adenine Dinucleotide (NAD+) is in every cell of our bodies, and is crucial for proper functioning of the mitochondria that power all activity in our cells.

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)

ORAL SUPPLEMENTATION OF NMN RESULTS IN QUICK SPIKE IN NAD+

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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.

LONGER TERM EFFECT ON NAD+ LEVELS

single dose experiment
In the single dosage experiment chart 1A above, NAD+ levels more than double and appear to be still rising at 30 minutes.

Unfortunately, this single dose experiment did not measure NAD+ metabolites over a longer period of time, so we don’t know how long the NAD+ levels remain elevated.

long term experiment

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In the long term experiment a significant increase in NAD+ is detectable in the liver and some fat tissue (BAT-Brown Adipose Tissue) as shown in chart E.

However, despite the relatively high daily dosage supplied continuously throughout the day, NAD+ levels were not significantly increased in blood plasma, skeletal muscle, nor other fat tissue (white adipose tissue – WAT).

Different than Nicotinamide Riboside (NR) effect on NAD+
This seems to indicate a different behavior than that shown in research on supplementation with NR. The chart below from Samuel Trammels recently published PHD research with Dr Brenner show blood plasma NAD+ levels are significantly elevated 24 hours after a single dose.

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Perhaps much of the NMN is consumed and/or converted to other metabolites of NAD+, but again, we don’t know since this research doesn’t measure all the metabolites that the Brenner team does.

Daily dosage of NMN resulted in increase NAD+ levels in Liver and some fat tissue.

Unlike supplementation with NR, no long term increase blood plasma NAD+ was recorded

LOWER FAT AND INCREASED LEAN MUSCLE MASS

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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

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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

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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.

DOSAGE

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.

CONCLUSION

This longterm NMN study indicates the importance of NAD+ decrease as a common trigger of age-associated physiological decline, and the possibility that supplementation to increase NAD+ can ameliorate some of this decline.

Some questions remain about the NAD+ boosting effect of NMN. Even with continuos supplementation it does not appear to significantly raise blood plasma circulation NAD+ levels.

This quote below from the Trammel PHD work on NR and NAD+ proposes that NR is more effective than NMN at boosting NAD+

NR contributed to the intracellular NAD metabolome more rapidly than NMN and increased NAD+ by more than 2 fold after 24 hours, indicating NR is kinetically superior to NMN

These points seem to indicate that NR is the most attractive NAD+ booster at present.

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.