Study shows mice on NMN drinking water stay young, makes questionable dosing conclusion


A team largely comprised out of researchers from the Washington University School of Medicine conducted a 12-month-long experiment in which they administrated nicotinamide mononucleotide (NMN) to normal mice. They observed that the NMN stopped age-associated physiological decline in mice.

It is increasingly common knowledge that NAD+ availability decreases with age and is implicated in various diseases related to aging. Nicotinamide mononucleotide (NMN) is a so called NAD+ intermediate and it has been shown in various studies, like this one, to positively impact health. Nicotinamide riboside (NR) is another pre-curser which shows largely overlapping health benefits in studies. Brenner and other researchers demonstrated convincingly the link between NMN and NR.

The researchers in this study carried out a 12-month-long NMN administration study with regular (C57BL/6N) mice.  The study differentiates itself from other experiments with NMN due to the oral supplementation method (versus injection) combined with dosing levels that are somewhat realistic for human oral supplementation.  The two (mice) dosing levels used were 100 and 300 mg/kg/day. The feeding method was ad libitum (= as desired) in the drinking water. The supplementation started when the mice reached an age of 5 months and ended 12 months later at 17 months of age. To add perspective to this, mice are considered young adults when reaching an age of 2 months so the supplementation started at adult age and lasted into senior age.

In addition the researchers carried out an oral gavage supplementation experiment with three-month-old C57BL/6N male mice which contained NMN (300 mg/kg).

The notable finding in the oral gavage results is that the researchers report rapid rise, in minutes, in plasma NMN followed by a noticeable NAD+ increase in the liver after 30 minutes. At first sight this appears to be unique behavior for NMN because NR has been reported to reach its peak  impact on NAD+ after 7-8 hours (in humans). However that may not necessarily be the case. The following table comes from the Trammel dissertation work, it measures the increases of metabolities on a larger time interval as opposed to the very granular measurement in the NMN study:

non-zoom-capture-trammel-table-5-1

Zooming in on the first hour one can notice that there is also a marked increase in the metabolites in the first 1/2 hour after which there is a drop off:

zoom-capture-trammel-table-5-1

The other human study in the Trammel paper had a first measurement after 1 hour so the initial responses cannot be concluded from that. In the mice experiment in the Trammel paper it would seem that the first measurement is done after 15 minutes. The NMN paper shows that after 15 minutes the NMN peak is over and has returned to baseline level so nothing can be concluded from the 15 minutes Trammel measurement. On the other hand unfortunately the NMN researchers did not continue to follow the metabolites on a longer time scale so it is not clear whether a secondary effect and higher peak would also occur with NMN supplementation after several hours. In the recent interview given by Brenner he refers to a second stage increase as result of NR supplementation. While the above is speculative, and very possibly wrong, the author believes it is too early to conclude whether NR and NMN have different behaviors. It will be of interest to see whether either of the research groups will address this in future studies.

Moving on to the other findings.

In the study NMN suppresses age-associated body weight gain. The body weight reduction compared to control mice were 4% and 9% in 100 and 300 mg/kg/day groups, respectively. And at 12 months, the 300 mg/kg/day group tended to have a decreased fat mass and an increased lean mass compared to controls. This while NMN-administered mice were having a higher level of food and water consumption, the mice at the highest level dosing consumed the most (this is a sign of youthfullness). Somewhat inline with the body weight findings the researchers observed that after 12 months of NMN administration (mice were then 17 months old), the mice showed significantly improved insulin sensitivity compared to the control group.

Anti-aging effect were observed in gene expression. The long-term NMN administration reversed age-associated gene expression changes in a tissue specific manner. The researchers concluded that from comparisons in selected gene expressions at the start of supplementation versus later time points, as well as compared to younger and older control groups. They noted that 76.3%, 73.1%, and 41.7% of the selected genes that changed in the aging control mice in skeletal muscle, white adipose tissue (WAT), and the liver of control mice were not significantly altered in NMN-administered mice. Analysis (PCA) on the entire gene sets of skeletal muscle, WAT, and the liver showed that compared to aged control mice the NMN-administered mice showed a shift towards young mice. These comparison were done with the 300 mg/kg/day dosed mice. It was also found that immune function and inflammation were significantly upregulated in aged control mice, but not in NMN-administered mice.

From the gene study the researchers also suggested that some of the observed changes are supportive of increased mitonuclear protein imbalance. Inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins, has been shown to trigger the mitochondrial unfolded protein response and results in lifespan extension in C. elegans (worms). The mitochondrial unfolded protein response, is believed to impact longevity in similar ways across many species.

The study also looked into differences in age related health conditions in the NMN-administered mice versus control mice. The C57BL/6N mouse strain appear to carry a mutation that makes them more sensitive to age-dependent degradation of eyesight. All control mice showed the hallmark of this degradation which is many light-colored spots in their fundus (= interior surface of the eye opposite the lens and includes for example the retina). Two and four out of five mice at 100 and 300 mg/kg/day doses, respectively showed a dramatic reduction in these spots suggesting that NMN prevents this age-associated degradation. Tear production, which is known to decline with aging was also looked at. In the highest dosing at 300 mg/kg/day group it was comparable to the maximal tear production seen throughout the mouse lifespan. Also detected were increases in bone density in NMN-administered mice, again best results at the higher dose.

Then the impacts on energy metabolism. They measured oxygen consumption, energy expenditure and respiratory quotient. Oxygen consumption significantly increased in both 100 and 300 mg/kg/day groups. Energy expenditure also showed significant increases. The researchers noted a difference in the nightly behavior between the two NMN doses. Mice administered with 100 mg/kg/day NMN showed significantly higher hourly activity during the dark period, whereas mice administered with 300 mg/kg/day NMN showed improved but slightly lower activity. They also noted that the 300 mg/kg/day group exhibited decreases in rearing activity throughout the night period. Later in the conclusions the researchers somewhat suggest that the 300mg / kg / day dosing may thus be too high writing:
– “100 mg/kg/day of NMN improved oxygen consumption, energy expenditure, and physical activity better than 300 mg/kg/day.”
That seems a perhaps too far reaching conclusion. Figure 3E of the study would suggest that the 300mg / kg / day fed mice have an overall higher energy consumption and a nightly activity peak closer to the 6 month control group than the 100 mg / kg /day group:
energy-consumptionIn addition the study, as mentioned above, stated that the 300mg / kg / day fed mice consume the most food and have lowest body weight which also indicates a higher energy expenditure level. Overall NMN, at the highest dose, appears to have more pronounced  health impacts in the various experiments.

Using FDA specified guidelines  we can calculate the Human Equivalent Dose (HED) for the NMN diet given to the mice. Using this guideline 300mg/kg dosing in mice translates into a HED of approx. 24mg/kg. Or into approximately 1.7g daily NMN dosing for a person weighing 70kg.  For the lower dosing of 100mg / kg that translates into approx. 560mg daily dosing.  To stay in sync with the study this should be taken multiple times a day.

Overall the study is extremely encouraging that boosting NAD+ may indeed be an effective anti-aging strategy and highlights the potential of NMN. More clarification on the NAD+ boosting effects of NMN are however needed. Is it really only a very short term booster which would mean it needs continuous supplementation? Ontop NMN has still a distance to go to becoming a widely available supplement at affordable prices. That combined with this study suggesting that NR is more effective than NMN means, in the view of the author of this blog, that nicotinamide riboside is currently the best available NAD+ booster for consumers.

You can find the study here.

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