Published: 1:45 p.m. PST May 10, 2022 | Updated: 1:05 p.m. PST May 18, 2022
- Healthy human subjects who took two 125 mg doses of NMN per day for 12 weeks nearly doubled their whole blood nicotinamide adenine dinucleotide (NAD) levels.
- No adverse physiological side effects, such as altered body weight or elevated blood pressure, were observed following NMN supplementation.
- Whole blood NAD+ levels plateaued after four weeks of NMN usage and persisted for the 12-week duration of the study.
Healthy aging has become a keynote topic as the world’s population grows older and the proportion of elderly individuals becomes larger. Known as the “silver tsunami,” the number of individuals over the age of 60 is expected to double by 2050. Accumulating research from the last 10 years or so suggests that enhancing cell energy production with NAD+ precursors, including NMN and nicotinamide riboside (NR), prevents the waning organ and tissue function associated with aging. Furthermore, scientists are seeking to confirm whether these precursors effectively increase blood concentrations of the essential molecule NAD+.
Published in Frontiers in Nutrition, Nakagawa and colleagues recently demonstrated that in healthy humans between 22 and 64 years old, NMN substantially increased blood NAD+ levels with oral usage of 250 mg per day. Blood NAD+ levels almost doubled and plateaued at approximately four weeks of usage and were sustained for the 12-week duration of the clinical trial. No negative blood measurements pertaining to blood fats, white blood cell counts, or liver function markers were observed after four weeks of NMN supplementation. No adverse effects on body weight or blood pressure were seen, either. What’s more, elevations in heart rate were strongly correlated with increased whole blood NAD+ levels, indicating that a higher heart rate facilitates the metabolism of NAD+, leading to greater NAD+ levels.
“We demonstrated that taking 250 mg of NMN every day for 12 weeks is a safe and well-tolerated practice in healthy individuals,” stated Nakagawa and colleagues in their publication. “These results suggest that the oral administration of NMN is safe and can be a practical strategy to boost NAD+ levels in humans.”
Nakagawa and colleagues looked at the NAD+ and NMN levels in whole blood measurements during the 12-week time course of NMN administration. The researchers found that NAD+ levels nearly doubled from over 20 µM to almost 45 µM concentrations in blood after four weeks. These blood NAD+ values plateaued to about week 12 and then expectedly dissipated after four weeks of stopping NMN supplementation. Moreover, the levels of NMN itself in blood showed no differences compared to subjects who did not receive NMN, suggesting that cells almost completely metabolize NMN from the blood. These findings show that 250 mg of NMN is easily metabolized and leads to nearly doubled blood NAD+ levels, which trend toward dissipating after four weeks.
(Okabe et al., 2022 | Frontiers in Nutriton) Supplementing with NMN for 12 weeks stimulates nearly double-fold levels of blood NAD+ without increasing whole blood NMN levels. Beginning at four weeks of taking NMN orally at 250 mg per day, whole blood levels of NMN nearly double and plateau for the remainder of the treatment duration (graph on the left). Blood NMN levels remain unchanged throughout the 12-week supplementation duration and four weeks following NMN dosing cessation (week 16). These results demonstrate that supplementing humans with NMN not only nearly doubles blood NAD+ levels but also that NMN levels do not increase, showing that blood NMN may be substantially metabolized.
NAD+ plays a vital role in thousands of biochemical reactions within cells and maintains energy levels by supporting the generation of the molecule adenosine triphosphate (ATP), the primary energy currency of our cells. In mouse models, increasing NAD+ throughout the body protects against the age-related organ and tissue degeneration associated with diseases like cardiovascular disease, Alzheimer’s disease, and liver disease. To promote proper physiological function, proteins called poly (ADP-ribose) polymerases (PARPs) consume NAD+ to repair damaged DNA. Other proteins called Sirtuins utilize NAD+ to regulate gene function, metabolism, and the body’s stress response. All of these findings regarding NAD+ demonstrate that increasing the cellular abundance of this molecule may hold the key to promoting far healthier aging in humans. However, when it comes to boosting NAD+ in humans, safety becomes a critical factor.
To then test whether taking 250 mg/day doses of NMN drives any adverse side effects, the Japan-based research team examined a few important physiological parameters. Nakagawa and colleagues found that 12-week NMN supplementation had no effect on body weight, showing no weight gain or loss. The research team also found no significant changes in body mass index, a ratio of body weight over physical height used as a measurement of body fat. Also, blood pressure measurements remained stable during supplementation. These data suggest that no adverse physiological side effects could be attributed to taking 250 mg per day of NMN for 12 weeks.
(Okabe et al., 2022 | Frontiers in Nutriton) Oral NMN supplementation with 250 mg per day for 12 weeks causes no significant changes in physiological measurements of body weight or blood pressure. Starting from the left, the graphs show that administering oral NMN causes no changes in body weight (BW), body mass index (BMI), heart pumping pressure (systolic blood pressure), or pressure from the heart filling with blood (diastolic blood pressure). These findings indicate that supplementing with NMN gives no major physiological side effects.
Nakagawa and colleagues sought to find whether pulse rate correlated with an increase in total blood NAD+ levels. They found a strong correlation (R=0.768) between blood NAD+ levels and pulse rates. For example, subjects with a pulse rate of 100 beats per minute displayed about double the blood NAD+ levels compared to those with pulse rates of about 60 beats per minute. These results support the notion that a higher heart rate drives the metabolism of NMN into NAD+.
(Okabe et al., 2022 | Frontiers in Nutriton) A higher pulse rate is correlated with greater blood NAD+ levels over a four-week time course while taking 250 mg per day of NMN. Over four weeks of taking NMN, pulse rates as high as 100 beats per minute correlated with almost double the blood NAD+ levels compared to pulse rates of about 60 beats per minute. Research still does not know the exact reason or mechanism for this intriguing finding, but the possibility remains that increasing pulse rate with exercise after NMN consumption may further increase blood NAD+ levels.
Conclusive Results About NMN Will Require More Subjects and Longer Study Durations
There are several limitations to this study that necessitate further research. The current study included only 15 healthy subjects who took NMN, so future studies with more participants will be necessary to confirm the finding. While Nakagawa and colleagues show that NMN increases blood NAD+ levels, this does not necessarily mean that NAD+ levels are increased in any specific organ or tissue. Other human studies have failed to show that NMN or NR supplementation increases NAD+ levels in skeletal muscle. Therefore, future studies should also test whether administering oral NMN increases NAD+ in other organ tissues outside of the blood. In this study, the long-term effects of increasing NAD+ levels were also not tested. In order to identify any potential long-term side effects, researchers should look at human metabolic profiles following longer time courses, such as years of NMN supplementation, in healthy and non-healthy subjects.
One of the more interesting findings of this study is that higher pulse rates are correlated with increased levels of NAD+ blood availability. If true, this finding could mean that activities inducing an elevated heart rate, such as exercising, stimulate higher blood NAD+ levels.
Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, Tobe K, Nakagawa T. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front Nutr. 2022 Apr 11;9:868640. doi: 10.3389/fnut.2022.868640. PMID: 35479740; PMCID: PMC9036060.