Introduction: Recently, Shintarou Kimura et al. published a study on NAD+ in "Research Square", showing that intravenous injection of NMN in humans is safe and beneficial for preventing aging-related diseases. The results of this study have gained more market application possibilities for NAD.

l NMN administration is tolerated by humans

l Effectively improve sleep quality

l Effectively increases NAD+ without significant damage to organs

l NMN helps prevent aging-related diseases such as diabetes, Alzheimer's disease, and heart disease

Currently, the effectiveness of increasing NAD levels in the body in relieving age-related diseases and extending healthy life expectancy has been confirmed in previous studies on NMN, and recent clinical trials on healthy Japanese men have further verified the safety of oral administration of NMN. However, the efficacy and safety of intravenous administration of NMN remain unclear.

First, the authors speculate that NMN can be safely provided by intravenous administration because it is a metabolite produced in the body.

Second, NAD+ has been studied as a coenzyme required to activate sirtuin family proteins with anti-aging functions.

Among the members of the sirtuin family, sirtuin 1 (SIRT1) has been studied as a factor that directly prevents aging. In addition, SIRT1 controls circadian rhythms by binding to the circadian motor output cycle kaput (CLOCK)-brain and muscle Arnt-like protein 1 (BMAL1) and cycle circadian protein 1 (PER1) in an NAD+-dependent manner, and deacetylate these proteins to facilitate their degradation.

Based on the above, the authors assessed the activity of NAD+ and SIRT1 in blood cells as well as the degree of fatigue and sleep quality after intravenous injection of NMN.

A total of 10 healthy male and female subjects (20-70 years old) were included in this study. The authors dissolved NMN (300 mg) in saline and administered intravenous injections to the subjects, and their electrocardiogram, pulse, blood pressure, and related metabolic markers were monitored, the authors then tested the blood samples of the subjects.

l Improve sleep quality

The results showed no significant changes in body weight or body mass index 5 hours before and after intravenous administration of NMN. Fatigue was slightly improved after 1 month of intravenous NMN administration, but not significantly different from pre-dose. Compared with the month before dosing, sleep quality was significantly improved (Table 1).

l No burden on organs

The authors then investigated the pharmacokinetics of metabolic markers in the liver, heart, pancreas, and kidneys following intravenous administration of NMN, as intravenously administered drugs can rapidly reach organs throughout the body and cause a burden on specific organs.

First, the authors assessed the effect of intravenous NMN on hepatic metabolism by (a)(b)(c)(d)(e)(f)(g)(h)(i) in figure 1.

The authors then assessed pancreatic metabolism based on (j)in figure 1; cardiometabolism by (k) and (l) in figure 1; and renal metabolism by (m)(n)(o)(p) in figure 1.

As can be seen, the levels of liver, pancreas, heart and kidney-related metabolic markers in plasma measured at 0.5, 1, 2, 3, and 5 hours after intravenous injection of NMN were not significantly different from those before dosing.

Likewise, there was no significant effect on plasma electrolytes at 0.5, 1, 2, 3, and 5 hours after intravenous NMN (Fig. 2).

In addition, as we can see from Figure 3, analysis of red blood cells (f)(g)(h)(i), white blood cells (j)(k)(l)(m)(n), platelets, and related markers in blood (a)(b)(c)(d)(e) showed that there were no significant changes before and after 0.5, 1, 2, 3, and 5 hours of intravenous NMN.

l Overall NAD+ increase

    The authors then measured the total amount of NAD+/NADH in the blood and the ratio of NAD+ to NADH to determine whether intravenously administered NMN could effectively increase the amount of NAD+ in blood cells（Fig. 4）.

NAD+/NADH levels in blood measured at 0.5, 1, 2, 3 and 5 hours after intravenous NMN administration showed a significant increase in NAD+ levels from 0.5 to 3 hours compared to pre-dose (a), and Significant increases in total NAD+ levels were noted, except 4 hours after dosing (b).

Conversely, NADH levels could not be accurately measured because the measurements were highly variable（Panel c, Fig. 5）.

l Increased activation of nuclear SIRT1

To inhibit aging, sirtuin family proteins should use NAD+ as a coenzyme during their elevated levels [14]; therefore, the authors sought to determine whether SIRT1, which is thought to be particularly important for aging, is activated by intravenous NMN. After intravenous injection of NMN, nuclear SIRT1 tended to be activated 30 min to 1 h after NMN administration, similar to the increase in NAD+ levels (Fig. 5, (e)); however, no significant difference was observed due to the large variability in measurements. Cytosolic SIRT1 activation was almost unchanged before and after intravenous administration of NMN (Fig. 5, (f)).

In conclusion, the authors' clinical study demonstrated that 300 mg of NMN administration was tolerated by humans as it did not cause significant damage to blood cells, liver, pancreas, heart, and kidneys when administered intravenously and was effective in increasing NAD+ in blood cells amount.

In addition, intravenous administration of 300 mg of NMN may help prevent aging-related diseases such as diabetes, Alzheimer's disease, and heart disease, as the authors' findings suggest that SIRT1 may be activated.

Reference : Kimura, Shintarou, et al. "Intravenous Uptake of NMN is Safely Metabolize and Increases NAD+ Levels in Healthy Subjects." (2022).