Nicotinamide Mononucleotide (NMN)

Another possibility is that sirtuin is inhibited by NAM, the main breakdown product of NR. Mouse studies have shown that NR may be metabolized in the intestine to NAM or NA before it even enters the bloodstream. But be that as it may—unlike in mice, NR does not seem to increase NAD+ levels in human muscles, so it is not surprising that no change in sirtuin activity was found in muscle tissue samples. That would explain the differing results. In fact, the tissue samples showed that the enzyme most important for NAD+ synthesis is suppressed by NR supplementation. That does not happen in mice, but it does in humans. Presumably, this downregulation is an adaptive response to the unnatural flood of NR coming into the system.

In mice, not only can the microbiome affect NR, but NR can also affect the microbiome. Part of NR’s benefit can be transferred through fecal transplantation between mice. So, at least in mice, part of NR’s benefit could be due to modulation of the microbiome. The pronounced differences between the intestinal flora of humans and rodents could provide another explanation for why NR works in them but not in us.

In contrast to NAM, supplementation with NR did not lead to an increase in homocysteine levels, but in one study with a combination of NR and the resveratrol analog pterostilbene, LDL cholesterol rose high enough to theoretically kill one in 40 long-term users. It is suspected that this effect is attributable to the pterostilbene, because NR alone does not raise LDL cholesterol, whereas pterostilbene does.

In one study, NR appeared to cause a slight decline in hemoglobin, hematocrit, and platelet count in humans within a week after starting supplementation. It was suspected that this shift toward a more anemic state was the reason for the reduced physical performance of rats that had been given NR. However, the observed performance drop of 35 percent did not reach statistical significance. NR led to a significant increase in systemic oxidative stress, and another rodent study found a worsening of inflammation and a deterioration of metabolic health, but if the positive effects in rodents do not translate to humans, perhaps we should expect the same of the negative ones.

Regulatory authorities in Australia, Canada, Europe, and the United States have approved NR as safe, at least up to 300 milligrams per day (230 mg in pregnant and breastfeeding individuals). But since no clinical benefit has been demonstrated, supplementation with NR is effectively ruled out.

Nicotinamide Mononucleotide (NMN)

Both NR and NMN proved useful in rodents, but they have not yet been tested head-to-head. Both precursors raise blood NAD+ levels in humans, but here, too, they have not yet been studied in direct comparison. One possible advantage of NMN over NR could be that it is more stable in the bloodstream. At least in mouse blood, most NR is converted into NAM within an hour, whereas NMN levels remain the same. One could also argue that NMN is better because it is a direct precursor of NAD+, whereas NR first has to be converted into NMN, so one might as well take NMN right away. Ironically, however, one can also justify the exact opposite, because NMN cannot penetrate cell membranes.

By composition, NMN is simply NR with a phosphate group. The phosphate prevents NMN from entering or leaving cells; therefore, to get into a cell, NMN must first be converted into NR. Once inside the cell, the NR can be converted back into NMN and form NAD+. So if NMN has to be converted into NR to enter the cell, the argument goes, one might as well take NR right away. But a controversial NMN transporter was recently identified (at least in the intestines of mice), so in the end NMN may indeed be able to skip the NR step and enter cells directly to form NAD+ there.

NMN benefits rodent healthspan in diverse ways, but unlike NR, it still has to prove its life-extending effect in mammals. And specifically in humans? So far, only a few NMN studies in humans have been published. A small study in healthy middle-aged men found that different single doses had no detectable effect on any of the measured variables, including retinal function, sleep quality, heart rate, blood oxygenation, or body temperature. A twelve-week trial with daily NMN supplementation in middle-aged men and women likewise had no significant effects on, for example, lean mass, muscle mass, body fat, blood sugar, cholesterol, and insulin sensitivity. NMN did raise blood NAD+ levels, but they reached a maximum after the first month and declined in the second and third month, which could mean there was an adaptive reduction in NAD+ synthesis, as was also suspected with NR. Like NR, NMN also fails to increase NAD+ levels in muscles.

As part of a study with the incantatory title “Nicotinamide Mononucleotide Supplementation Increases Aerobic Capacity in Amateur Runners,” young and middle-aged recreational runners received three different NMN dosages or a placebo for six weeks. Aerobic capacity was increased at the first ventilatory threshold, but not at the second. No overall benefit was found for aerobic capacity, maximal performance, or any of the ten other indices of cardiopulmonary function. If you take enough measurements, statistical outliers—both positive and negative—can appear as chance hits. For example, the researchers found a significantly better test result for standing on one leg, but NMN had no effect on physical functionality such as grip strength, push-ups, and flexibility in the sit-and-reach test. And on closer inspection, the balance benefit for standing on one leg existed only in the medium-dose group compared with the high-dose group, and for none of the doses compared with the placebo. (The high-dose group performed somewhat worse compared with baseline.)