Like many other supplements, such as creatine, NMN is naturally present in small amounts in dietary sources, but these amounts are much lower than those found in the supplements used in clinical studies for improving longevity. Trace amounts of NMN (concentrations no more than 0.002% by weight) are found in fruits and vegetables including avocados, broccoli, tomatoes, cucumbers, cabbage, and edamame.^[13]

Not likely. Although NAD+ and NADH differ by only the respective absence or presence of an electron and NADH is a commercially available supplement, no effects of oral NADH supplements on plasma and/or cellular NAD+ levels have been reported in humans.

NADH can be converted to NAD+ via the enzyme NADH reductase, an enzyme present in mitochondria. However, NADH bioavailability is likely low when taken orally, as suggested by a rodent study, which failed to detect absorption of orally administered NADH. The investigators also found that the NADH molecule was unstable under the acidic conditions of the stomach.^[19]

Although NADH supplements do seem to be safe, and have shown some potential efficacy in helping to improve energy levels and quality of life levels in people with chronic fatigue syndrome,^[20][21][22] the mechanism(s) at work are not clear, and may occur independently of NAD+.

NMN has been shown to slow aging-associated decline in rodents, bringing about the following effects:^[14]

• improved insulin sensitivity
• reduced inflammation
• improved mitochondrial function
• improved cognition and brain health

Aside from potential differences between human and rodent physiology that may cause different responses to NMN supplementation, early human clinical trials always err on the side of caution when testing safety. Initial NMN trials in humans tested doses of up to 500 mg NMN daily, with no adverse effects; more recent human trials have tested doses approaching 1000 mg/day. However, in mice NMN is typically administered in doses of up to 500 mg/kg daily, which, taking into account the more rapid turnover of NMN in mice than in humans, may be roughly equivalent to a 75 kg human taking 3,000 mg NMN per day.^[10]

Although NMN has shown postive effects in clinical trials to date, there may be potential drawbacks in particular contexts. NMN’s interactions in neurological health warrant further investigation. NAD+ is also a cofactor for the enzyme sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), an enzyme that instigates neuronal degeneration after injury.^[16] In people with neurological disorders and reduced activity of a specifc enzyme that converts NMN to NAD+ (nicotinamide mononucleotide adenylyltransferase 2, or NMNAT2), NMN supplementation could theoretically enhance neuron degeneration by increasing SARM1 activity.^[17] However, in the context of healthy NMNAT2 enzyme activity, NMN supplementation could potentially be neuroprotective^[18] Although more research is needed, it is safe to assume that NMN supplementation could have potential drawbacks in certain contexts, which warrants further study.

Under certain conditions NMN can enhance the pro-inflammatory characteristics of senescent cells, promoting chronic inflammation. However there's currently no evidence that this occurs in humans in the range of NMN supplement doses tested to date.

Most research has suggested that NMN supplements reduce inflammation. Numerous animal models^[23] and one study using cultured primary human cells^[24] have indicated that boosting cellular NAD+ levels with NMN has is anti-inflammatory effects, and evidence is mounting that increased inflammation associated with aging is linked to low NMN levels.

However, the terms “always” and “never” rarely apply in the life sciences. Additional research models have suggested that NMN can potentially promote inflammation in older, senescent cells which accumulate during aging by enhancing their pro-inflammatory characteristics. In this type of cells, the concern is that NMN could have the unintended consequence of increasing the production of pro-inflammatory cytokines, leading to chronic inflammation. This could theoretically impair tissue repair regeneration, promote further accumulation of senescent cells, and create conditions permissive for the development cancer.^[7][25]

Outside of cancer biology, normal, well-behaved cells undergo a finite number of cell divisions. This is thought to be a general anti-cancer mechanism, since tired, older cells with metabolic dysfunction and increased exposure to environmental toxins- if they were to divide- are more likely to accumulate, and pass on mutations that cold promote the development of cancer. Because senescent cells have permanently exited the cell cycle, they are no longer at risk for passing along potentially harmful DNA mutations to daughter cells, potentially reducing cancer risk.^[26]

However, cellular senescence can be a double-edged sword. Senescent cells tend to develop pro-inflammatory characteristics, constantly secreting low-levels of pro-inflammatory molecules. This phenomenon has been called SASP (Senescence-associated secretory phenotype). Although senescent cells with SASP are at a lower risk for developing into tumors themselves, their tendency create a pro-inflammatory tissue microenvironment in/around their non-senescent neighbors has been implicated in NAD+ depletion ^[27] and potentially the development of cancer in neighboring cells.^[25]

On one hand, increasing cellular NAD+ levels in non-senescent cells can suppress the transition to senescence by reducing DNA damage and mitochondrial dysfunction. On the other hand, increased NAD+ levels could actually enhance SASP by encouraging sensecent cells to develop the SASP, as well as increasing pro-inflammatory cytokine production in cells that already have the SASP.^[28]

Research has shown that the resulting increased level of pro-inflammatory cytokines produced by senescent cells with SASP lead to increased levels of the NAD+ consuming enzyme CD38 in neighboring cells. This has the effect of reducing NAD+ levels in normal cells nearby senescent cells with the SASP.^[27][29][30] When NAD+ levels are reduced in the normal, non-sensescent cells, mitochondrial dysfunction and the accumulation of DNA-damage can in-turn promote the development of senescence.^[28]

Thus, the theoretical concern is that increasing NAD+ levels, in spite of all of the healthy / anti-inflammatory effects in normal cells, could also increase inflammation while promoting neighboring cells to transtion to sensescence and SASP in a potential viscious cycle. More research is needed to determine whether the potential for NMN supplements to promote SASP is only a theoretical one, or if caution may be warranted for NMN supplementation in certain individuals or populations. Nonetheless, it is important to emphasize the no evidence has been found so far in human clincal trials to date that NMN may promote SASP.

Enzymes are simply proteins that are folded into a configuration that allows them to bind other molecules and compounds, catalyzing chemical reactions. Often they can’t accomplish this catalysis alone—many enzymes also require cofactors (aka coenzymes) to function.

The way that NAD+ functions as an enzyme cofactor depends on the enzyme. First, NAD+ helps to catalyze ‘redox’ (reduction-oxidation) reactions by accepting electrons from other compounds and molecules, becoming reduced (gaining electrons) in the process and forming the compound NADH. The reduction of NAD+ to NADH is critical for a number of enzymes and pathways associated with metabolic regulation and energy homeostasis.

Second, some enzymes consume NAD+ in the course of carrying out their catalytic function, converting NAD+ into other forms. In many cases, NAD+-consuming enzymes convert NMN to nicotinamide, which can later be recycled back to NMN. Some examples are the class of enzymes known as sirtuins, which have anti-aging activity,^[11] and poly (ADP-ribose) polymerases (PARPs), which help to repair DNA damage.

NAD+ levels decrease during aging through two main mechanisms. The first one is reduced biosynthesis—the older we get, the less NAD+ is produced by the body, possibly due to oxidative stress and chronic inflammation.^[15] The second mechanism is thought to be increased NAD+ consumption. Increased activity of NAD+-dependent enzymes, coupled with a decreased total pool of available NAD+, creates a situation where there’s not enough NAD+ to support maximal function of the dependent enzymes. For example, DNA damage tends to increase during aging, causing PARP enzymes to consume more NAD+, leaving less of this cofactor available to support the function of other enzymes, such as the sirtuins.