·   NMN increases natural killer cell capabilities to destroy cancer cells (cytotoxicity) without increasing immune cell numbers.
·   The study supports that taking NMN may be a way to rejuvenate natural killer immune cell activation to preserve tissue health during aging.

As the average human lifespan increases, people are experiencing poor health and age-related diseases longer, incurring major financial and societal costs. One substantial contributing factor to age-related diseases and their progression is degraded immune function. Specifically, NK cells that terminate cancer and virally infected cells become less effective. At present, no remedy exists to restore the function of NK cells during aging. So, compounds that stimulate NK cell activation may prevent age-related ailments or slow their advancement.

Okumura and colleagues from Juntendo University in Japan treated mice with nicotinamide mononucleotide (NMN) to restore NK cell cytotoxicity — the ability to destroy malfunctioning cells. Published in Biomedical Research, NK cell stimulation in mice occurred when NMN was injected (313, 625, or 1250 mg/kg) or orally administered (625 mg/kg) for four days. Notably, the boosted NK cell cytotoxicity didn’t come from their enhanced proliferation or higher NK cell numbers but rather improved NK cell abilities to destroy cancer cells. These findings support that NMN supplementation may boost NK cell immunity and overall tissue health by curtailing the accumulation of precancerous and viral-infected cells as people age.

NAD+ Levels and Immune Function Drop With Age

Many aspects of immunity decline with age, and NK immune cell function is no exception to this phenomenon. The age-related deterioration of immune function with age is linked to levels of an essential molecule called nicotinamide adenine dinucleotide (NAD+), which also declines with age. However, boosting NAD+ levels has been shown to improve immune function in mice. For example, studies have shown that increasing NAD+ levels by inhibiting an NAD+-consuming enzyme improves immunity to attenuate tumors in mice

The NAD+ precursor NMN helps with age-related disorders like insulin insensitivity and metabolic impairments like obesity in aged mice. Also, since boosting NAD+ levels have been shown to work against tumors in mice, it may also potentially enhance anti-tumor NK cell activity. Figuring out whether NMN has these immunity-restoring effects in NK cells is critical for determining if it is the compound we’ve been looking for to restore their cytotoxicity.

(Paul & Lal, 2017 | Frontiers in Immunology) The natural killer (NK) immune cell cytotoxic response targets cancer and viral-infected cells. In the first step (A), the NK cell recognizes the target cell and clusters toward it. In the second step (B), the cell reorganizes its internal structure to orient towards the target cell. The third step (C) encompasses the NK cell docking and moving closer to the target cancer cell. The fourth and final step (D) entails the NK cell destroying the target cancer cell so that it bursts open. 

Injecting NMN Enhances Mouse Immune Cell Activity

To analyze NMN’s influence on NK cells, Takeda and Okumura injected mice at various ages with NMN and evaluated the activation and cytotoxicity of NK cells. The research duo injected varying doses of 1250, 625, 313, or 125 mg/kg/day of NMN for four days into 36-week old mice and then harvested NK cells from the liver and spleen. These NK cells were then put into a dish with cancer cells at different ratios and were analyzed for cytotoxicity based on the percentage of destroyed cancer cells. These findings indicate that injecting 313 mg/kg or more of NMN enhances aged NK cell capabilities to destroy dysfunctional cells in mice.

(Takeda & Okumura, 2021 | Biomedical Research) NMN injections (313 mg/kg/day or greater) significantly enhanced NK cell cytotoxicity in 36-week old mice. The effector/target ratio represents the proportion of NK cells to cancer cells. The cytotoxicity percentage – the percentage of destroyed cancer cells among those analyzed – varied with different effector/target ratios. An effector/target ratio of 10 and 5 showed substantial enhancements of cytotoxicity with NMN in the liver, and an effector/target ratio of 100 was optimal for NMN’s efficacy in the spleen. The upside-down solid triangles represent 125 mg/kg/day doses, the upright and solid triangles show 313 mg/kg/day doses, the solid square signifies 625 mg/kg/day doses, and the solid circle shows 1250 mg/kg/day dose values. These results indicate that NMN’s beneficial cytotoxicity-promoting benefits have tissue-specific effects that optimize at different effector/target cell ratios depending on tissue type.

Oral NMN Dosing Improves Mouse Immune Cell Function

Using the same cytotoxicity measurement method, the research team then sought to determine whether similar benefits come from administering NMN orally. In the 32-week-old mice Takeda and Okumura used for their analysis, 625 mg/kg of orally-supplemented NMN significantly enhanced NK cell cytotoxicity. Neither injecting or orally dosing NMN increased the NK cell numbers. This result strongly supports that NMN supplementation improves overall NK cell cytotoxicity in mice, because NK cells show improved, potent cancer cell-destroying abilities without becoming more abundant.

(Takeda & Okumura, 2021 | Biomedical Research) Oral NMN supplementation with 625 mg/kg/day doses enhances cytotoxicity in the spleen and liver. The optimal effector/target ratios – the proportion of NK cells to cancer cells – were 5, 10, and 20 for the liver and 200 for the spleen. At these ratios, the percentage of destroyed cancer cells, the cytotoxicity percentage, increased substantially at 625 mg/kg/day doses (solid squares on the graphs). These findings show that orally dosing with NMN as well as injections can improve NK cell cytotoxicity in two different mouse strains.

“We have herein demonstrated that intraperitoneal or oral administration of NMN, a key NAD+ intermediate in mammals, augments the cytotoxicity of NK cells,” said Okumura and colleagues in their publication.

Studies continue to show the translatability of NMN’s health benefits from mice to humans in conditions like reduced insulin sensitivity, running endurance, and aged muscle function. So, although how and whether these results apply to humans remain up in the air, the study offers hope for the tantalizing prospect that NMN improves aged human immunity through improved NK cell cytotoxicity.

Some study limitations include that NMN boosts NK cell cytotoxicity optimally at different ratios of NK cells to cancer cells, but the significance of this finding wasn’t explored. For example, the optimal proportion of NK cells to cancer cells with oral dosages is 10 to 20 in the liver but 200 in the spleen. The precise meaning of this finding remains uncertain. 

Another limitation is that the cytotoxicity analyses were done in laboratory dishes, which don’t always translate to live tissue. Future experiments can utilize cytotoxicity measurements in live animal tissues to further support that NMN boosts NK cell cytotoxicity.