NMN Confirmed to Fight Cancer! New Japanese Study: NMN Resists Immune Cell Senescence, Inhibits Tumor Growth by 71.4%!

Since Harvard Professor David Sinclair discovered that NMN can extend the lifespan of mice in 2013, the anti-aging effects of NMN—known as the "anti-aging supplement"—have been continuously explored.

To date, clinically proven anti-aging effects of NMN include: improving insulin sensitivity[1]; delaying arteriosclerosis[2], muscle atrophy[3], skin aging[4], and intestinal aging[5], among others.

Recently, a team led by Professor Haruka Wada from Hokkaido University, Japan, discovered that NMN also has anti-cancer effects.

This new study, published in the Journal for ImmunoTherapy of Cancer, shows that cancer stem cells induce senescence in macrophages (the body’s first line of defense against cancer cells). However, supplementing NMN to mice implanted with cancer stem cells improves this condition: it significantly inhibits tumor growth, extends the mice’s lifespan, and increases their survival rate[6].

First, researchers co-cultured cancer stem cells with immune cells (including macrophages and T cells) in a culture medium to observe whether cancer stem cells affect the activity of these immune cells.

Macrophages can kill pathogens, phagocytose apoptotic and necrotic cells, and play important roles in anti-infection and anti-tumor responses[7]; T cells can more specifically recognize and eliminate specific pathogens (preventing cancer caused by pathogen accumulation) and remain "alert" after recovery to provide long-term protection for the body[8].

Observations showed that the proliferation of macrophages was significantly inhibited in terms of quantity. Moreover, these macrophages appeared flat, enlarged, and round in shape—morphologically resembling a "senescent-like state."

To confirm whether these "aged-appearing" macrophages were truly senescent, researchers used SA-β-gal (one of the most widely used senescence biomarkers) to measure the senescence level of macrophages: increased SA-β-gal activity is a key characteristic of cellular senescence.

The results showed that the SA-β-gal activity in these macrophages met the criteria for classifying them as senescent cells.

Furthermore, in subsequent analysis of "senescence-related genes," researchers found that these macrophages highly expressed two genes—p21 and Glb1—both known to be closely associated with cellular senescence.

All the above findings confirm that macrophages co-cultured with cancer stem cells "became senescent due to exposure to cancer stem cells," entering a senescent state.

The research team found that in the co-culture environment with cancer stem cells, macrophages are not the only immune cells affected—T cell function (immune cells that specifically recognize and eliminate certain pathogens) is also impaired by cancer stem cells.

Observations showed that despite T cell infiltration in the cancer stem cell environment, tumor tissue grew unchecked. This indicates that T cell activity must have been inhibited in this environment.

Further research revealed that the "traitorous ally" disrupting T cell function was senescent macrophages: they secrete arginase-1, a potent immunosuppressive molecule, which inhibits T cell reactivity and causes T cell dysfunction.

It is precisely because of arginase-1 that T cells with inhibited activity can no longer fight and eliminate cancer cells in the environment with cancer stem cells. This explains why tumors develop in mice with normal immune function in the immunocompetent mouse tumor model.

However, identifying arginase-1 is not enough—this substance secreted by senescent macrophages is not the root cause. The real culprit should be the factor that induces senescence in normal macrophages.

In-depth research revealed that the culprit is interleukin-6 (IL-6) produced by cancer stem cells—a known senescence-associated secretory phenotype (SASP) cytokine.

It is IL-6 that "turns" macrophages (which should resist cancer): not only does it render macrophages non-functional, but it also incites them to secrete arginase-1, disabling the "ally" T cells.

To summarize the entire process by which cancer stem cells "inactivate" immune cells and "nourish" tumors:

As the research progressed, the team observed that senescent-like macrophages highly express CD38.

CD38 is a key enzyme involved in the degradation of NMN (a NAD precursor) in the body, and its expression increases with aging. In other words, the older the body, the more CD38 it has—and the lower the NAD content.

Thus, researchers hypothesized: if senescent-like macrophages lack NAD, could supplementing NMN (a NAD precursor) partially alleviate or even prevent macrophage senescence?

The results matched the hypothesis: after adding NMN, the number of senescent-like macrophages decreased; in the co-culture of cancer stem cells and macrophages, NMN reduced the expression of arginase-1 (the "arch-enemy" of T cells) by three times.

These two phenomena confirm that NMN effectively prevents macrophage senescence and T cell dysfunction.

Additionally, in the immunocompetent mouse tumor model, researchers found that approximately 70% of mice in the control group developed tumors and died; in the NMN-treated group, only about 20% of mice developed tumors—equivalent to a 71.4% reduction in cancer incidence—and the survival rate increased.

Based on this, the researchers concluded: NMN treatment inhibits arginase-1, improves arginase-1-induced T cell dysfunction, thereby preserving the anti-cancer function of T cells and temporarily preventing tumor development in mice with normal immune function.

Professor Haruka Wada, corresponding author of the study, stated: "Our findings suggest that drugs targeting senescent macrophages can treat cancer—this is an unprecedented advancement."

[1] Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., Sindelar, M., Pietka, T., Patterson, B. W., Imai, S., & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224–1229. https://doi.org/10.1126/science.abe9985
[2] Takeshi K, Sachi Uehata, Noe N, et al. (2022). Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-1802944/v1
[3] Igarashi, M., Nakagawa-Nagahama, Y., Miura, M., Kashiwabara, K., Yaku, K., Sawada, M., Sekine, R., Fukamizu, Y., Sato, T., Sakurai, T., Sato, J., Ino, K., Kubota, N., Nakagawa, T., Kadowaki, T., & Yamauchi, T. (2022). Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. Npj Aging, 8(1). https://doi.org/10.1038/s41514-022-00084-z
[4] Gao, J. F., Tang, L., Luo, F., Zhang, Y. Y., Chen, L., Ding, H., & Meng, Z. D. (2022). Nicotinamide mononucleotide ameliorates DNFB-induced atopic dermatitis-like symptoms in mice by blocking activation of ROS-mediated JAK2/STAT5 signaling pathway. International Immunopharmacology, 109, 108812. https://doi.org/10.1016/j.intimp.2022.108812
[5] Ru, M., Wang, W., Zhai, Z., Wang, R., Li, Y., Liang, J., Kothari, D., Niu, K., & Wu, X. (2022). Nicotinamide mononucleotide supplementation protects the intestinal function in aging mice and d-galactose induced senescent cells. Food & Function, 13(14), 7507–7519. https://doi.org/10.1039/d2fo00525e
[6] Wada, H., Otsuka, R., Germeraad, W. T., Murata, T., Kondo, T., & Seino, K. (2023). Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition. Journal for ImmunoTherapy of Cancer, 11(11), e006677. https://doi.org/10.1136/jitc-2023-006677
[7] Hirayama, D., Iida, T., & Nakase, H. (2017). The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis. International journal of molecular sciences, 19(1), 92. https://doi.org/10.3390/ijms19010092
[8] Cleveland Clinic Medical Professional. (n.d.). T-Cells. https://my.clevelandclinic.org/health/body/24630-t-cells