"Anti-Aging 'Miracle Drug'" Also Powers Cancer Fight? Chinese Team Discovers Dual Roles of NMN—Solving Two Major Issues with One Agent

Natural killer cells (NK cells), a type of immune cell, see a sharp decline in their ability to clear tumor cells and senescent cells as aging progresses[1]. To maintain NK cell activity, nicotinamide adenine dinucleotide (NAD+)—a key hub for cellular metabolism and signal transduction—has become a primary focus of investigation.

But through which pathways does NAD+ activate NK cells? And how does it assist in enhancing NK cells’ anti-tumor capabilities?

To verify if NAD+ is indeed the factor activating NK cells, researchers intraperitoneally injected mice with the pro-inflammatory cytokine IL-15 to induce multi-organ inflammation and cytotoxicity in mice. While triggering inflammatory aging and activating NK cells, they performed NAD+-related genome enrichment analysis.

The study found that the expression of 4 NAD+ metabolism-related genes and 2 key enzymes for NAD+ synthesis (Nampt and Nmrk1/2) was significantly upregulated, showing a strong response to NK cell activation[2]. This confirms the hypothesis: NAD+ is the unsung hero that sustains NK cell health and activity.

In NK cells activated by exogenous NAD+, the levels of interfering proteins (IFN-γ, TNFα, and perforin) that inhibit cell proliferation and development were significantly increased. It seems exogenous NAD+ acts like "powerful weapons" for NK cells, greatly enhancing their ability to clear inflammatory cells.

Additionally, the proliferative capacity and vitality of these enhanced NK cells were significantly improved, while their apoptosis rate decreased. NAD+ truly lives up to its role as NK cells’ "solid backing"—it not only induces and stimulates NK cells to clear unwanted cells but also maintains their functional and internal homeostasis.

NAD+ synthesis occurs via three pathways: de novo synthesis, the Preiss-Handler pathway, and the salvage pathway. After 16 hours of starvation of NK cells, researchers found that supplementing with NMN (a NAD+ precursor) effectively increased NAD+ levels through the salvage pathway[2].

Further exploring the mechanism of NMN supplementation in NK cells with fragmented, damaged mitochondria, the team discovered that the expression of genes encoding mitochondrial electron transport complex (ETC) proteins in NK cells was significantly upregulated. This suggests the salvage pathway improves the electron transport system of damaged mitochondria, enhances ATP synthesis, and thereby maintains NK cell mitochondrial homeostasis and cellular metabolism[3].

With the accumulation of senescent cells, the body experiences increased inflammation and declined immune function, leading to replication errors in normal cells and the induction of tumor cells[4]. To effectively clear tumor cells later, NK cells deploy "tumor-infiltrating NK cells (TINKs)"—a "reconnaissance force" for tumor cells—to test the waters.

Transcriptional analysis of TINKs revealed that NAD+ metabolism-related genes were negatively enriched in TINKs. This indicates that under tumor stress, the NAD+ synthesis pathway in TINKs is significantly inhibited[2].

Could supplementing NMN enhance NK cells’ clearance efficiency against tumor cells, similar to its effect on senescent cells? The team supplemented exogenous NMN in both liver cancer and melanoma mouse models. They found that the level of reactive oxygen species (ROS)—a major threat to the mitochondrial electron transport chain and mitochondrial membrane—was drastically reduced. This significantly improved mitochondrial metabolism and synthesis pathways, enhanced NK cell activity, and greatly boosted anti-tumor resistance[2].

It is clear that with the support of NMN, NK cell activity is enhanced—transforming NAD+ (their "backing") into a "spear." Using the same mechanism as clearing inflammatory senescent cells, NK cells effectively inhibit tumor growth.

Since the discovery of NK cells decades ago, their mechanism for clearing senescent or tumor cells has remained unclear. Through experiments on model organisms and human tumor cells, this study finally identifies NAD+ and its precursor NMN as the key factors behind NK cells’ anti-tumor activity.

However, the role of NAD+ in promoting or treating cancer has long been controversial.

This study was published in Hepatology under the title NAD+ Salvage Governs Mitochondrial Metabolism Invigorating NK Cell Anti-Tumor Immunity. The corresponding authors are Associate Professor Xiaohong Liang (Shandong University) and Attending Physician Tao Li (Qilu Hospital), with Xiaowei Guo as the first author.

Funding support for this study includes:

[1] Campbell, K. S., & Hasegawa, J. (2013). Natural killer cell biology: An update and future directions. Journal of Allergy and Clinical Immunology, 132(3), 536–544. https://doi.org/10.1016/j.jaci.2013.07.006
[2] Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., Li, M., Wang, Y., Zhang, Y., Yan, Y., Dong, Z., Yan, L., Yue, X., Wu, Z., Li, C., Yamagata, K., Gao, L., Ma, C., Li, T., & Liang, X. (2022). NAD+ salvage governs mitochondrial metabolism invigorating NK cell anti-tumor immunity. Hepatology. https://doi.org/10.1002/hep.32658
[3] Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S., & Medzhitov, R. (2017). Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science, 356(6337), 513–519. https://doi.org/10.1126/science.aal3535
[4] Poznanski, S. M., Singh, K., Ritchie, T. M., Aguiar, J. A., Fan, I. Y., Portillo, A. L., Rojas, E. A., Vahedi, F., El-Sayes, A., Xing, S., Butcher, M., Lu, Y., Doxey, A. C., Schertzer, J. D., Hirte, H. W., & Ashkar, A. A. (2021). Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metabolism, 33(6), 1205–1220.e5. https://doi.org/10.1016/j.cmet.2021.03.023