Recently, a team led by Professor Haruka Wada of Hokkaido University in Japan found that NMN also has anti-cancer effects.
The new study, published in the Journal for ImmunoTherapy of Cancer, shows that cancer stem cells trigger the aging of macrophages (which are our body's first barrier responsible for destroying cancer cells), but that NMN supplementation in mice vaccinated with cancer stem cells can improve this, It can significantly prevent tumor growth, prolong the survival time and improve the survival rate of mice [6].
First, the researchers put cancer stem cells and immune cells (including macrophages and T cells, etc.) together in the culture medium, and co-culture to see if the cancer stem cells will affect the activity of these immune cells.
Macrophages can kill pathogens, absorb apoptotic and necrotic cells, and play an important role in anti-infection and anti-tumor [7]. T cells can be more targeted to recognize and destroy specific pathogens (to avoid the accumulation of pathogens that can cause cancer), and remain "vigilant" after recovery, providing long-term protection for the body. [8]
The results showed that the proliferation of macrophages was significantly inhibited in terms of quantity. In addition, these macrophages appear flat and enlarged round, which is more akin to an "aging-like state" in morphology.
To determine whether these "aging" macrophages were indeed aging, the researchers used one of the most widely used aging biomarkers, SA-β-gal, to measure the degree of aging of macrophages: increased SA-β-gal activity is a key feature of the process of cellular aging.
The results showed that the SA-β-gal activity in these macrophages met the criteria for senescent cells.
Not only that, in a subsequent "cell senescence related genes" analysis, the researchers also found that these macrophages highly expressed p21 and Glb1, two genes known to be closely related to cell aging.
The above findings all prove that the macrophages cultured together with cancer stem cells are indeed "close to the ink black" and enter the state of aging.
The team found that macrophages were not the only immune cells affected in the co-culture environment with cancer stem cells; the function of T cells (immune cells that can specifically recognize and destroy specific pathogens) was also disrupted by cancer stem cells.
It has been observed that despite the infiltration of T cells in the cancer stem cell environment, tumor tissue can grow recklessly. This suggests that T cell activity must be inhibited in this environment.
Further research found that what interfered with the normal work of T cells was the "renegade friendly" - aging macrophages. It secretes a powerful immunosuppressive molecule, arginase-1, which suppresses T cell reactivity and causes T cells to malfunction.
Because of the emergence of arginase-1, in the presence of cancer stem cells in the environment, the activity of the inhibited T cells has been unable to fight and destroy cancer cells. This is why, in immune-active mouse tumor models, tumors developed in mice that were originally immune to normal function.
But it's not enough to dig up arginase-1, which is secreted by aging macrophages and is not the culprit. The real culprit, I think, is the guy who causes normal macrophages to age.
A closer look revealed that cancer stem cells produce interleukin-6, a known secretory phenotype cytokine associated with aging.
It is it that "turns" the macrophages that are supposed to fight cancer - not only does the macrophage itself not work, but also causes it to secrete arginase-1, so that friendly T cells can not work.
At this point, let's sort out the whole process of cancer stem cells "inactivating" immune cells and "nourishing" tumors:
First, cancer stem cells secrete the "pro-aging factor" interleukin 6, which induces macrophages to age. These aging macrophages then begin to express argininase-1, inducing T cell dysfunction; Finally, macrophages and T cells, which have anti-cancer properties, are no longer working properly, and tumors can grow unchecked.
With the culprit identified, the next question is, what can be done to save these aging immune cells?
As the study progressed, the team observed that CD38 was highly expressed in aging-like macrophages.
CD38 is a major enzyme involved in the degradation of NMN, the precursor of NAD, and its expression increases with aging. In other words, the older the age, the more CD38, and correspondingly, the less NAD content in the body.
Therefore, the researchers wondered whether supplementing NAD precursor NMN could partially alleviate or even prevent the aging of macrophages since NAD was lacking in senescent macrophages.
The results were consistent with the hypothesis: the number of senescent macrophages decreased after the addition of NMN. In a co-culture of cancer stem cells and macrophages, NMN also reduced expression of the immunosuppressive molecule arginase-1, a T-cell foe.
These two phenomena prove that NMN can effectively prevent macrophage senescence and T cell dysfunction.
In addition, in a tumor model of immunoactive mice, the researchers found that about 70 percent of the mice in the control group developed tumors and died from them; In the NMN group, tumor development was observed in only about 20% of mice, equating to a 71.4% reduction in cancer incidence and improved survival.
The researchers concluded that NMN treatment inhibited argininase-1 and improved its induced T cell dysfunction, thereby preserving the anticancer function of T cells and therefore temporarily preventing tumorigenosis in mice with normal immune function.
"Our results show that a drug targeting aging macrophages can treat cancer - an unprecedented development," said Professor Haruka Wada of Hokkaido University, corresponding author of the study.