The author of this article is Dr.ZHAO, Shandong University
Review expert of this article: Professor Li Jing from the Affiliated Hospital of Jiangsu University
introduction
Natural killer cells (NK) are key effector cells of the innate immune system and are the first line of defense against viral infections and malignant cells. In older adults, a decrease in NK cell activity has been shown to be associated with an increase in the incidence and severity of viral infections. The decline in NK cell function that accompanies physiological aging may have a much broader health impact on older adults than previously thought. According to the literature in the journal Ageing Res Rev, after aging, the biological function of NK cells also undergoes significant changes, including the accumulation of senescent cells, the delay in the resolution of inflammation, and the weakening of antimicrobial immunity, which have an important impact on the health of the elderly.
Natural killer (NK) cells are the superheroes in our bodies, responsible for fighting off mischievous viruses and malignant cells. It plays an important role in the innate immune system and has always guarded our health. However, as it ages, its two major weapons, direct cytotoxicity (NKCC) and secretion of chemokines, become less sharp. This makes the elderly more susceptible to the virus when facing it, and the disease may be more severe.
Not only that, NK cells are also involved in many other biological processes, such as regulating immunity, fighting bacteria, and finding and eliminating senescent cells. Today, we're going to talk more about how this superhero has changed as humans age[1].
NK cells' two tricks:
"Missile launch" and "kiss of death"
NK cells have two killer features, one is NK cytotoxicity (NKCC), and the other is secretion of cytokines and chemokines. NK cells also have two tricks that can directly destroy those bad cells: one is granular exocytosis, and the other is death receptor linkage.
Particle exocytosis acts like a "missile launch system" for NK cells (Figure 1A). When NK cells find a target, they quickly fire toxic proteins that hit the target cell like a missile, destroying its structure and making it impossible for it to survive. Among them, the most powerful weapons are perforin and granzyme, which can quickly destroy cell membranes, leaving target cells with nowhere to escape.
In addition to missile attacks, NK cells also have a "kiss of death" trick, which is to bind to death receptors (Figure 1B).
When the NK cell is activated, it equips its surface with Fas ligands and TRAIL, and once in contact with the target cell, these weapons bind to the receptor on the target cell, forming a lethal signaling complex. This complex acts like a death switch that, once activated, causes the death program inside the target cell to be executed immediately, resulting in cell death.
When activated, NK cells secrete large amounts of immunomodulatory cytokines and chemokines, as if they were giving a command to mobilize other immune cells to fight together. These factors can enhance the activity of bystander cells and expand the range of immune responses, while also influencing the early stages of adaptive immune responses, such as promoting dendritic cell maturation and T cell differentiation.
Figure 1. Mechanisms of direct cytotoxicity in NK cells. (A) Particulate exocytosis pathway. (B) Death receptor binding pathway. [1]
Human aging is associated with a decline in NK cell function
Studies have confirmed that human aging is associated with a decline in NK cell function, including senescent cell accumulation, delayed resolution of inflammation, and reduced antimicrobial immunity. NK cells not only play a key role in anti-viral immunity, but also play an important role in resolving inflammation and identifying and removing senescent cells. As a result, the health implications of NK cell immune function in older adults may be much broader than previously thought.
1. Accumulation of senescent cells
A distinctive feature of physiological senescence is the accumulation of senescent cells in the body. These cells, which are commonly found in the skin, bones, and endothelial cells of older adults, remain metabolically active despite being in a state of cell cycle arrest and secrete a range of growth factors, pro-inflammatory cytokines, and proteases that adversely affect tissue health. NK cells remove senescent cells by granulosa exocytosis. Thus, NK cytotoxicity (NKCC) decreases with age and may be a reason for the increased frequency of senescent cells in senescent tissues.
2. Delay in resolution of inflammation
The new role of NK cells in immune regulation is gradually being discovered. In a viral mouse model, NK cells are able to lyse dendritic cells as well as CD4+ and CD8+ T cells in a perforin-dependent manner. At the same time, NK cells can also induce neutrophil apoptosis through death receptor linkage. With age, the cytotoxicity mediated by perforin (NKCC) of NK cells decreases, suggesting that the immunomodulatory function of NK cells may be impaired. This change may result in older people having more severe symptoms at the time of infection and a longer recovery period after infection.
3. Weakening of antimicrobial immunity
NK cells are also involved in the immune response against bacteria and fungi, directly attacking these pathogens through perforin-mediated cytotoxicity and secretion of interferon-γ (IFN-γ), or by synergistically fighting by enhancing the activity of other immune cells. The incidence of bacterial and fungal infections is higher in older people compared to younger people. NK cells' cytotoxic effects mediated by the granulosa exocytosis pathway (NKCC) wanes with age, which reduces their antifungal activity.
At the same time, the ability of NK cells to secrete IFN-γ also decreases with age, which affects their ability to clear bacteria. Therefore, a decrease in NK cell function may impair overall antimicrobial immunity.
brief summary
NK cells are not only involved in antiviral and tumor immunity, but also play a key role in immune regulation, adaptive immune response initiation, and senescent cell clearance. As the human body ages, the function of NK cells gradually declines, which may lead to a decrease in the efficacy of vaccination, the accumulation of senescent cells, and an increase in the infection rate in the elderly. Therefore, it is of great significance to study how to prevent, delay or reverse the decline of NK cell function to improve the health level of the elderly.
Bibliography:
[1] Hazeldine J, Lord JM. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev. 2013; 12(4):1069-1078. doi:10.1016/j.arr.2013.04.003