International Journal of Molecular Medical Science, 2025, Vol.15, No.4, 165-174 http://medscipublisher.com/index.php/ijmms 168 ways to relieve stress may help counteract these negative effects. This indicates that a holistic approach is needed to enhance the efficacy of vaccines for physically weak elderly people. 4 Immunological Mechanisms 4.1 Decline and dysfunction of T-cell immune responses When people age, the ability of an important type of immune cell - T cells - will significantly decline, which is one of the main manifestations of the aging of the immune system. This includes a decrease in T cell division, a reduction in the number of "new recruit" T cells capable of dealing with new pathogens, and an increase in T cells that "remember" old pathogens and "age". These changes combined have made the body less responsive to new pathogens and vaccines (Lewis et al., 2022; Zhang et al., 2024). In an aging immune system, T cells are also more prone to "exhaustion", which is manifested as a decline in combat effectiveness and a deterioration in memory. This further weakens the body's ability to defend against bacteria and the effectiveness of vaccines (Mittelbrunn and Kroemer, 2021; Gao et al., 2022). Aging is also related to the shrinking of the thymus (where T cells are produced) and problems with the "energy factory" (mitochondria) within T cells. This will lead to a reduction in the types of "tools" (TCRS) that T cells use to recognize pathogens and also slow down the initiation of responses. These changes lead to a decline in the ability of T cells to kill bacteria, and the signals they emit become weaker, thereby reducing the body's ability to clear infections or have a strong response to vaccines. Overall, frail elderly people are more prone to illness, and the protective effect of vaccines will also be weakened (Mittelbrunn and Kroemer, 2021; Lewis et al., 2022). 4.2 Reduced B-cell responses and decreased antibody quality Another important type of immune cell - B cells, their functions also deteriorate with age, affecting the quantity and quality of antibodies produced by the body. Although the total number of B cells in the blood may not change much, aging can cause problems with the B cells themselves, such as: The ability of antibodies to "upgrade" deteriorates (reduced switching recombination), the capacity to produce antibodies that "hold more firmly" declines (impaired somatic hypermutation), and the ability to manufacture high-quality antibodies weakens (reduced production of high-affinity antibodies). These deficiencies lead to a reduction in the number of specific antibodies produced after vaccination, a weakening of the antibodies' ability to capture and kill germs, and a narrowing of the types of germs that the antibodies can deal with (Frasca and Blomberg, 2020; Frasca et al., 2020). In addition, in the bodies of the elderly, the number of B cells that are prone to "inflammation" and those that specifically "apply the brakes" (regulatory B cells) increases, which further suppresses effective immune responses (Catalan et al., 2021). The ultimate result is that the body's fluid defense (humoral response) after vaccination is not ideal, and the protection against infectious diseases declines. Elderly people with weak constitutions are more likely to be infected even after vaccination (with a greater risk of breakthrough infections) (Frasca and Blomberg, 2020; Frasca et al., 2020). 4.3 Dual impact of chronic low-grade inflammation and immunosuppressive factors A long-term state of mild inflammation (also known as "inflammation") in the body is a sign of aging and is closely related to the aging of the immune system. Persistently high levels of "inflammatory signals" (such as IL-6 and TNF-α) in the body can disrupt the function of immune cells and increase the number of some specialized "brake pedal" immune cells, such as bone marrow-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-type macrophages (Thomas et al., 2021). These cells release "brake pedal" substances (such as IL-10, TGF-β, arginase-1), which prevent T cells and B cells from dividing and functioning, further suppressing the response to vaccines (Figure 1) (Salminen, 2021; Cisneros et al., 2022; Salminen, 2022). This double blow forms a vicious cycle: long-term inflammation triggers a physiological "braking" (immunosuppression), and this "braking" in turn makes the immune system function worse, reducing its response to vaccines. The interaction between long-term inflammation and the immune "brake" network is a major reason for the poor efficacy of vaccines in physically weak elderly people, which indicates that we need to find ways to specifically break this vicious cycle (Salminen, 2021; Thomas et al., 2021; Cisneros et al., 2022; Salminen, 2022).
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