This thesis of LetÃcya Melo dos Santos provides a comprehensive investigation into the role of cellular senescence in immune cells, focusing on macrophages and microglia in aging, diseases, and therapeutic responses, as well as the immune landscape during COVID-19. Cellular senescence, characterized by irreversible cell-cycle arrest, is marked by key markers such as p16, p21, and p53, which contribute to a pro-inflammatory state called SASP. This state influences tissue homeostasis, immune responses, and disease progression, especially in aging and chronic diseases like cancer and neurodegeneration.
A central theme of the thesis is the complexity of defining senescent immune cells. Macrophages and microglia exhibit a spectrum of states from quiescence to transient senescence, with the potential for proliferation in specific contexts. During the COVID-19 pandemic, the accumulation of senescent immune cells was linked to severe outcomes in older individuals. Findings suggest that therapies like inhaled nitric oxide (iNO) can modulate immune responses by preventing immune exhaustion and excessive inflammation.
The role of p16+ macrophages and senescent microglia in diseases like cancer and neurodegeneration was extensively studied. While targeting senescent tumor-associated macrophages (TAMs) offers therapeutic potential, it also poses challenges due to the dual protective and harmful roles of senescent cells.
By integrating novel markers like EMB and CD93, this work proposes strategies for selectively targeting senescent cells without compromising normal functions. The findings underscore the need for context-dependent therapies that balance the elimination of harmful senescent cells with preserving their beneficial roles in aging, cancer, and viral infections
