Senescent Cells in Aged Tissues May Use Immune Checkpoints to Prevent Immune Clearance
Immune clearance of senescence cells falters with age, becoming less efficient. This allows lingering senescent cells to accumulate, and their disruptive, inflammatory secretions contribute meaningfully to degenerative aging and age-related mortality. Greater knowledge of how exactly the immune system fails in its job may open novel avenues in the development of senolytic therapies to clear senescent cells - look at the work of Deciduous Therapeutics, for example. Here, researchers note that senescent cells appear to make use of immune checkpoints to fend off immune clearance. This area of biochemistry is well explored in connection with cancer immunology, and it may turn out to help in the context of senescent cells.
The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues.
Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T cells and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPĪ± receptors.
Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.