Cooperation between inhibitory immune checkpoints of senescent cells with immunosuppressive network to promote immunosenescence and the aging process.

The accumulation of senescent cells within tissues promotes the aging process by remodelling the functions of the immune system. For many years, it has been known that senescent cells secrete pro-inflammatory cytokines and chemokines, a phenotype called the senescence-associated secretory phenotype (SASP). Chemokines and colony-stimulating factors stimulate myelopoiesis and recruit myeloid cells into aging tissues. Interestingly, recent studies have demonstrated that senescent cells are not only secretory but they also express an increased level of ligand proteins for many inhibitory immune checkpoint receptors. These ligands represent "don't eat me" markers in senescent cells and moreover, they are able to induce an exhaustion of many immune cells, such as surveying natural killer (NK) cells, cytotoxic CD8 T cells, and macrophages. The programmed cell death protein-1 (PD-1) and its ligand PD-L1 represent the best known inhibitory immune checkpoint pathway. Importantly, the activation of inhibitory checkpoint receptors, e.g., in chronic inflammatory states, can also induce certain immune cells to differentiate toward their immunosuppressive phenotype. This can be observed in myeloid derived suppressor cells (MDSC), tissue regulatory T cells (Treg), and M2 macrophages. Conversely, these immunosuppressive cells stimulate in senescent cells the expression of many ligand proteins for inhibitory checkpoint receptors. Paradoxically, senescent cells not only promote the pro-inflammatory state but they maintain it at a low-grade level by expressing ligands for inhibitory immune checkpoint receptors. Thus, the cooperation between senescent cells and immunosuppressive cells enhances the senescence state of immune cells, i.e., immune senescence/exhaustion, and cellular senescence within tissues via bystander effects.