Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related...

Aging is a progressive degenerative process involving a chronic low-grade inflammation and the accumulation of senescent cells. One major issue is to reveal the mechanisms which promote the deposition of pro-inflammatory senescent cells within tissues. The accumulation involves mechanisms which increase cellular senescence as well as those inhibiting the clearance of senescent cells from tissues. It is known that a persistent inflammatory state evokes a compensatory immunosuppression which inhibits pro-inflammatory processes by impairing the functions of effector immune cells, e.g., macrophages, T cells and natural killer (NK) cells. Unfortunately, these cells are indispensable for immune surveillance and the subsequent clearance of senescent cells, i.e., the inflammation-induced counteracting immunosuppression prevents the cleansing of host tissues. Moreover, senescent cells can also repress their own clearance by expressing inhibitors of immune surveillance and releasing the ligands of NKG2D receptors which impair their surveillance by NK and cytotoxic CD8⁺ T cells. It seems that cellular senescence and immunosuppression establish a feed-forward process which promotes the aging process and age-related diseases. I will examine in detail the immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging. In addition, I will discuss several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases.