Cellular senescence and the host immune system in aging and age-related disorders

Cellular senescence is a complex process involving a close-to-irreversible arrest of the cell cycle, the acquisition of the senescence-associated secretory phenotype (SASP), as well as profound changes in the expression of cell surface proteins that determine the recognition of senescent cells by innate and cognate immune effectors including macrophages, NK, NKT and T cells. It is important to note that senescence can occur in a transient fashion to improve the homeostatic response of tissues to stress. Moreover, both the excessive gen-eration and the insufficient elimination of senescent cells may contribute to pathological aging. Attempts are being made to identify the mechanisms through which senescent cell avoid their destruction by immune effectors. Such mechanisms involve the cell surface expression of immunosuppressive molecules including PD-L1 and PD-L2 to ligate PD-1 on T cells, as well as tolerogenic MHC class-I variants. In addition, senescent cells can secrete factors that attract immunosuppressive and pro-inflammatory cells into the microenvi-ronment. Each of these immune evasion mechanism offers a target for therapeutic inter-vention, e.g., by blocking the interaction between PD-1 and PD-L1 or PD-L2, upregulating immunogenic MHC class-I molecules and eliminating immunosuppressive cell types. In addition, senescent cells differ in their antigenic makeup and immunopeptidome from their normal counterparts, hence offering the opportunity to stimulate immune response against senescence-associated antigens. Ideally, immunological anti-senescence strategies should succeed in selectively eliminating pathogenic senescent cells but spare homeostatic senescence.

Automated summary

Cellular senescence involves cell cycle arrest, the acquisition of senescence-associated secretory phenotype (SASP), and changes in cell surface proteins influencing the recognition of senescent cells by immune effectors. Excessive or insufficient senescent cell generation can contribute to pathological aging. Mechanisms such as immunosuppressive molecule expression and secretion of factors attracting immune cells into the microenvironment allow evasion of immune destruction. Immune interventions can target these mechanisms and stimulate an immune response against senescence-associated antigens.