Accumulation of senescent cells - mechanisms and consequences

Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. We show that Prf1^-/- mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and lower survival. Strikingly, pharmacological elimination of senescent-cells by a Bcl-2 family inhibitor ABT-737 partially alleviates accelerated aging phenotype in these mice. In LMNA^+/G609G progeroid mice reduced survival is also concomitant with accumulation of senescent cells. Impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan of these mice. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence expression signature in multiple tissues and increases median survival. Our findings show for the first time that accumulation of senescent cells during aging is regulated by the immune system. We also demonstrate that even transient elimination of senescent cells can lead to reduction of inflammatory load, improved structure and function of multiple tissues, and extend median survival. Our finding propose new possibilities of modulation the presence of senescent cell through the immune regulation and thus point to novel approaches to target age-related diseases.