Impaired immune surveillance accelerates accumulation of senescent cells and aging

Yossi Ovadya, Tomer Landsberger, Hanna Leins, Ezra Vadai, Hilah Gal, Anat Biran, Reut Yosef, Adi Sagiv, Amit Agrawal, Alon Shapira, Joseph Windheim, Michael Tsoory, Reinhold Schirmbeck, Ido Amit, Hartmut Geiger and Valery Krizhanovsky ()
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Yossi Ovadya: The Weizmann Institute of Science
Tomer Landsberger: The Weizmann Institute of Science
Hanna Leins: Ulm University
Ezra Vadai: The Weizmann Institute of Science
Hilah Gal: The Weizmann Institute of Science
Anat Biran: The Weizmann Institute of Science
Reut Yosef: The Weizmann Institute of Science
Adi Sagiv: The Weizmann Institute of Science
Amit Agrawal: The Weizmann Institute of Science
Alon Shapira: The Weizmann Institute of Science
Joseph Windheim: The Weizmann Institute of Science
Michael Tsoory: The Weizmann Institute of Science
Reinhold Schirmbeck: University Hospital of Ulm
Ido Amit: The Weizmann Institute of Science
Hartmut Geiger: Ulm University
Valery Krizhanovsky: The Weizmann Institute of Science

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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. Here 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 ABT-737 partially alleviates accelerated aging phenotype in these mice. In LMNA+/G609G progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.

Date: 2018
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DOI: 10.1038/s41467-018-07825-3

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