TY - JOUR
T1 - Impaired immune surveillance accelerates accumulation of senescent cells and aging
AU - Ovadya, Yossi
AU - Landsberger, Tomer
AU - Leins, Hanna
AU - Vadai, Ezra
AU - Gal, Hilah
AU - Biran, Anat
AU - Yosef, Reut
AU - Sagiv, Adi
AU - Agrawal, Amit
AU - Shapira, Alon
AU - Windheim, Joseph
AU - Tsoory, Michael
AU - Schirmbeck, Reinhold
AU - Amit, Ido
AU - Geiger, Hartmut
AU - Krizhanovsky, Valery
N1 - We thank Carlos López-Otin (Universidad de Oviedo, Spain) for the LmnaG609G mice. We thank all members of the Krizhanovsky Laboratory for critical reading of the manuscript and insightful discussions. We thank Ori Brenner (WIS) for his assistance in pathological evaluation of old mice, and Inbal Biton (WIS) for assisting in micro-CT analysis. H.G and R.S were supported by RTGCEMMA funded by the DFG. Y.O. was supported by German-Israeli Helmholtz Research School. This work was supported by grants to V.K. from the European Research Council under the European Union’s FP7, and from the Israel Science Foundation.
PY - 2018/12/21
Y1 - 2018/12/21
N2 - 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 senescentcell presence in aging, and could motivate new strategies for regenerative medicine.
AB - 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 senescentcell presence in aging, and could motivate new strategies for regenerative medicine.
UR - http://www.scopus.com/inward/record.url?scp=85058920616&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-018-07825-3
DO - https://doi.org/10.1038/s41467-018-07825-3
M3 - مقالة
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5435
ER -