Journal
NATURE CELL BIOLOGY
Volume 17, Issue 8, Pages 1049-U416Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3195
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Funding
- National institutes of Health (NIH) [AG045288, AG909266-16, CP143858, CA155679, CA071468, AG032113, AG025961, CA164188, CA165573, CA097186, AG09909, AG017212, AG041122]
- Hillblom Medical Foundation
- DOD-PCRP grant [PC111703]
- National Natural Science Foundation of China [81472799]
- Prostate Cancer Foundation
- NATIONAL CANCER INSTITUTE [R21CA155679, U24CA143858, U01CA164188, P50CA097186, R01CA071468, R01CA165573] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG017242, P01AG041122, K99AG045288, R56AG009909, T32AG000266, P01AG025901, R37AG009909, R01AG045835, P30AG013319, RL1AG032113, R01AG009909] Funding Source: NIH RePORTER
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The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-kappa B transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
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