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. 2011 Feb 21;192(4):547–556. doi: 10.1083/jcb.201009094

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© 2011 Rodier and Campisi

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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Figure 3. — Temporal organization of the senescent phenotype. Upon experiencing a potentially oncogenic insult, cells assess the stress and must “decide” whether to attempt repair and recovery, or undergo senescence. After an interval (decision period), the length of which is imprecisely known, the senescence growth arrest becomes essentially permanent, effectively suppressing the ability of the stressed cell to form a malignant tumor. One early manifestation of the senescent phenotype is the expression of cell surface–bound IL-1α. This cytokine acts in a juxtacrine manner to bind the cell surface–bound IL-1 receptor, which initiates a signaling cascade that activates transcription factors (NF-κB, C/EBPβ). The transcription factors subsequently stimulate the expression of many secreted (SASP) proteins, including increasing the expression of IL-1α and inducing expression of the inflammatory cytokines IL-6 and IL-8. These positive cytokine feedback loops intensify the SASP until it reaches levels found in senescent cells. SASP components such as IL-6, IL-8, and MMPs can promote tissue repair, but also cancer progression. Some SASP proteins, in conjunction with cell surface ligands and adhesion molecules expressed by senescent cells, eventually attract immune cells that kill and clear senescent cells. A late manifestation of the senescent phenotype is the expression of microRNAs (mir-146a and mir-146b), which tune down the expression IL-6, IL-8, and possibly other SASP proteins, presumably to prevent the SASP from generating a persistent acute inflammatory response. Despite this dampening effect, the SASP can nonetheless continue to generate low-level chronic inflammation. The accumulation of senescent cells that either escape or outpace immune clearance and express a SASP at chronic low levels is hypothesized to drive aging phenotypes. Thus, senescent cells, over time (yellow line), develop a phenotype that becomes increasingly complex (blue triangle), with both beneficial (tumor suppression and tissue repair) and deleterious (tumor promotion and aging) effects on the health of the organism.