Abstract
Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer’s disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally.
Highlights
Cellular senescence is an anti-tumor program that is triggered by different insults like telomere shortening, oxidative stress and oncogene activation [1,2,3]
Cell fate decisions between apoptosis or senescence upon DNA damage occur at cell cycle checkpoints [21]
We describe our proposal for the mechanisms involved in the regulation of astrocyte senescence and SASP upon checkpoint induction
Summary
Cellular senescence is an anti-tumor program that is triggered by different insults like telomere shortening, oxidative stress and oncogene activation [1,2,3]. Experimental evidences support that senescent cells accumulate in aging mammal tissues and have an altered phenotype, called SASP (senescence-associated secretory phenotype), that apparently contributes to several aging diseases including Alzheimer’s disease (AD) [3,4,5,6]. SASP contributes to ‘inflamm-aging’ (the development of a systemic proinflammatory status with normal aging) which involves an increase of blood plasma levels of inflammatory cytokines like interleukin 6 (IL-6) [7]. In the case of AD, astrocyte senescence is claimed to be an important contributor to the development of the pathology [5]. Astrocytes are the most numerous cell type in the human brain and are involved in many essential physiological functions that keep the brain homeostasis, PLOS ONE | DOI:10.1371/journal.pone.0125217. Astrocytes are the most numerous cell type in the human brain and are involved in many essential physiological functions that keep the brain homeostasis, PLOS ONE | DOI:10.1371/journal.pone.0125217 May 8, 2015
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