Abstract
Replicative senescence has initially been defined as a stress reaction of replication-competent cultured cells in vitro, resulting in an ultimate cell cycle arrest at preserved growth and viability. Classically, it has been linked to critical telomere curtailment following repetitive cell divisions, and later described as a response to oncogenes and other stressors. Currently, there are compelling new directions indicating that a comparable state of cellular senescence might be adopted also by postmitotic cell entities, including terminally differentiated neurons. However, the cellular upstream inducers and molecular downstream cues mediating a senescence-like state in neurons (amitosenescence) are ill-defined. Here, we address the phenomenon of abortive atypical cell cycle activity in light of amitosenescence, and discuss why such replicative reprogramming might provide a yet unconsidered source to explain senescence in maturated neurons. We also hypothesize the existence of a G0 subphase as a priming factor for cell cycle re-entry, in analogy to discoveries in quiescent muscle stem cells. In conclusion, we propose a revision of our current view on the process and definition of senescence by encompassing a primarily replication-incompetent state (amitosenescence), which might be expanded by events of atypical cell cycle activity (pseudomitosenescence).
Highlights
Hans-Berger Department of Neurology, Jena University Hospital, 07747 Jena, Thuringia, Germany; Jena Center for Healthy Ageing, Jena University Hospital, 07747 Jena, Thuringia, Germany
Thereby, the induction of mH2A might be directly indicative of an altered suppression state under senescence, and reflect a compensatory response to unscheduled cell cycle re-entry in neurons
We hypothesize that a reinduced cell cycle in postmitotic cells, which per se can undergo senescence, might link cellular stress to the induction of a senescent-like but vital state of pseudomitosenescence, and enable neurons to repurpose their preserved cell cycle machinery for alternative homologous recombination (HR)-independent DNA repair strategies
Summary
We recently found that mature non-replicative G0 neurons are subjected to an age-related telomere erosion process [9], supporting the concept of amitosenescence and a role of telomere attrition in postmitotic senescence. According to recent developments in neuroscience, terminally differentiated neurons might adopt a senescence-like state out of a quiescent G0 phase, e.g., consecutive to cellular stress imposed by DNA and telomere damage, a process termed here as ‘amitosenescence’.
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