Effectors of cellular senescence states

Brown University, Providence RI

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Abstract

DESCRIPTION (provided by applicant): Replicative cellular senescence is a phenomenon of irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. The great majority of normal cell types from all vertebrate species examined display this response. It is becoming increasingly evident that what has classically been described as cellular senescence is a collection of interrelated states that can be triggered by distinct intrinsic and extrinsic stimuli. The underlying cause of senescence due to replicative exhaustion is telomere shortening. In addition, it is now apparent that many types of stress, reactive oxygen species, pharmacological agents, and even nutrient imbalances can trigger a senescence response. Activation of some oncogenes also induces senescence in normal cells, and recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism. In contrast, the connections between cellular senescence and the aging of organisms are significantly more tenuous. The necessary first step is to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. We, and others, have recently developed a method based on the microscopic detection of DNA damage markers localized to telomeres, designated the `TIF' assay (for `telomere dysfunction-induced foci'). TIFs are a robust biomarker of telomere-initiated senescence, which we used to demonstrate a marked age-associated accumulation of senescent cells in normal primate tissues. This proposal is aimed to give us a better understanding of multiple cellular senescence processes, focusing on their roles in organismal aging. Aim 1 will examine the in vivo occurrence of telomere-induced senescence in mouse, primate and human models, and probe the links between cellular senescence and pathways that functionally influence aging. Aim 2 will extend recent studies linking genome-wide changes in chromatin structure with cellular senescence by developing new assays to assess in vivo states of heterochromatin in cells and tissues. These new biomarkers of cellular senescence will then be applied to the models developed in Aim 1. Aim 3 will seek to discover what causes the age-dependent upregulation of the cyclin-dependent kinase inhibitor p16, an important effector implicated in regulating multiple senescent states.