Cellular senescence: from growth arrest to immunogenic conversion

Abstract

Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical^senescent states that may occur independent of DNA damage.

Biomarkers to identify and isolate senescent cells

“…Interestingly, cellular senescence can also be induced by stress (Toussaint et al, 2000) and oncogenes (Bartkova et al, 2006), demonstrating that cellular senescence is not only caused by exhaustion of replicative capacity as first thought. Such heterogeneity of cellular senescence, which we will briefly discuss in the next paragraph, has led a field to sometimes unnecessary ambiguity, leaving researchers to disagree what cellular senescence entails (Burton and Faragher, 2015).…”

A Peripheral Blood Transcriptome Biomarker Test to Diagnose Functional Recovery Potential in Advanced Heart Failure

“…HF-related frailty and cardiac cachexia are similar if not the same phenotype [110,111]. In AdHF, tissue wasting and cardiac cachexia have been associated with upregulation of the inflammatory biomarkers IL-1 and IL-6, C-reactive protein and TNF-α [112], T-cell and innate immune cell dysfunction [58,85,113], increased numbers of terminally differentiated T cells [114], immunosenescence and immune exhaustion [115,116].…”

Current indications for transplantation: stratification of severe heart failure and shared decision-making

“…They are therefore at increased risk for OD and death after MCS or HTx surgery. HF-related preoperative immunologic impairment is a component of poor outcomes after MCS and HTx, owing to the known associations between increased age, T cell and innate immune cell dysfunction (17)(18)(19), increased numbers of terminally differentiated T cells (20), immune-senescence (deficient replicative ability), and immune-exhaustion (impaired antigen response) (21,22).…”