The senescent cell induced bystander effect

Abstract

The induction of senescence in response to persistent stress induces major phenotypic changes in senescent cells, including the secretion of a host of inflammatory factors and reactive oxygen species. Recent evidence has implicated senescent cells in the diseases of ageing and cancer; however, the mechanism by which this occurs is still unknown. This thesis uses a reporter cell line with cells expressing a fluorescent conjugate that allows real time live cell imaging of a sub set of cells within a co-culture, to provide the first evidence that senescent cells can induce a DNA damage response in healthy cells, and thus implicates a potential mechanism by which senescent cells could non-autonomously contribute to the ageing process. The use of specific inhibitors, stimulation, and targeted repression indicate that gap junctions, reactive oxygen species, p38, mTOR and NF-κB all play a key role in this observed bystander effect of senescent cells, and offer potential targets for therapies designed to reduce the damaging effects of senescent cells.