Non-Intrinsic, Systemic Mechanisms of Cellular Senescence

Cellular senescence is believed to contribute to aging and disease through the activity of secreted factors that promote inflammation, remodel the extracellular matrix, and adversely modify the behavior of non-senescent cells. While the markers and properties of senescent cells are still under investigation, it is postulated that cellular senescence manifests in vivo as the consequence of cellular damage that accumulates and becomes exacerbated with time. Yet, the notions that senescence has a solely intrinsic and time-dependent nature are questioned by the rapid induction of senescence in young mice and young cells in vitro by exposure to blood from aged animals. Here, we review some of the research on the systemically present factors that increase with age and may contribute to extrinsically induced senescence or "bystander senescence". These include proteins, reactive oxygen species, lipids, and nucleic acids, which may be present in individual soluble form, in vesicles, and in non-membranous multi-component macromolecules.