Free radicals and senescence

Abstract

There is a significant body of experimental evidence that a rise in intracellular reactive oxygen species (ROS) contributes to senescence. Here we review experiments where entry into senescence has been evaluated in cells whose intracellular ROS levels have been modulated by growth in either high or low ambient oxygen concentrations, or where the cellular antioxidant status has been perturbed. In addition, we discuss the observations that senescence triggered by oncogene expression also appears to be in part mediated by a rise in ROS levels. Finally, we discuss the emerging evidence that in vivo senescence might also be triggered by a rise in cellular oxidant levels. Although these data tend to support a role for ROS in mediating senescence, significant questions remain as to whether ROS act in a random or specific fashion and what precise oxidant species acts as the potential senescence trigger.

Figure

ROS as a common mediator of cellular senescence. Various extrinsic or intrinsic manipulations including changing the intracellular antioxidant status, raising ambient oxygen concentration, directly exposing cells to hydrogen peroxide or the expression of certain oncogenes, all appear to produce a rise in intracellular ROS levels. This rise in ROS within cells accompanies and potentially triggers senescence entry. As discussed in the text, oxidants may directly activate certain redox-sensitive pathways linked to senescence. Alternatively, oxidants might non-specifically induce a spectrum of damage to cellular components (e.g. DNA) that directly leads to senescence or this damage might induce senescence by secondarily activating important intracellular pathways, such as the DNA damage response.