Elsevier

Experimental Cell Research

Volume 314, Issue 9, 15 May 2008, Pages 1918-1922
Experimental Cell Research

Review
Free radicals and senescence

https://doi.org/10.1016/j.yexcr.2008.01.011Get rights and content

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.

Section snippets

Ambient oxygen and cellular senescence

The observations by Hayflick that normal human diploid cells have a finite number of population doublings [1] provided the impetus for many other laboratories to begin to define the genetic and environmental factors regulating in vitro senescence. There was considerable concern initially that senescence was not an intrinsic property of cells and that it was the artificial nature of tissue culture systems that was in some way responsible for limiting the growth of cells. For instance, many were

Oncogene-induced senescence: a role for ROS

As noted above, senescence can be induced simply by growing cells in culture (replicative senescence) or by subjecting cells to non-lethal stress such as hydrogen peroxide. A significant insight into the potential physiological relevance of senescence came with the observation that primary cells with high level expression of the Ras oncogene underwent rapid senescence [15]. These results were unexpected because the property of oncogenes was routinely associated with uninhibited and increased

Senescence, ROS and disease

The original ‘Free Radical Theory of Aging’ postulated that ROS contributed not only to the rate we age but also served as the impetus for a number of age-related diseases [26]. There are numerous studies suggesting that oxidants might contribute to a wide spectrum of human maladies including cancer, cardiovascular disease and a host of neurodegenerative conditions [6]. There is also a growing body of literature suggesting that senescence within progenitor cells or resident mature cells might

Summary

On a cellular level there is abundant evidence that a rise in ROS levels contributes to senescence. Nonetheless, multiple questions remain. One unresolved issue is whether there is a gradient of ROS-induced effects. This notion was first inferred from the addition of exogenous hydrogen peroxide where it was clear that in some cells, very high doses of hydrogen peroxide (> 1 mM) induced cell death, moderate doses (100–500 μM) induced senescence, while lower doses either were without effect or

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