Trends in Biochemical Sciences
OpinionOxidative stress shortens telomeres
Section snippets
Heterogeneity in replicative senescence
In a classic experiment, Smith and Whitney [8] demonstrated huge heterogeneity, and even bimodality, in the doubling potential of individual cells from a clonally derived cell population. Other studies using BrdU labelling [9], Ki67 staining [10] or a p53-activity reporter assay [11] have shown that, with increasing population doubling level, fewer and fewer cells remain in the actively proliferating pool. This has been interpreted as indicating that a certain proportion of cells drop
Stress dependency of replicative senescence
The irreversible loss of replicative capacity leads to a senescent phenotype, which is characterized by: irreversible growth inhibition, mostly in G1; changes in cell morphology such as flattening and enlargement; increased staining for senescence-associated β-galactosidase; a changed gene-expression pattern; and upregulation of the activities of p53 or p21. Such arrest is produced not only after accumulated population doublings in culture, with concomitant telomere shortening, but also as a
How does oxidative stress cause telomere shortening?
The lowest telomere shortening rates in human fibroblasts are around 10–20 bp per population doubling (Fig. 2). This shows that polymerase α can position the most distal primer very close to the physical end of the chromosome. Faster telomere shortening rates are observed in other cell strains, which also have higher peroxide levels, indicating less efficient antioxidant defence 25., 31.. The clear implication is that the contribution to telomere loss caused by oxidative damage is, in many
Conclusion
Cellular replicative senescence is heterogeneous even within a clonally derived cell population growing under standard (i.e. low-stress) conditions, and the rates of cellular ageing and telomere shortening in bulk culture depend on the balance between oxidative stress and antioxidative defence. This strongly suggests that the main mechanism of senescence under low and mild stress conditions is telomere shortening, and that telomere shortening itself is stress dependent. The rate of telomere
Acknowledgements
My work leading to this article was supported by Verum Foundation Munich, the Deutsche Forschungsgemeinschaft, Germany and the Medical Research Council (UK). I thank T. Kirkwood for critically reading the article.
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