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M311980200v1
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Papers In Press, published online ahead of print February 12, 2004
J. Biol. Chem, 10.1074/jbc.M311980200
Submitted on October 31, 2003
Revised on February 12, 2004
Accepted on February 12, 2004

Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative lifespan

Carmen Martin-Ruiz, Gabriele Saretzki, Joanne Petrie, Juliane Ladhoff, Jessie Jeyapalan, Wenyi Wei, John Sedivy, and Thomas von Zglinicki

Gerontology, University of Newcastle, Newcastle upon Tyne NE4 6BE

Corresponding Author: t.vonzglinicki{at}ncl.ac.uk

The replicative lifespan of human fibroblasts is heterogeneous, with a fraction of cells senescing at every population doubling. To find out whether this heterogeneity is due to premature senescence, i.e. driven by a non-telomeric mechanism, fibroblasts with a senescent phenotype were isolated from growing cultures and clones by flow cytometry. These senescent cells had shorter telomeres than their cycling counterparts at all population doubling levels and both in mass cultures and in individual sub-clones, indicating heterogeneity in the rate of telomere shortening. Ectopic expression of telomerase stabilised telomere length in the majority of cells and rescued these from early senescence, suggesting a causal role of telomere shortening. Under standard cell culture conditions, there was a minor fraction of cells which showed a senescent phenotype and short telomeres despite active telomerase. This fraction increased under chronic mild oxidative stress, which is known to accelerate telomere shortening. It is possible that even high telomerase activity cannot fully compensate for telomere shortening in all cells. The data show that heterogeneity of human fibroblast replicative lifespan can be caused by significant stochastic cell-to-cell variation in telomere shortening.


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