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J. Biol. Chem., Vol. 279, Issue 17, 17826-17833, April 23, 2004

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Stochastic Variation in Telomere Shortening Rate Causes Heterogeneity of Human Fibroblast Replicative Life Span^*

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

From the Henry Wellcome Biogerontology Laboratory, School of Clinical Medical Sciences, University of Newcastle, General Hospital, Newcastle NE4 6BE, United Kingdom and the ^¶Department of Molecular Biology, Cell Biology and Biochemistry, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912

The replicative life span 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 nontelomeric 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 subclones, indicating heterogeneity in the rate of telomere shortening. Ectopic expression of telomerase stabilized telomere length in the majority of cells and rescued them from early senescence, suggesting a causal role of telomere shortening. Under standard cell culture conditions, there was a minor fraction of cells that 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 the human fibroblast replicative life span can be caused by significant stochastic cell-to-cell variation in telomere shortening.

Received for publication, October 31, 2003 , and in revised form, February 4, 2004.

^* This work was supported by grants from Medical Research Council and Research into Aging, UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 44-191-256-3310; Fax: 44-191-256-3445; E-mail: t.vonzglinicki{at}ncl.ac.uk.

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