, Vol 8 No 5
those that did not. Cells with longer telomeres did notundergo senescence, whereas those with short telomeresdid [1,2]. Telomere length is therefore one criterion thatdetermines entry into cell senescence (Figure 2).
The interpretation and the future
Like all good experiments, this discovery raises more ques-tions than it answers. At the simplest level there aredetailed questions about how telomere length might signalentry into senescence. What is measured? The length of the shortest telomere? The average telomere length, or thetotal number of telomere repeats? How is the signal sentand what are the pathways that respond? The medicalimplications of the experiment are also important toexplore. Extending the life span of primary cells could sig-nificantly enhance the ability to grow cells
for autol-ogous transplantation. This technique could be useful ingrowing extra skin cells for burn victims, for example.Telomerase has also been proposed for gene therapy toextend the life span of cells
. Before such app-roaches are implemented, it will be important to under-stand better why cells senesce. If cellular senescenceindeed is a mechanism of tumor suppression (reviewed in), activation of telomerase might pre-dispose cells totumor formation by overcoming one of the many stepsrequired for transformation.Recent experiments have shown that mouse cells lackingtelomerase become transformed and cause tumors .Does this suggest that telomerase activation will not play arole in the transformation of human cells? Probably not,because there are important differences between humanand mouse cells. First the length of telomere repeatsequence on mouse chromosomes is two-to-five timeslonger than human telomere tracts [31–33], suggestingmouse cells may be less sensitive than human cells totelomere shortening. Second, mouse cells immortalizemuch more readily than human cells. Humans, as a long-lived species, may have evolved have additional mecha-nisms to protect against cell immortalization and cancer.Human cells may use telomeres to signal senescence andthus limit cells growth, while mouse cells do not. With therecent advances in understanding the basic structure andsynthesis of telomeres, it is now possible to test whetherextending cell life span might predispose human cells totumor formation.
I thank members of the Greider laboratory research group and Titia deLange, Jef Boeke and Nathaniel Comfort for helpful discussions and usefulcomments on the manuscript. Work in my lab is supported by the NationalInstitutes of Health.
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In cell strains that do not express telomerase, telomere repeats arelost during cell division. When telomeres reach a certain length, asignal is sent to initiate a program of cellular senescence.
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C e l l d i v i s i o n s