Replicative Senescence and the Telomere Hypothesis

In the 19th century, August Weismann, a German zoologist, had the idea that ageing could be a consequence of somatic cells having a finite life span (Kirkwood and Cremer 1982). Eighty years were necessary to prove Weismann's prediction experimentally. Hayflick and Moorhead showed that embryo-derived fibroblasts can divide 50±10 times before arresting irreversibly when cultured in vitro (Hayflick and Moorhead 1961). The potential number of divisions became known as the "Hayflick limit," and the phenomenon was termed replicative senescence.

Early on, it was suggested that the shortening of telomeres, the ends of chromosomes, might function as a replicometer (counting the finite number of cell divisions) and as a trigger of replicative senescence in normal diploid cells (Olovnikov 1971, Watson 1972). Later, this idea was tested experimentally (Harley et al. 1990). The best evidence in support of a telomere-dependent senescence mechanism is the observation that ectopic expression of the catalytic subunit of telomerase, an enzyme able to counteract telomere shortening, can lead to cell immortalization on its own (Bodnar et al. 1998). It is believed that telomere shortening destabilizes telomeric loops (Griffith et al. 1999) and as a consequence increases the probability of telomere uncapping.

These findings led to a generalized notion of cellular senescence as result of a "biological clock" that counts the number of cell divisions through telomere shortening.

0 0

Post a comment