Cellular senescence and telomerase

Cells of nearly every complex organism do not have an unlimited ability to divide.  This phenomenon was described by Leonard Hayflick in 1961 (Hayflick 1965).  The number of potential divisions – about fifty – was dubbed the “Hayflick Limit” and sometimes is called cellular senescence.  For the first time, it was appreciated that cells could be mortal (normal cells) or immortal (tumor cells).  This distinction underpins much of modern cancer research.

The mechanism accounting for the Hayflick Limit remained an enigma for many years to come.  The first major clue occurred in 1986 when Cooke and Smith observed that the ends (telomeric regions) of human sex chromosomes were substantially shorter in non-germline cells than in germline cells (Cooke and Smith 1986).  Like scientists of their time, they appreciated that in the absence of an active mechanism, some telomeric DNA would otherwise be lost during each replication cycle.  Less than a year earlier, Greider and Blackburn provided evidence for an enzyme-mediated mechanism to maintain telomeres:  they discovered that the ends of the linear chromosomes in Tetrahymena, a ciliated protozoan, were maintained by an enzyme, telomerase, which added new terminal DNA sequences (Greider and Blackburn 1985).  In their paper, Cooke and Smith hypothesized that telomerase might not be active in somatic cells (non-germline cells).  Furthermore, they provocatively proposed that sustained loss of telomeric DNA could eventually limit the ability of somatic cells to divide.  Eventually a mechanism to explain the phenomenon emerged, two and a half decades after discovery of the Hayflick Limit.

The hypothesis that telomere loss eventually limits replication of human cells was not universally accepted.  Critics cited apparent exceptions:  telomeres in mouse cells are much longer than in human cells, but mouse cells don’t have significantly more proliferative potential (Kipling and Cooke 1990); and senescent human cells still have telomeres.  On the other hand, many observations supported the causal relationship between telomerase, telomeres and cell proliferation.  For example, human cells with shorter telomeres could not replicate as many times as cells with longer telomeres (Allsopp et al. 1992), and telomerase activity was detected in immortal or tumor cells but not in normal cells (Kim et al. 1994).  While the evidence favored a causal relationship, the evidence was circumstantial or correlative.

Definitive proof that shortened telomeres are responsible for cellular senescence finally emerged in 1998.   Bodnar et al. forced expression of telomerase in normal human cells by transfection of retinal pigment epithelial cells and foreskin fibroblasts with a vector encoding the human telomerase enzyme.  Remarkably, these cells exhibited elongated telomeres, “divided vigorously”, and proliferated at least 20 doublings beyond their normal life-span; in contrast, the control cells showed shortening of telomeres and senescence (Bodner et al.1998).  Thus, in typical somatic cells, human telomeres normally undergo shortening at each cell division, and when several kilobases of telomeric DNA is gone, cell division halts and senescence manifests.

Unlimited proliferative potential of cells is not necessarily advantageous to organisms.  It may seem that an unlimited capacity to replicate would be a good thing – the body could undergo self-repair in response to disease or trauma.  Yet, replication is not a risk-free event – mutations can accumulate, chromosomes can break or incompletely separate, etc.  If multiple mutations are required for tumorigenesis, then fewer replications favor maintenance of a normal phenotype.   Thus, one consequence of the Hayflick Limit appears to be beneficial to the organism, acting as part of a tumor suppressor mechanism.