Mitotic Clock

The majority of cell types grown in laboratory cultures have a finite ability to proliferate. After a number of population doublings, the cell cultures enter the terminally nondividing state referred to as replicative senescence (Hayflick Limit) (111). Many investigations have established a link between aging in vivo (live animals) and the proliferative potential of cells in culture. For example, cell cultures derived from one of the longest-lived species of animals, the Galapagos tortoise, doubled up to 130 times whereas cultures derived from mice with maximum life spans of three years were capable of doubling only 10 or fewer times.

One of the most compelling theories for explaining replicative senescence is that incomplete replication of specialized structures at the ends of chromosomes called telomeres account for the gradual loss of proliferation potential (112). Telomeres are essential for proper chromosome structure and function including complete replication of the genomeā€”if organisms could not overcome the "end-replication" problem, they would fail to pass their complete genetic complement from generation to generation (Chapter 4). The simplest theory for accounting for the Hayflick Limit is one in which permanent cell-cycle arrest is due to a checkpoint mechanism that interprets a critically short telomere length as damaged DNA and causes cells to exit the cell cycle. This telomere hypothesis of aging provides a molecular mechanism for counting cell divisions in the normal somatic cell. According to the telomere-shortening model of cell senescence, to avoid telomere loss and eventual cell-cycle arrest, it is necessary for cells to synthesize telomeric DNA by expressing the enzyme. Therefore, a prediction of this model and one that is borne out in recent studies (113-115) is that telomerase activity will be absent in normal somatic cells but present in germ line cells and carcinoma cells. Although telomere length has historically been used as a means to predict the future life of cells, a new model frames the connection between telomere shortening and cellular senescence by introducing the concept of a stochastic and increasing probability of switching to the uncapped/noncycling state (116).

It is widely believed that senescence evolved to limit the number of available cell divisions and therefore that it serves as a brake against the accumulation of the multiple mutations needed for a cell to become malignant (117). Results of new studies (118,119) support the notion that DNA repair pathways and antioxidant enzymes are adequate for protecting against the accumulation of mutations and development of cancer in small organisms (mice) whose cells do not seem to have a cell division-counting mechanism but that replicative senescence evolved in long-lived species to ensure that they would have the greatly increased protection that their longevity necessitated.

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