Replicative Senescence

Cellular senescence was first formally described as the process that limits the proliferation of human fibroblasts in culture (2). Such cells often grow well when first cultured, but gradually lose the ability to divide after 40 or more population doublings (Fig. 1).

Nonetheless, the cells remain viable. They continue to metabolize RNA and protein, but arrest growth with a G1 DNA content and do not initiate DNA replication in response to physiological mitogens (3,4). This phenomenon is often termed "replicative senescence," and cells that undergo replicative senescence are said to have a finite replicative life span. Replicative senescence is now considered a specific example of a more widespread response termed "cellular senescence" (discussed below).

Many cell types from many species undergo replicative senescence—both in culture and in vivo. However, the mechanisms responsible for replicative senescence vary, depending on the cell type and species (5-10). This chapter focuses on mammalian cells, principally from rodents and humans. Nonetheless, a finite replicative life span may be an ancestral

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FIGURE 1 Replicative senescence and immortalization. Most normal mitotically competent cells proliferate for only a finite number of population doublings, a process known as replicative senescence. For any pool of cells, cell type, genotype, and species determine the number of population doublings at which complete replicative senescence is achieved (no remaining proliferative capacity). For example, mouse or rat fibroblast populations generally reach complete senescence after 10 to 15 doublings, whereas many human fibroblast populations proliferate for >50 population doublings. Cells from mice or rats often spontaneously immortalize (achieve replicative immortality) after a period of genomic instability termed crisis. Human cells, by contrast, rarely spontaneously immortalize.

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Population Doublings

FIGURE 1 Replicative senescence and immortalization. Most normal mitotically competent cells proliferate for only a finite number of population doublings, a process known as replicative senescence. For any pool of cells, cell type, genotype, and species determine the number of population doublings at which complete replicative senescence is achieved (no remaining proliferative capacity). For example, mouse or rat fibroblast populations generally reach complete senescence after 10 to 15 doublings, whereas many human fibroblast populations proliferate for >50 population doublings. Cells from mice or rats often spontaneously immortalize (achieve replicative immortality) after a period of genomic instability termed crisis. Human cells, by contrast, rarely spontaneously immortalize.

phenotype. Even simple organisms such as single-celled yeast have only a finite capacity for cell division (11).

Replicative senescence has been studied most extensively using mammalian cells in culture. These studies have led to several general conclusions (Fig. 1) (12-16):

1. Most normal somatic cells do not divide indefinitely, although the mechanisms that limit replicative life span vary.

2. The germ line and early embryonic cells have an unlimited cell division potential (replicative immortality).

3. Most cancer cells have an unlimited cell division potential.

4. Replicative (and cellular senescence) is controlled by tumor-suppressor genes, which are inactivated by mutations or epigenetic changes in most cancer cells.

5. Replicative senescence is exceedingly stringent in human cells, which only rarely spontaneously immortalize.

6. Replicative senescence is less stringent in rodent cells, which, after a period of genomic instability termed "crisis," often become replicatively immortal.

7. Immortalization greatly increases the probability of malignant transformation.

Figure 1 illustrates the dynamic changes in proliferative capacity that cell populations undergo during replicative senescence and immortalization.

How to Stay Young

How to Stay Young

For centuries, ever since the legendary Ponce de Leon went searching for the elusive Fountain of Youth, people have been looking for ways to slow down the aging process. Medical science has made great strides in keeping people alive longer by preventing and curing disease, and helping people to live healthier lives. Average life expectancy keeps increasing, and most of us can look forward to the chance to live much longer lives than our ancestors.

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