From cells to organisms: can we learn about aging from cells in culture?

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Abstract

Can studying cultured cells inform us about the biology of aging? The idea that this may be was stimulated by the first formal description of replicative senescence. Replicative senescence limits the proliferation of normal human cells in culture, causing them to irreversibly arrest growth and adopt striking changes in cell function. We now know that telomere shortening, which occurs in most somatic cells as a consequence of DNA replication, drives replicative senescence in human cells. However, rodent cells also undergo replicative senescence, despite very long telomeres, and DNA damage, the action of certain oncogenes and changes in chromatin induce a phenotype similar to that of replicatively senescent cells. Thus, replicative senescence is an example of the more general process of cellular senescence, indicating that the telomere hypothesis of aging is a misnomer, Cellular senescence appears to be a response to potentially oncogenic insults, including oxidative stress. The growth arrest almost certainly suppresses tumorigenesis, at least in young organisms, whereas the functional changes may contribute to aging, although this has yet to be critically tested. Thus, cellular senescence may be an example of antagonistic pleiotropy. Cross-species comparisons suggest there is a relationship between the senescence of cells in culture and organismal life span, but the relationship is neither quantitative nor direct.

Section snippets

Cells, organisms, and the concept of immortality

Eukaryotic cells, from yeast to mammals, are strikingly similar in the mechanisms by which they execute basic cellular processes such as cell cycle control and DNA repair. Moreover, specialized cells, such as neurons, fibroblasts and secretory epithelial cells, are often remarkably similar in structure and function, even when they originate from very different types of multicellular organisms. Needless to say, organisms are exceedingly diverse in the rates at which they age, despite

Replicative senescence, tumor suppression and aging

Replicative senescence is the progressive decline in the ability to proliferate that is an intrinsic property of most normal somatic cell populations. Replicative senescence is limited to cells that have the ability to divide in vivo, and hence does not apply to post-mitotic cells such as mature neurons or muscle. During replicative senescence, cells sense the number of division they have completed, not chronological time. There is a substantial stochastic component to replicative senescence:

Cellular senescence, tumor suppression and aging

In the past several years, it has become apparent that cell proliferation and telomere shortening are not the only inducers of the senescent phenotype (the irreversible growth arrest, resistance to apoptosis and altered cellular functions described above). There is now ample evidence that at least three additional stimuli can induce senescence, with little or no cell division (reviewed by Campisi, 2000a).

First, certain types of DNA damage induce normal mammalian cells to undergo a senescence

The telomere/telomerase hypothesis of aging

The findings that telomere shortening triggers replicative senescence in human cells, and that telomeres shorten in several cell types during human aging, has led to the hypothesis that telomere shortening is an important determinant of human aging (Harley, 1997, Hodes, 1999). How valid is this hypothesis, and is it applicable to other species?

Telomere-independent senescence, stress, and species-specific life span

Since neither telomere length nor the presence of telomerase predicts the replicative life span of cultured cells, much less the life span of organisms, why then do cultured cells from species with relatively short life spans cease division more readily than cells from species with longer life spans?

One possibility is that cells vary in their sensitivity to culture conditions, which may cause a telomere-independent damage arrest (Sherr and DePinho, 2000, Wright and Shay, 2000). The most obvious

Summary

In summary, cell cultures can provide information and molecular handles on the intrinsic sensitivity of cells to oxidation and other stresses, the ability to sense and handle DNA damage and telomere dysfunction, and the response to oncogenic stimuli. This information, in turn, is very likely related to species life span.

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