Replicative senescence of human fibroblast-like cells in culture

Abstract

The life history of fibroblast and fibroblast-like cells includes an initial stage of outgrowth and establishment in culture; a period of vigorous proliferation which has a variable length, depending on the tissue of origin, age of the donor, etc.; a period of declining proliferative vigor which includes substantial cell death; and finally, the emergence of an (apparently) long-lived population which is unable to proliferate in response to growth factors. During the phase of declining proliferative vigor, the cells acquire characteristics, some of which are similar to the characteristics of cells in older individuals. Eventually the culture completely loses proliferative capacity. A comparable life history has been described for glial cells, keratinocytes, vascular smooth muscle cells, endothelial cells, and lymphocytes which suggests that this life history is characteristic of those cell types that, in vivo, retain the capacity for proliferation throughout the life span. Numerous studies have shown a correlation between the age of the tissue donor and the replicative life span of the cells in culture. In addition, for a small sample of species, there is a direct correlation between fibroblast replicative life span in vitro and maximum life span potential of the species. The period in the life history that is usually referred to as the "senescent phase" is probably more complicated than was originally thought, since studies with life span modulators suggest that there is a "conditionally" senescent state from which cells can be rescued for one or more additional rounds of DNA synthesis. Finally, the cells enter an "obligatory" arrested state in which only SV40 infection can reverse the block to DNA synthesis but not the block to mitosis. The modern era of aging research in tissue culture is just over 30 years old. The inception of the field really began with the recognition by Hayflick and Moorhead (109) that the phenomenon of senescence in vitro paralleled, in some of its characteristics, cell aging in vivo and thus provided a model that could be used to study the cellular mechanisms underlying senescence in controlled environmental conditions. The research in this area began with a detailed characterization and comparison of young versus senescent cell morphology and physiology. These studies provided the basis for a wide variety of subsequent studies that addressed possible mechanisms underlying cell senescence. These included studies on DNA repair, protein synthetic errors, chromatin structure and function, and mechanisms for modulating replicative life span.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging, tumor suppression and cancer: high wire-act!

“…Rather, senescent cells adopt a complex phenotype that entails many changes in gene expression (Cristofalo and Pignolo, 1993;Campisi et al, 1996;Faragher, 2000;Krtolica and Campisi, 2002). In addition to imposing a block to cell cycle progression, the senescence response causes changes in cell morphology (generally, adoption of an enlarged flattened shape).…”

Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes

“…Early ideas proposed that, because senescent cells are incapable of self-renewal, cellular senescence might cause or contribute to aging phenotypes such as immune failure, poor would healing, skin atrophy, the decline gastrointestinal function, and so forth -phenotypes that are presumed to arise owing to a loss of cell proliferative (and hence tissue regenerative) capacity. These ideas arose primarily because the first stimulus that was recognized to cause cellular senescence was repeated cell division (replicative senescence) (Cristofalo and Pignolo, 1993;Campisi et al, 1996;Smith and Pereira-Smith, 1996). Subsequent studies showed that replicative senescence is caused, in large measure, by the progressive shortening of telomeres that occurs with each cell cycle in cells that do not express the enzyme telomerase (Levy et al, 1992;Bodnar et al, 1998;Shay and Wright, 2001).…”

Relationship between donor age and the replicative lifespan of human cells in culture: A reevaluation

“…The finite replicative lifespan of normal cells in culture is thought to result from multiple environmental and genetic mechanisms (3) and is frequently used as one model of human aging. Supporting the usefulness of this model, several laboratories, by using different types of normal human cells maintained in culture, have presented evidence for a negative correlation between donor age and proliferative lifespan in vitro (4)(5)(6)(7)(8)(9)(10)(11).…”