Cellular Aging: Basic Phenomena
Senescence And Cell-cycle Progression
The growth arrest observed in senescent cultures is not random; senescent cells appear to stop dividing at a unique point in the cell cycle. Treatment of cells that have divided a relatively small number of times with growth stimulators (generically referred to as mitogens) is followed by a so-called gap phase (G1), which is a period during which cells appear quiescent (see Figure 2). In fact, many biochemical changes occur during G1, but these are not apparent from gross cell morphology. After G1, cells enter a synthesis (S) phase in which chromosomes are replicated. A second pause or gap occurs after the S phase (G2) and before mitosis (M). When essential growth factors are removed or decreased, young cells may enter a distinct quiescent phase called G0. The cells in living tissues are generally thought to be in a G0 state of growth. Much evidence supports the view that cultures of senescent cells are blocked in late G1 near the G1/S boundary in the cell cycle. It is clear, though, that the irreversibly arrested condition ultimately reached by senescent cells is distinct from the G0 phase young cells enter or any other definable stage of the cell cycle. When senescent cultures are maintained with reduced levels of mitogens that induce a quiescent state (G0) in early-passage cells, the pattern of gene expression exhibited by senescent cells is different from that of a functional G0 state. Furthermore, chromatin condensation patterns are consistent with arrest in late G1. The fact that cells near the end of their proliferative life can express some of the gene characteristics of the G1/S boundary suggests an abortive attempt to initiate DNA synthesis and arrest that growth in a unique state.
The reason that senescent cells fail to enter the S phase is unclear. Both young and senescent cells appear to respond to fresh mitogens by carrying out some of the same cell-cycle processes in roughly the same time frame. However, the ability to complete the mitogen-initiated cascade of signal transduction pathways and to synthesize DNA is lost in senescent cells. In fact, the hallmark of senescence in culture is the inability of cells to replicate their DNA following stimulation with mitogens.
In general, the synthesis rate of macromolecules decreases as cells approach the end of their proliferative life span in vitro, while the cellular content of macromolecules (except DNA) increases. This observation seems to indicate that, in senescent cells, there is a general dysregulation of coordinated processes, which uncouples DNA synthesis from the synthesis of other macromolecules. The synthetic rates of DNA, RNA, and protein decrease in cultures nearing the end of their proliferative potential, which may be related to altered chromatin template activity in senescent cells. Gorman and coworkers tested the possibility that the replicative enzymes themselves and/or replicationassociated processes such as control of DNA hierarchical structural orders, were reduced or altered during senescence. They observed that, when treated with simian virus 40 (SV40), senescent cells can initiate an additional round of semiconservative DNA synthesis in old cells, indicating that the proteins necessary for DNA synthesis can still function in senescent cells following at least some types of stimuli.
- Cellular Aging: Basic Phenomena - Growth Signals And Senescence
- Cellular Aging: Basic Phenomena - Changes In Cell Morphology And Contact
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