Functional Changes

In addition to the arrest of cell proliferation and resistance to apoptosis, cellular senescence entails selected changes in differentiated cellular functions.

Some of the phenotypic changes that are characteristic of senescent cells are common to most, if not all, cell types. These changes include an enlarged cell size, an increase in lysosome biogenesis, and a decrease in the rates of protein synthesis and degradation (27,91,92,124). In addition, most senescent cells express a neutral beta-galactosidase, termed the senescence-associated beta-galactosidase (118). The function of this enzyme is unknown, but, because it can be detected by a simple histochemical reaction, it is a useful marker for the senescent phenotype.

Senescent cells also display changes in the expression or regulation of cell type-specific genes. For example, replicative senescence of human adrenocortical epithelial cells causes a selective loss in the ability to induce 17a-hydroxylase, a key enzyme in cortisol biosynthesis (125). Senescent human dermal fibroblasts, by contrast, show a marked increase in expression of collagenase and stromelysin (metalloproteinases that degrade extracellular matrix proteins) and reduced expression of TIMP1 and 3 (tissue inhibitors of matrix metalloproteinases) (126,127). On the other hand, when human endothelial cells undergo senescence in culture, there is a marked increase in the expression of interleukin-1a and the cell-specific adhesion molecule I-CAM (128,129). There is also a striking decrease in the expression of thymosin-p-10 (122). Interestingly, endothelial cells that simultaneously express the senescence-associated beta-galactosidase and lack expression of thymosin-p-10 (presumptive senescent endothelial cells) have been identified at the sites of atherosclerotic lesions in tissue samples from adult human donors (122). Very little is known about the molecular basis for the phe-notypic changes that occur when cells undergo a senescence response. However, because many of the genes that are overexpressed by senescent cells encode secreted factors, it has been proposed that senescent cells can, in principle, disrupt local tissue integrity and thus contribute to age-related pathology (130-131).

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