INSIGHTS FROM MODEL SYSTEMS The Genetics of Cellular Senescence

Human aging is a highly complex process, resulting from a number of small changes that differ from tissue to tissue. Several major obstacles have interfered with the study of aging in whole organisms. These include the genetic heterogeneity between individuals and the difficulty in distinguishing the consequences of normal aging from the effects of diseases that occur throughout life (see Schächter 1998 [in this issue]). For these reasons, human cells grown in culture offer a simplified and attractive model with which to study cellular processes involved in aging. More than 30 years ago, Hayflick and Moorhead reported that diploid fibroblasts undergo a finite number of cell divisions, after which they stop proliferating. This phenomenon was equated with normal cellular aging and was termed “replicative senescence” (Hayflick 1965). Various other cell types have since been found to undergo replicative senescence, including epidermal keratinocytes, smooth-muscle cells, lens epithelial cells, glial cells, endothelial cells, melanocytes, T lymphocytes (see Effros 1998 [in this issue]), and adrenocortical cells. What defines replicative senescence? Cells having completed a finite number of divisions in culture become irreversibly growth arrested in the G1 stage of the cell cycle. A distinctive feature of senescent cells is that they persist in this state from months to as long as several years, remaining metabolically active but incapable of DNA synthesis (Matsumura et al. 1979). This block in cell-cycle progression in senescent cells is irreversible and is not associated with programmed cell death. Senescent cells also undergo morphological changes that include enlargement and flattening of the cells and an unexplained expression of a b-galactosidase activity at pH 6 (Dimri et al. 1995). These criteria are few, in part because many changes that occur in senescence are also seen in