Replicative Senescence: Implications for in Vivo Aging and Tumor Suppression

Abstract

Normal cells have limited proliferative potential in culture, a fact that has been the basis of their use as a model for replicative senescence for many years. Recent molecular analyses have identified numerous changes in gene expression that occur as cells become senescent, and the results indicate that multiple levels of control contribute to the irreversible growth arrest. These include repression of growth stimulatory genes, overexpression of growth inhibitory genes, and interference with downstream pathways. Studies with cell types other than fibroblasts will better define the role of cell senescence in the aging process and in tumorigenesis.

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…Thus, 'type A' methylation, rather than being a prelude to cancer (Issa et al, 1994;Ahuja et al, 1998;Ahuja and Issa, 2000), might represent a component of 'normal' aging. Cellular senescence protects against cancer (Smith and Pereira-Smith, 1996;Ishikawa, 2003;Hornsby, 2007). Thus, it is conceivable that impaired senescence of the colorectal mucosa, as recorded by attenuated age-specific 'type A' methylation, could reflect a biological imbalance between DNA repair, regeneration and aging, and a predisposition to adenomas (Smith and Pereira-Smith, 1996;Ishikawa, 2003;Hornsby, 2007;Hoeijmakers, 2009).…”

Cell cycle arrest is sufficient for p53-mediated tumor regression

“…However, molecular analysis has previously identified changes in gene expression that occurs when cells stop proliferating and become senescent. 30 These molecular changes might contribute to tumor regression in the absence of major morphological changes. Experiments are ongoing to compare the profile of genes expression in p53 expressing and non-expressing tumors.…”

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

“…However, with increasing age, senescent cells, which are incapable of regeneration and show marked changes in function (discussed below), can accumulate. Again, this accumulation can lead to an overall loss of tissue structure and function (Campisi, 1996(Campisi, , 2003a(Campisi, , 2003bSmith and Pereira-Smith, 1996;Faragher, 2000). Like apoptosis, cellular senescence may contribute to the degenerative diseases of aging.…”