Cancer, aging and cellular senescence

Normal cells do not divide indefinitely due to a process termed cellular, or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particulally mammals, fiom developing cancer. Senescent cells differ fiom their presenescent counterparts in three way: 1) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; 3) they acquire altered differentiated functions. Replicative senescence occurs because, owing to the biochemistry of DNA,replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells, respond to a number of potentially oncogenic stimuli by adopting a senescent phenoytpe. These findings suggest that the senescence response is a failsafe mechanism that protects cells fiom tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However many benign or relatively well controlled tumors may also harbour, many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many,malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to olganismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.