There is now very persuasive evidence that both cellular senescence and apoptosis are crucial for preventing the development of cancer (14,94,97,113-115), which is a major age-related disease (111,116).

First, most mammalian cancers harbor mutations that blunt or inactivate the senescence response and/or render them resistant to cell death (1). In addition, several well-recognized oncogenes, such as those encoded by oncogenic papillomavi-ruses, act primarily by blocking senescence and/or apoptotic responses (117). Conversely, well-recognized tumor suppressors, such as p53, control cellular senescence and apoptosis. These tumor suppressors, or one of their regulators or effectors, are inactivated in the vast majority of cancers (118,119).

Second, genetically engineered mouse models have been developed in which cells fail to undergo cellular senescence or apoptosis in response to specific stimuli (111,120-122). These mice inevitably develop tumors at an early age, and generally die of cancer. Human clinical data likewise suggest that apoptosis and/or senescence restrains malignant tumorigenesis (93,113,118). For example, human naevi are benign tumors of melanocytes that frequently harbor oncogenic mutations. Naevi, but not malignant melanomas, also frequently contain high levels of senescent cells (123). In addition, DNA-damaging chemotherapy can cause tumor cells to undergo apoptotic or senescence responses that, like the response of normal cells, are controlled by the p53 or p16/pRB pathways. Tumors that fail to respond are much more likely to be lethal (124).

Together, these findings strongly suggest that cellular senescence and apoptosis are powerful tumor-suppressive mechanisms. Nonetheless, mammals do develop cancer, although generally late in life. Thus, senescence and apoptosis are effective at preventing cancer in relatively young organisms, but less effective in older organisms. Why might this be the case?

Mutations are essential for the development of cancer (1), and it takes time for cells to accumulate the mutations that allow them to avoid senescence and/or apoptosis. Mutations accumulate throughout the mammalian life span (125,126). However, the exponential rise in cancer that occurs during the last half of the life span (111,116) cannot be explained by mutations alone. Cancer also requires a permissive tissue in which to develop; in many cases, a healthy tissue environment can suppress the development of cancer from even highly mutated cells (111,127-129). Aging entails changes in tissue structure and integrity, which may create a permissive environment for the growth and malignant transformation of mutant cells.

How do cellular senescence and cell death contribute to aging? At present, there is no precise answer to this question. There is, however, mounting indirect evidence that both processes can and do contribute to aging phenotypes, both directly and indirectly.

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