Mechanisms of the Effect of Aging on Carcinogenesis

27 May

In view of Peto’s finding that carcinogenesis  was dependent on the presence of the carcinogen rather than the age of the animal, one possible mechanism for the effect of aging is a differential effect of chemical  carcinogens  in inducing neoplasia  as a function of age. Anisimov  has re- viewed much of the data on organ-specific carcinogenesis by a variety of chemicals and radia- tion and found no distinct pattern of modification of the carcinogenic effect by the aging process (Anisimov, 1989). Somewhat similar discrepancies have been seen in a few examples of chemi- cal carcinogenesis in aging humans (Leutzinger and Richie, 1995). An interesting effect of aging was noted in the development of sarcomas from foreign-body implantation in rats (Paulini et al.,1975). In this study, young animals were seen to first develop malignant  mesenchymal  neo- plasms after a mean of 17.2 months, whereas old rats had developed similar lesions after only 6.3 months. Furthermore, Lijinsky et al. (1993) demonstrated that, with rare exceptions, the ad- ministration  of chemical  carcinogens  to rats did not alter the incidence  of spontaneous  neo- plasms occurring with age.

Another potential mechanism of the increased incidence of neoplasia with age is that the immune system fails to suppress spontaneous and induced neoplasms. In a later chapter (Chap- ter 19) there is a more extensive discussion of the immune system in relation to carcinogenesis and neoplasia. In old animals, the thymus, an important organ of the immune system, is atrophic. This is accompanied by excessive apoptosis of mature lymphocytes from the thymus (T lympho- cytes) in humans (Phelouzat et al., 1996). There is also an increase in the proportion of commit- ted or memory-type T (thymic) lymphocytes as compared with naïve T cells and a decline in the response  of naïve T cells to activation  and their capacity to enter the cell cycle (Globerson,

1995). In part, this may be due to a decline in the production of interleukin-2, a growth factor for T lymphocytes (Pahlavani and Richardson, 1996). Natural killer (NK) cell functions in humans and mice are somewhat discrepant. In the mouse, there is a profound loss of NK cell function in spleen and lymph nodes in older animals, while in the human, blood-derived NK cells show little if any age effect (Miller, 1996). Both T cell–mediated immunity and NK-cell cytotoxicity have been implicated in the host immune response to some neoplasms (Chapter 19). Thus, the aging process, in modifying  this immune response, may allow the growth of neoplasms  that would otherwise be suppressed by the immune response.

Just as aging of the immune response is a theoretical mechanism for the increased inci- dence of cancer seen in the aged, our increasing understanding of genes involved in cellular se- nescence and apoptosis may also offer a genetic or inherent mechanism for the effect of aging resulting in an increased incidence of neoplasia (Barrett et al., 1994; Benson et al., 1996). Such a hypothesis, however, is not in line with the experiment of Peto (1975; Figure 8.4), which argues that the aging process itself is not a major factor in the increased incidence of neoplasia noted in older organisms. A better understanding of the interrelated mechanisms of the process of aging and of neoplasia offers promise of potential applications of this area to the control of neoplastic disease.

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