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The potential relationships between aging and cancer
Experimental Gerontology, Vol. 27, pp. 469-476, 1992 Printedin the USA.All rightsreserved.
THE POTENTIAL
0531-5565/92$5.00 + .00 Copyright© 1992PergamonPressLtd.
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BETWEEN
AGING AND
GARY M. WILLIAMS t AND GEORGE T. BAKER, III 2 tAmerican Health Foundation, Dana Road, Valhalla, New York 10595, ZShock Aging Research Foundation, 14628 Carona Drive, Silver Spring, Maryland 20905, and Nathan W. Shock Laboratories, Gerontology Research Center, National Institute on Aging/National Institutes of Health, 4940 Eastern Avenue, Baltimore, Maryland 21224
Abstract - - The potential relationships between aging and cancer have received consid-
erable attention in the scientific literature in recent years. While it is clear that the rates of most types of cancer increase with advancing age and that both the processes of aging and those of cancer are time dependent, an unequivocal relationship between the etiology of cancers and the mechanistic processes of aging has yet to be established. This article discusses the potential causal relationships between the processes of aging and the etiologies of most cancers. Key Words: aging, cancer, common mechanisms, oncogenes, suppressor genes, cancer etiology
INTRODUCTION THE INCIDENCE of most cancers is significantly more common in older individuals (Horm et al., 1985; Yancik et aL, 1988), but basic questions such as, Does the exposure of an older individual to a given carcinogen, qualitatively or quantitatively, result in more cancers than in a younger individual? have not been satisfactorily resolved (Zimmerman and Carter, 1989). Is the incidence of cancer a simple dose- and length-of-exposure-dependent phenomenon as Peto et al. (1975) suggested, or as much epidemiological data would suggest, is chronological age an independent contributing variable (Anisinmov, 1983; Dix, 1989)? DISCUSSION The etiology of cancer is generally thought to proceed through multistages (Pitot, 1985). These stages include the pheonmena of initiation, promotion, and progression. Initiation of neoplasia can occur by chemical, radiation, or viral actions on the genome. Promotion is also known to be associated with chemical agents as well as other biological processes. The progression stage of carcinogensis (the appearance of malignant neoplasms) is prob-
Correspondence to: G.T. Baker, III. 469
470
G.M. WILLIAMSAND G.T. BAKER,III
ably the least understood, and is the stage within which endogenous age-related alterations (i.e., imparied DNA repair, inaccurate DNA replication, faulty DNA methylation, etc.) could play a direct role in the development of age-associated metastases. Both initiation and promotion likely reflect irreversible alterations in the genome of the cell, whereas progression involves potentially reversible alterations in gene expression and cellular proliferation. Figure 1 presents some of the time-dependent events common to both the processes of aging and the etiology of cancer. The central questions to be addressed in discussing the potential relationships between the processes of aging and the incidence of cancer are graphically shown in Fig. 2. Figure 2a poses a senario wherein cancer incidence is only exposure-time dependent. That is, the processes of aging per se do not contribute to the observed increase in cancer incidence with advancing age. Figure 2b depicts a direct relationship between exposure to a given carcinogen, promotional or progession factor(s), and the incidence of cancer. Implied here is that exposure to a carcinogen at an older age will more likely result in a cancer. Figure 2c presents an intermediate relationship wherein the processes of aging only partially contribute to the increased incidence of cancer with advancing age. To date, a conclusive statement as to which of these interrelationships between the etiology of cancer and the processes of aging is correct is not possible. It is likely, nevertheless, that, depending on the mechanism(s) of action of a given carcinogen/promotional agent/ progression factor, different relationships are plausible. Just as the etiologies of cancers are of diverse origins (Williams and Weisburger, 1991), the processes of aging are multidimensional (Baker and Shock, 1991). Therefore, it should be expected that exposure to dif-
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ferent carcinogens/promotional agents or factors might exhibit differential manifestations in relation to chronological age. Experimental studies on tumor induction in aged animals as compared to young ones have reported starkly different findings (Anisinmov, 1987). Zimmerman et al. (1982) reported that a single i.p. injection of nitrosomethylurea to 24-month-old mice produced neoplasms in 20% of the animals, whereas none were seen in mice exposed at 3 or 12 months. However, Peto et al. (1975) concluded that old animals were no more susceptible to carcinogenesis than were younger animals, based on a study in which outbred mice received skin applications of benzo(a)pyrene beginning at ages 10, 25, 40, and 55 weeks and continuing for life. The resulting skin papillomas depended strongly on the duration of exposure, but not on the age of the mice. In a study on the persistence of initiation, Stenback et al. (1981) applied 7,12-dimethylbenz(a)anthracene as an initiator once to the skin of Swiss mice at different ages, followed by 15 weeks of promotion, then termination. In this study the number of skin papillomas was lower when animals were initiated at 48 weeks as compared to 8 weeks of age, which indicated a decrease in neoplasm induction in the older mice. There was, however, less time for tumors to develop before death from other causes occurred, and the number of animals and tumors in the high age groups was small. A variety of factors may account for the differences in the reported findings. Most likely are animal species and strain, nature of the carcinogenic agent, and differences in time intervals used for comparisons. Other important considerations are: (1) What in fact constitutes older age in experimental animal models?, (2) What is the occurrence of unrelated diseases resulting in variable survival rates not due to carcinogen exposure and tumor development?, and (3) What is the adequacy of the tumor response for statistical analysis? To resolve such issues studies are needed in which the animal groups are large enough at distinctly old ages to provide meaningful results, and in which animals are strictly comparable in number, duration of exposure to carcinogen, and time for development of neoplasms, as well as general health status. The shape of cancer age-incidence patterns are often complex and difficult to interpret. Furthermore, such patterns vary not only with cancer type, but also from population to population. It would appear, however, that exposure to environmental carcinogens cannot fully explain the common shape of age-incidence patterns for most cancers (Dix, 1989). This would suggest, therefore, that age in and of itself must play a role in cancer incidence. More critically, if the intrinsic processes of aging do render an organism more susceptible to cancer, what are those age-dependent changes? Specifically, how does age influence the initiation, promotion, and progression of tumorigenesis? Recent molecular genetic evidence suggests that there may be more closely linked mechanisms operative in both aging and cancer--in particular, those that are involved in the regulation of cell proliferation and differentiation (Porter et al., 1990). For example, Stein et al. 1990) have recently demonstrated that failure to phosphorylate the retinoblastoma gene product (p 110 Rb)results in a G~-arrested sensecent state in human diploid fibroblasts in culture. The retinoblastoma-susceptibility gene product is an inhibitor of cell proliferation, based on its absence or inactivation in retinoblastoma as well as other tumor types. The wild-type retinoblastoma-susceptibility gene product has been demonstrated to suppress tumorigenicity when reintroduced into retinoblastoma and osteosarcoma cells. Understanding the regulation of expression of such genes during cellular senescence may well lead to insights into the mechanism of oncogenesis. R a s oncogenes activation has been implicated in a number of common forms of cancer, including carcinomas of the lung, colon, and pancreas. Although the role of these ras
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oncogenes in carcinogenesis is not completely understood, their activation has been demonstrated to precede the onset of neoplasia (Kumar et al., 1990). We propose that the ras genes are randomly activated throughout the life span of healthy individuals, either by exposure to carcinogenic agents or by sporadic errors during cell replication. Subsequent exposure of cells containing the activated ras genes to growth-promoting agents or further genetic alterations (as may result during the processes of aging) would then trigger neoplastic development. The demonstration by Vogelstein and colleagues (Vogelstein et al., 1988; Baker et al., 1989) of a number of sequential and discrete genetic events in the development of human colorectal cancer from benign polyp to metastatic carcinomas, including specific deletions on the 5th chromosome, hypomethylation of DNA, ras gene activation, and loss in chromosomes 17 and 18, lends support to the concept of cancer pathogenesis as being a time/age-dependent process. This time dependency for multiple events to occur could, at least in part, explain the higher incidence of cancer in older individuals. The work of Friend and colleagues (Malkin et al., 1990) is also relevant in this regard. These workers identified mutations in the suppressor gene, p53, in patients with Li-Fraumeni syndrome, a rare familial cancer syndrome with high mortality. Although all the cells of affected family members carry mutations in the p5 3gene, these individuals may be free from cancer or develop only one or a few cancers later in life. This would suggest that mutations at other sites are also necessary to complete the transformation of a susceptible cell to a cancerous one. Multidependent events have also been proposed in the development of familial multiple endrocrine neoplasias (Brandi et al., 1987). There are numerous identified age-related alterations that could render cells more susceptible to the initiation and/or promotion of carcinogenesis. Table 1 lists some of the more likely age-related changes that are putative effectors of cancer incidence with advancing age. Other factors, such as decline in immune function with advancing age, have also been implicated in the age-associated increase in the incidence of most types of cancers (Gatti and Good, 1970). There are, however, a number of issues that must be resolved before one can embrace the theory that immune deficiency with advancing age is responsible for the observed age-
TABLE 1. PUTATIVE EFFECTORS OF CANCER INCIDENCE WITH ADVANCINGAGE
Alteration Deficient DNA repair capacity
Diminished fidelity of DNA polymerase Altered DNA methylation Decreased fidelity of protein synthesis Increased number of fragile sites Altered hormonal levels and sensitivity Increased free radical damage Altered protein structure Altered regulation of cell cycle
Reference Hart and Setlow, 1976 Trosko and Chu, 1975 Warner and Price, 1989 Singh et al., 1990 Krauss and Linn, 1986 May-Hoopes, 1989 Orgel, 1963 Yunis and Hoffman, 1989 Anisimov and Turisov, 1981 Everitt and Meites, 1989 Ames, 1991 Gafni, 1990 Cristofalo, 1973
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G.M. WILLIAMSANDG.T. BAKER.111
related increased incidence of cancer in humans. For example, why do immune-deficient patients not exhibit a wider range of cancers such as occur in aging, rather than the rather specific lymphomas and Kaposi's sarcoma? Also, why do some immune-deficient patients not develop tumors at all (Schwartz, 1975)? A full and excellent discussion of alterations in immune function and the effects of caloric restriction on the age-associated incidence of cancer is presented by Weindruch and Walford (1988). The well-documented effect of caloric restriction on both the retardation of the processes of aging and the age-associated incidence of most cancers is relevant to our discussion here. Since the earlier work of McCay and Tannenbaum (McCay et al., 1935; Tannenbaum, 1940, 1942; McCay et al., 1943; Tannenbaum, 1945), caloric restriction has been widely known to retard the incidence of tumors, as well as to increase life span and functional capcity in laboratory rodents. It is also well established that other dietary factors can influence the processes of aging and the age-associated incidence of various diseases, including cancers (Ingram et al., 1991). One could argue that, if the incidence of cancer was purely a function of exposure time to a carcinogenic agent, then the age-specific incidence rates for cancers should not be altered by caloric restriction. There is, however, no conclusive evidence to support such a conclusion. Indeed, most studies demonstrate that the effect of caloric restriction on the reduced incidence of most common cancers is relatively proportional to its effect on life span. Indeed, Albanes (1987), in surveying a number of reports on caloric restriction and tumor incidence in mice with increasing age, described an almost linear relationship between caloric intake and tumor incidence. One might therefore conclude that caloric restriction reduces tumor incidence by altering or delaying intrinsic age-dependent changes. It could be these same modulated biological mechanisms that impart enhanced longevity and functional capacity to the calorically restricted animal that are also responsible for reduced tumor incidence. This is obviously a rather simplistic argument fraught with any number of caveats; however, it does strongly suggest that the rates of aging and the pathogenesis of a number of cancer are in fact linked by at least some underlying basic mechanism(s) common to both, most likely at the level ofgene expression. CONCLUSION In summary, given the range of putative age-related alterations that can affect cell function, it is difficult not to conclude that the increased incidence of many cancers with advancing age must, at least for some aspects, be attributed to either intrinsic and/or extrinsic processes of time (i.e., biological aging). Acknowledgments ~ The authors wish to thank Drs. Huber Warner, Donald Ingram, George Martin, and Jeffrey Metter for helpful discussion and editorial comments during the preparation of this manuscript.
REFERENCES ALBANES, D. Total calories, body weight, and tumor incidence in mice. CancerRes. 47, 1987-1992, 1987. AMES, B.N. Endogenous DNA damage as related nutrition and aging, In: The Potentialfor Nutritional Modulation of Aging Processes, lngram, D.K., Baker, G.T., III, and Shock, N.W. (Editors), pp. 251-261, Food & Nutrition Press, Inc., Trumbull, CT, 1991. ANISINMOV, V,N. Carcinogensis and aging. Adv. CancerRes. 40, 365-424, 1983. ANISINMOV, V.N. Carcinogenesis andAging. CRC Press, Boca Raton, FL, 1987.
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ANISINMOV, V.N. and TURISOV, V.S. Modifying effect of aging on chemical carcinogensis. Mech. Ageing Dev. 15, 399-414, 1981. BAKER, G.T., III and SHOCK, N.W. Theoretical concepts governing gerontological research. In: The Potential for Nutritional Modulation of Aging Processes. Ingrain, D.K., Baker, G.T., III, and Shock, N.W. (Editors), pp. 3-15, Food & Nutrition Press, Inc., Trumbull, CT, 1991. BAKER, S.J., FEARON, E.R., NIGRO, J.M., HAMILTON, S.R., PREISINGER, A.C., JESSUP, J.M., VANTUINEN, R., LEDBETTER, D.H., BARKER, D.F., NAKAMURA, Y., WHITE, R., and VOGELSTE1N, B. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217-221, 1989. BRANDI, M.L., MARX, G.D., AURBACH, G.D., and FITZPATRICK, I.A. Familial multiple endrocrince neoplasia Type I: A new look at pathophysiology. Endrocr. Rev. g, 391-405, 1987. CRISTOFALO, V.J. Cellular senescence: Factors modulating cell proliferation in cells in culture. I N S E R M 27, 64-92, 1973. DIX, D. The role of aging in cancer incidence: An epidemiological study. J. Gerontol. 44, 10-18, 1989. EVERITT, A. and MEITES, J. Aging and anti-aging effect of hormones. J. GerontoL 44, 139-147, 1989. GAFNI, A. Altered protein metabolism in aging. In: Annual Review of Gerontology and Geriatrics', Cristofalo, V.J. (Editor), pp. 117-131, Springer Publishing Company, New York, NY, 1990. GATTI, R.A. and GOOD, R.A. Aging, immunity and malignancy. Geriatrics 25, 158-168, 1970. HART, R.W., and SETLOW, R.B. DNA-repair in late-passage human cell. Mech. Ageing Dev. 567-77, 1976. HORM, J.W., ASIRE, A.J., YOUNG, J.L., and POLLACK, E.S. (Editors). SEER Program: Cancer Incidence and Mortality in the U.S., 1973-1981. NIH Publ. No. 85-1873. Department of Health and Human Services, Washington, DC, 1985. INGRAM, D.K., BAKER, G.T., III, and SHOCK, N.W. (Editors). The Potential for Nutritional Modulation of Aging Processes. Food & Nutrition Press, Inc., Trumbull, CT, 1991. KRAUSS, S.W. and LINN, S. Decreased fidelity of DNA polymerase activity isolated from aging human fibroblasts. Proc. Nat. Acad. Sci. U.S.A. 13, 2818, 1986. KUMAR, R., SUKUMAR, S., and BARBAC1D, M. Activation of ras oncogenes preceding the onset of newplasia. Science248, 1101-1104, 1990. MALKIN, D., LI, R.P., STRONG, L.C., FRAUMENI, J.F., JR., NELSON, C.E., K1M, D.H., KASSEL, J., GRYKA, M.A., BUSCHOFF, F.Z., TAINSKY, M.A., and FRIEND, S.H. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233-1238, 1990. MAY-HOOPES, L.L. DNA methylation in aging and cancer. J. Gerontol. 44, 35-36, 1989. McCAY, C.M., CROWELL, M.F., and MAYNARD, L.A. The effect of retarded growth upon the length of the life span and upon the ultimate body size. J. Nutr. 10, 63-79, 1935. McCAY, C.M., SPERL1NG, G., and BARNES, L.L. Growth, ageing, chronic diseasesand life span in rats. Arch. Biochem. Biophys. 2, 469, 1943. ORGEL, L.E. The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proc. Nat. Acad Sci. U.S.A. 49, 517-521, 1963. PETO, R., ROW, F.J.C., LEE, P.N., LEVY, L., and CLACK, J. Cancer and aging in mice and men. Br. J. Cancer 32, 421-426, 1975. PITOT, H.C. Principles of cancer biology: Chemical carcinogens. In: Cancer--Principles and Practices of Oncology. 2nd ed., DeVita, W.T., Heliman, S., Rosenberg, S.A. (Eds.), pp. 79-99, J.P. Lippincott, Philadephia, PA, 1985. PORTER, M.B., PEREIRA-SMITH, P.M., and SMITH, J.R. Novel monoclonal antibodies identify antigenic determinants unique to cellular senescence. J. Cell. Physiol. 142, 425-433, 1990. SCHWARTZ, R.A. Current concepts: Another look at immunologic surveillance. N. Engl. J. Med. 293, 525532, 1975. SINGH, N.P., DANNER, E.B., TICE, R.R., BRANT, L., and SCHNEIDER, E.L. DNA damage and repair with age in individual human lymphocytes. Mutat. Res. 237, 123-130, 1990. STEIN, G.H., BEESON, M., and GORDON, L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblast. Science 249, 666-669, 1990. STENBACK, F., PETO, R., and SHUBIK, P. Initiation and promotion at different ages and doses in 2200 mice. II. Decrease in promotion by TPA with aging. Br. J. Cancer 44, 15-23, 1981. TANNENBAUM, A. The initiation and growth of tumors. Introduction. I. Effects of underfeeding. Am. J. Cancer 38, 335-350, 1940. TANNENBAUM, A. The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res. 2, 460-467, 1942.
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TANNENBAUM, A. The dependence of tumor formation on the composition of the calorie-restricted diet as well as on the degree of restriction. CancerRes. 5, 616-625, 1945. TROSKO, J.E. and CHU, C.H. The role of DNA repair and somatic mutation in carcinogenesis. Adv. Cancer Res. 21, 391-425, 1975. VOGELSTEIN, B., FEARON, E.R., HAMILTON, S.R., KERN, S.E., PREISINGER, B.A., LEPPERT, M., NAKAMURA, Y., WHITE, R., SMITS, A.M.M., and BOS, J.L. Genetic alterations during colorectal tumor development. N. Engl. J. Med. 319, 525-532, 1988. WARNER, R.H. and PRICE, A.R. Involvement of DNA repair in cancer and aging. J. Gerontol. 44, 45-54, 1989. WEINDRUCH, R. and WALFORD, R.L. The Retardation of Aging and Disease by Dietary Restriction. Ch. C. Thomas, Springfield, IL, 1988. WILLIAMS, G.M. and WEISBURGER, J.H. Chemical carcinogenesis. In: Toxicology the Basic Science of Poisons. 4th ed., Amdur, M.O., Doull, J., and Klaasen, E.D. (Editors), pp. 127-200, Pergamon Press, New York, NY, 1986. YANCIK, R., KESSLER, L, and YATES, J.W. The elderly population: Opportunities for cancer prevention and detection. Cancer62, 1823-1828, 1988. YUNIS, J.J. and HOFFMAN, W.R. Nuclear enzymes, fragile sties, and cancer. J. Gerontol. 44, 37-44, 1989. ZIMMERMAN, J.A. and CARTER, T.H. Altered cellular response to chemical carcinogens in aged animals. J. Gerontol. 44, 19-24, 1989. ZIMMERMAN, J.A., TROMBETTA, L.D., CARTER, T.H., and WEISBROTH, S.H. Pancreatic carcinoma induced by n-methyl-n-nitrosourea in aged mice. Gerontology 28, 114-122, 1982.
THE POTENTIAL
0531-5565/92$5.00 + .00 Copyright© 1992PergamonPressLtd.
RELATIONSHIPS CANCER
BETWEEN
AGING AND
GARY M. WILLIAMS t AND GEORGE T. BAKER, III 2 tAmerican Health Foundation, Dana Road, Valhalla, New York 10595, ZShock Aging Research Foundation, 14628 Carona Drive, Silver Spring, Maryland 20905, and Nathan W. Shock Laboratories, Gerontology Research Center, National Institute on Aging/National Institutes of Health, 4940 Eastern Avenue, Baltimore, Maryland 21224
Abstract - - The potential relationships between aging and cancer have received consid-
erable attention in the scientific literature in recent years. While it is clear that the rates of most types of cancer increase with advancing age and that both the processes of aging and those of cancer are time dependent, an unequivocal relationship between the etiology of cancers and the mechanistic processes of aging has yet to be established. This article discusses the potential causal relationships between the processes of aging and the etiologies of most cancers. Key Words: aging, cancer, common mechanisms, oncogenes, suppressor genes, cancer etiology
INTRODUCTION THE INCIDENCE of most cancers is significantly more common in older individuals (Horm et al., 1985; Yancik et aL, 1988), but basic questions such as, Does the exposure of an older individual to a given carcinogen, qualitatively or quantitatively, result in more cancers than in a younger individual? have not been satisfactorily resolved (Zimmerman and Carter, 1989). Is the incidence of cancer a simple dose- and length-of-exposure-dependent phenomenon as Peto et al. (1975) suggested, or as much epidemiological data would suggest, is chronological age an independent contributing variable (Anisinmov, 1983; Dix, 1989)? DISCUSSION The etiology of cancer is generally thought to proceed through multistages (Pitot, 1985). These stages include the pheonmena of initiation, promotion, and progression. Initiation of neoplasia can occur by chemical, radiation, or viral actions on the genome. Promotion is also known to be associated with chemical agents as well as other biological processes. The progression stage of carcinogensis (the appearance of malignant neoplasms) is prob-
Correspondence to: G.T. Baker, III. 469
470
G.M. WILLIAMSAND G.T. BAKER,III
ably the least understood, and is the stage within which endogenous age-related alterations (i.e., imparied DNA repair, inaccurate DNA replication, faulty DNA methylation, etc.) could play a direct role in the development of age-associated metastases. Both initiation and promotion likely reflect irreversible alterations in the genome of the cell, whereas progression involves potentially reversible alterations in gene expression and cellular proliferation. Figure 1 presents some of the time-dependent events common to both the processes of aging and the etiology of cancer. The central questions to be addressed in discussing the potential relationships between the processes of aging and the incidence of cancer are graphically shown in Fig. 2. Figure 2a poses a senario wherein cancer incidence is only exposure-time dependent. That is, the processes of aging per se do not contribute to the observed increase in cancer incidence with advancing age. Figure 2b depicts a direct relationship between exposure to a given carcinogen, promotional or progession factor(s), and the incidence of cancer. Implied here is that exposure to a carcinogen at an older age will more likely result in a cancer. Figure 2c presents an intermediate relationship wherein the processes of aging only partially contribute to the increased incidence of cancer with advancing age. To date, a conclusive statement as to which of these interrelationships between the etiology of cancer and the processes of aging is correct is not possible. It is likely, nevertheless, that, depending on the mechanism(s) of action of a given carcinogen/promotional agent/ progression factor, different relationships are plausible. Just as the etiologies of cancers are of diverse origins (Williams and Weisburger, 1991), the processes of aging are multidimensional (Baker and Shock, 1991). Therefore, it should be expected that exposure to dif-
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AGING FIG. 1. Time dependency of cancer and aging processes.
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G.M. WILLIAMS AND G.T. BAKER, 111
ferent carcinogens/promotional agents or factors might exhibit differential manifestations in relation to chronological age. Experimental studies on tumor induction in aged animals as compared to young ones have reported starkly different findings (Anisinmov, 1987). Zimmerman et al. (1982) reported that a single i.p. injection of nitrosomethylurea to 24-month-old mice produced neoplasms in 20% of the animals, whereas none were seen in mice exposed at 3 or 12 months. However, Peto et al. (1975) concluded that old animals were no more susceptible to carcinogenesis than were younger animals, based on a study in which outbred mice received skin applications of benzo(a)pyrene beginning at ages 10, 25, 40, and 55 weeks and continuing for life. The resulting skin papillomas depended strongly on the duration of exposure, but not on the age of the mice. In a study on the persistence of initiation, Stenback et al. (1981) applied 7,12-dimethylbenz(a)anthracene as an initiator once to the skin of Swiss mice at different ages, followed by 15 weeks of promotion, then termination. In this study the number of skin papillomas was lower when animals were initiated at 48 weeks as compared to 8 weeks of age, which indicated a decrease in neoplasm induction in the older mice. There was, however, less time for tumors to develop before death from other causes occurred, and the number of animals and tumors in the high age groups was small. A variety of factors may account for the differences in the reported findings. Most likely are animal species and strain, nature of the carcinogenic agent, and differences in time intervals used for comparisons. Other important considerations are: (1) What in fact constitutes older age in experimental animal models?, (2) What is the occurrence of unrelated diseases resulting in variable survival rates not due to carcinogen exposure and tumor development?, and (3) What is the adequacy of the tumor response for statistical analysis? To resolve such issues studies are needed in which the animal groups are large enough at distinctly old ages to provide meaningful results, and in which animals are strictly comparable in number, duration of exposure to carcinogen, and time for development of neoplasms, as well as general health status. The shape of cancer age-incidence patterns are often complex and difficult to interpret. Furthermore, such patterns vary not only with cancer type, but also from population to population. It would appear, however, that exposure to environmental carcinogens cannot fully explain the common shape of age-incidence patterns for most cancers (Dix, 1989). This would suggest, therefore, that age in and of itself must play a role in cancer incidence. More critically, if the intrinsic processes of aging do render an organism more susceptible to cancer, what are those age-dependent changes? Specifically, how does age influence the initiation, promotion, and progression of tumorigenesis? Recent molecular genetic evidence suggests that there may be more closely linked mechanisms operative in both aging and cancer--in particular, those that are involved in the regulation of cell proliferation and differentiation (Porter et al., 1990). For example, Stein et al. 1990) have recently demonstrated that failure to phosphorylate the retinoblastoma gene product (p 110 Rb)results in a G~-arrested sensecent state in human diploid fibroblasts in culture. The retinoblastoma-susceptibility gene product is an inhibitor of cell proliferation, based on its absence or inactivation in retinoblastoma as well as other tumor types. The wild-type retinoblastoma-susceptibility gene product has been demonstrated to suppress tumorigenicity when reintroduced into retinoblastoma and osteosarcoma cells. Understanding the regulation of expression of such genes during cellular senescence may well lead to insights into the mechanism of oncogenesis. R a s oncogenes activation has been implicated in a number of common forms of cancer, including carcinomas of the lung, colon, and pancreas. Although the role of these ras
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oncogenes in carcinogenesis is not completely understood, their activation has been demonstrated to precede the onset of neoplasia (Kumar et al., 1990). We propose that the ras genes are randomly activated throughout the life span of healthy individuals, either by exposure to carcinogenic agents or by sporadic errors during cell replication. Subsequent exposure of cells containing the activated ras genes to growth-promoting agents or further genetic alterations (as may result during the processes of aging) would then trigger neoplastic development. The demonstration by Vogelstein and colleagues (Vogelstein et al., 1988; Baker et al., 1989) of a number of sequential and discrete genetic events in the development of human colorectal cancer from benign polyp to metastatic carcinomas, including specific deletions on the 5th chromosome, hypomethylation of DNA, ras gene activation, and loss in chromosomes 17 and 18, lends support to the concept of cancer pathogenesis as being a time/age-dependent process. This time dependency for multiple events to occur could, at least in part, explain the higher incidence of cancer in older individuals. The work of Friend and colleagues (Malkin et al., 1990) is also relevant in this regard. These workers identified mutations in the suppressor gene, p53, in patients with Li-Fraumeni syndrome, a rare familial cancer syndrome with high mortality. Although all the cells of affected family members carry mutations in the p5 3gene, these individuals may be free from cancer or develop only one or a few cancers later in life. This would suggest that mutations at other sites are also necessary to complete the transformation of a susceptible cell to a cancerous one. Multidependent events have also been proposed in the development of familial multiple endrocrine neoplasias (Brandi et al., 1987). There are numerous identified age-related alterations that could render cells more susceptible to the initiation and/or promotion of carcinogenesis. Table 1 lists some of the more likely age-related changes that are putative effectors of cancer incidence with advancing age. Other factors, such as decline in immune function with advancing age, have also been implicated in the age-associated increase in the incidence of most types of cancers (Gatti and Good, 1970). There are, however, a number of issues that must be resolved before one can embrace the theory that immune deficiency with advancing age is responsible for the observed age-
TABLE 1. PUTATIVE EFFECTORS OF CANCER INCIDENCE WITH ADVANCINGAGE
Alteration Deficient DNA repair capacity
Diminished fidelity of DNA polymerase Altered DNA methylation Decreased fidelity of protein synthesis Increased number of fragile sites Altered hormonal levels and sensitivity Increased free radical damage Altered protein structure Altered regulation of cell cycle
Reference Hart and Setlow, 1976 Trosko and Chu, 1975 Warner and Price, 1989 Singh et al., 1990 Krauss and Linn, 1986 May-Hoopes, 1989 Orgel, 1963 Yunis and Hoffman, 1989 Anisimov and Turisov, 1981 Everitt and Meites, 1989 Ames, 1991 Gafni, 1990 Cristofalo, 1973
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related increased incidence of cancer in humans. For example, why do immune-deficient patients not exhibit a wider range of cancers such as occur in aging, rather than the rather specific lymphomas and Kaposi's sarcoma? Also, why do some immune-deficient patients not develop tumors at all (Schwartz, 1975)? A full and excellent discussion of alterations in immune function and the effects of caloric restriction on the age-associated incidence of cancer is presented by Weindruch and Walford (1988). The well-documented effect of caloric restriction on both the retardation of the processes of aging and the age-associated incidence of most cancers is relevant to our discussion here. Since the earlier work of McCay and Tannenbaum (McCay et al., 1935; Tannenbaum, 1940, 1942; McCay et al., 1943; Tannenbaum, 1945), caloric restriction has been widely known to retard the incidence of tumors, as well as to increase life span and functional capcity in laboratory rodents. It is also well established that other dietary factors can influence the processes of aging and the age-associated incidence of various diseases, including cancers (Ingram et al., 1991). One could argue that, if the incidence of cancer was purely a function of exposure time to a carcinogenic agent, then the age-specific incidence rates for cancers should not be altered by caloric restriction. There is, however, no conclusive evidence to support such a conclusion. Indeed, most studies demonstrate that the effect of caloric restriction on the reduced incidence of most common cancers is relatively proportional to its effect on life span. Indeed, Albanes (1987), in surveying a number of reports on caloric restriction and tumor incidence in mice with increasing age, described an almost linear relationship between caloric intake and tumor incidence. One might therefore conclude that caloric restriction reduces tumor incidence by altering or delaying intrinsic age-dependent changes. It could be these same modulated biological mechanisms that impart enhanced longevity and functional capacity to the calorically restricted animal that are also responsible for reduced tumor incidence. This is obviously a rather simplistic argument fraught with any number of caveats; however, it does strongly suggest that the rates of aging and the pathogenesis of a number of cancer are in fact linked by at least some underlying basic mechanism(s) common to both, most likely at the level ofgene expression. CONCLUSION In summary, given the range of putative age-related alterations that can affect cell function, it is difficult not to conclude that the increased incidence of many cancers with advancing age must, at least for some aspects, be attributed to either intrinsic and/or extrinsic processes of time (i.e., biological aging). Acknowledgments ~ The authors wish to thank Drs. Huber Warner, Donald Ingram, George Martin, and Jeffrey Metter for helpful discussion and editorial comments during the preparation of this manuscript.
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