Vladimir N. Anisimov, MD

Disclosures

Cancer Control. 2007;14(1):23-31. 

In This Article

Interaction of Aging and Carcinogenesesis: Molecular Level

Oxydative Damage

One of the more developed theories of aging is the free radical theory proposed in 1954 by D. Harman.[14] This theory postulates that various oxidative reactions occuring in the organism (mainly in mitochondria) generate free radicals as a byproduct. This causes multiple lesions in macromolecules (nucleic acids, proteins, and lipids), leading to their damage and aging. This theory explains not only the mechanism of aging per se, but also a wide variety of age-associated pathologies, including cancer.[14,15,16] Recent evidence suggests that key mechanisms of both aging and cancer are linked via endogenous stress-induced DNA damage caused by reactive oxygen species. The links include oxydative nuclear and mitochondrial DNA damage and repair, telomere shortening, and telomere- driven cellular senescence. These have been discussed in a number of comprehensive reviews.[15,16,17] It is worthy to note that free radical processes also play a critical role in chemical- and radiation-induced carcinogenesis.[8,17]

DNA Damage and Repair

The intensity of natural damages to DNA is high. In a human cell, spontaneous depurinization takes place at a rate of up to 10,000 events per day and spontaneous deamination of adenine and cytosine at a rate of hundreds of events per day.[18] As a result, permanently active mechanisms of DNA repair have evolved. However, both of the most intensive natural mutation processes (depurinization and deamination) rarely involve thymidine,[18] and therefore the reparation schemes for thymidine may have evolved less intensely. Hence, if we want to induce uniformly distributed point mutations (and simultaneously minimize damages in other structures) in laboratory animals, it is suitable to use analogs of thymidine as a mutagen.

Some in vitro and in vivo effects of the thymidine analog 5-bromodeoxyuridine (BrdUrd) suggest that BrdUrd be used to investigate the role of selective DNA damage in both carcinogenesis and aging. BrdUrd is incorporated into replicating DNA in place of thymidine, and this effect is mutagenic.[19] Assuming a fairly even level of BrdUrd incorporation into the DNA of various tissues of neonatal rats and long-term persistence in them,[20] cells with the highest proliferative activity would be more likely to undergo malignant transformation. Exposure to BrdUrd has dramatic effects on cellular functions including cell differentiation, inactivation of regulatory genes or master switch and proliferation.[21] These changes in cellular function may favor tumor development.

In our series of experiments, rats received subcutaneous injections of BrdUrd at 1, 3, 7, and 21 days of postnatal life at the single dose of 3.2 mg per rat.[20,21,22,23] The exposure to BrdUrd was followed by a decrease in the mean lifespan of the animals of 38% in males and 27% in females and by an increase in the rate of aging (calculated according to the Gompertz equation) in comparison to controls. The monitoring of estrus showed an acceleration of natural age-related switching- off of reproductive function in female rats due to disturbances in the central regulation of gonadotropic function in the pituitary. The exposure of rats to BrdUrd was followed by signs of immunodepression and by an increase in the incidence of chromosome aberrations and spontaneous tumors. The latency of these tumors was decreased. In the offspring of rats neonatally treated with BrdUrd, an increased incidence of congenital malformations and spontaneous tumors and accelerated aging were both observed. Neonatal exposure of rats or mice to BrdUrd was followed by the initiation of the neoplastic process and, consequently, by increased tissue susceptibility to "latestage" carcinogens such as N-nitrosomethylurea (NMU), X-irradiation, urethane, estradiol-benzoate, persistent estrus syndrome, and 12-O-tetradecanoylphorbol-13- acetate (TPA).[21,22,23] Our data provided evidence that a sole perturbation of DNA induced by BrdUrd contributed substantially to the initiation of tumorigenesis and the acceleration of aging.

BrdUrd was found to induce in vitro a flat and enlarged cell shape characteristic of senescent cells and senescence-associated beta-galactosidase accumulation in mammalian cells regardless of cell type or species. In immortal human cells, fibronectin, collagenase I, and p21(wafl/sdi-1) mRNAs were immediately and strongly induced, and the mortality marker mortalin changed to the mortal type from the immortal type. Human cell lines lacking functional p21(wafl/sdi-1), p16(ink4a), or p53 behaved similarly. The protein levels of p16(ink4a) and p53 did not change uniformly, while the level of p21(wafl/sdi-1) was increased by varying degrees in positive cell lines. Telomerase activity was suppressed in positive betagalactosidase cell lines, but accelerated telomere shortening was not observed in tumor cell lines.[24,25] These results suggest that BrdUrd induced senescence- like phenotypic resemblance in both mortal and immortal mammalian cells and, possibly, activated a common senescence pathway present in both types of cells.[25]

The level of gene expression in HeLa cells and normal human diploid fibroblasts, TIG7 cells, exposed to BrdUrd has been examined.[25] BrdUrd induced expression of various known and novel genes in addition to several senescence-marker genes in HeLa cells, and more than half of these genes were found to be induced in normally senescent human fibroblasts. The affected genes in BrdUrd-treated HeLa cells include those involved in remodeling of extracellular matrix, cell cycle progression, and metabolism of intracellular compounds essential for normal cell growth. The authors believe that this observation can explain features characteristic of normally senesced cells, eg, specific morphological changes and the cell cycle arrest at the G1/S boundary, and it supports their view that BrdUrd induces a senescence-like phenomenon. In more recent in vitro experiments, it was shown that BrdUrd clearly activates a silenced transgene integrated in HeLa cells.[25] The authors suggest that similar mechanisms may operate in the regulation of the BrdUrdinducible genes and the senescence-associated genes. It is important to stress that BrdUrd immediately induces premature senescence in normal cells and the senescence-like phenotype in any type of immortal cells. Recently, Minagawa et al[26] showed that BrdUrd immediately and dramatically induces senescence-associated genes in human cells.

Mathematical modeling of the processes of aging and carcinogenesis in tissues based on the experimental data on in vivo exposure to BrdUrd[22,23,27] has been considered.[28] Modeling was carried out on the basis of recurrent algorithms constructed on stochastic equations in terms of semimartingale characteristics of the processes. The results confirm the conclusion that under BrdUrd treatment, there is an accelerated aging in tissues with proliferating cells and an increment of death caused by tumor growth. These results can serve as an indirect validation of the hypothesis that the level of tissue damage during mutagenesis and oxidative stress influence both the rate of aging and the rate of carcinogenesis. The above-mentioned observation on in vitro-inducing cellular senescence effect of BrdUrd[24,25,26] is in agreement with this conclusion.

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