Oxygen Free Radicals Aging And Cancer

The diseases of aging include cardiovascular disease, decline in function of the immune system, brain dysfunction, and cancer. People living in the United States who are 65 or older have

decreases with age. There is a fair amount of circumstantial evidence to support this latter hypothesis (reviewed in References 114-116). Oxidative damage to DNA, proteins, lipids, and other macromolecules accumulates with age. Oxidation products formed during normal metabolic processes in cells include superoxide (O2~), hydrogen peroxide (H2O2), and hydroxyl radical (OH). These are also produced in cells by radiation, and they are capable of damaging DNA and producing mutagenesis. Of these, the hydroxyl radical appears to be the primary DNA-damaging species, but it has a short halflife and high reactivity, so it must be generated in close proximity to DNA.117 This may occur in the cell nucleus by an interaction of H2O2 with chromatin-bound metals such as Fe+2 by the following reaction:

Figure 2-12. Immediate and long-term effects of ultraviolet (UV) radiation on skin cells and their genomes are complex. Immediate cellular responses to UV can occur through stress pathways (p38, mitogen-activated protein kinase [MAPK] and Jun N-terminal kinase [JNK]), cell surface receptors (receptors tyrosine kinase [RTKs]) and direct DNA damage. The response to DNA damage is largely mediated by p53, which can arrest growth and facilitate DNA repair or, if the damage is too extensive, induce apoptosis. Mutation-bearing melanocytes that escape these fates and survive are the seeds of potential future melanomas. Proteins of the Rb pathway, such as p16Ink4a and cyclin-dependent kinase 6 (Cdk6), are important biological targets of UV. However, the genetic changes observed (loss of p16Ink4a and amplification of Cdk6 [green]) are not characteristic of UV-induced mutagenesis and, hence, these consequences are probably indirect, with stochastic mutations selected for in cells that go on to become melanomas. Arrows do not necessarily represent direct interactions. ATM, ataxia telengiectasia mutated; ATR, ataxia telengiectasia and Rad3 related. (From Merlino and Noonan,113 with permission.)

10 times the risk of those under age 65 for developing cancer.

Part of the increase in cancer incidence with aging could be due to an accumulation of damage to DNA over a lifetime of exposure to carcinogenic substances. Another, perhaps more likely, possibility is that cellular damage produced by endogenous oxidants accumulates over time and the body's ability to repair this damage

Singlet oxygen, which is produced by lipid peroxidation or by the respiratory bursts from neutrophils, is also mutagenic and has a much longer half-life than the hydroxyl radical. Lipid peroxidation can also give rise to mutagenic products such as lipid epoxides, hydroperoxides, alkanyl and peroxyl radicals, and a, p unsaturated aldehydes.114

Cells have multiple mechanisms to protect themselves from oxidative damage, including superoxide dismutase, catalase, glutathione per-oxidase, and glutathione-S-transferases. In addition, DNA damaged by oxidants is subject to repair (see below), oxidized proteins are degraded by proteases, and lipid peroxides are destroyed by glutathione peroxidase. Nevertheless, some oxidative damage and misrepair may persist, and the ability to carry out these repair mechanisms decreases with aging. It is estimated that the human genome suffers about 10,000 ''oxidative hits'' to DNA per cell per day.114 Mutations accumulate with age in the rat so that an ''old'' rat (2 years old) has twice as many DNA lesions per cell as a young rat. Furthermore, the frequency of somatic mutations found in human lymphocytes is about ninefold higher in the aged than in neonates.118 How much of this mutation frequency is due to oxidative damage of DNA isn't clear, but a number of altered bases have been observed in cells undergoing oxidative stress. These include hydroxy-methyl uracil, thymine glycol, 8-hydroxyguanine,

8-hydroxyadenine, and formamido derivatives of altered purines.119 Some of these products appear in the urine and may be an index of oxidative damage. They are also produced by exposure of DNA to ionizing radiation and oxygen-radical generators. 8-Hydroxyguanine appears to be the most frequently altered base to result from oxi-dative damage to DNA, and if this base is left unrepaired in DNA it produces G?T trans-

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