Oxidation and Damage to DNA, Protein, and Lipids

Oxidative damage to DNA, proteins and other macromolecules accumulates with age and has been postulated to be a major, but not the only, type of endogenous damage leading to aging. Superoxide(O2.-), hydrogen peroxide (H2O2), and hydroxyl radical (.OH), which are mutagens produced by radiation, are also by-products of normal metabolism. Lipid peroxidation gives rise to mutagenic lipid epoxides, lipid hydroperoxides, lipid alkoxyl and peroxyl radicals, and enals ([[alpha]], ß-unsaturated aldehydes). Singlet oxygen, a high energy and mutagenic form of oxygen, can be produced by transfer of energy from light, the respiratory burst from neutrophils, or lipid peroxidation.

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Animals have numerous antioxidants defenses, but since these defenses are not perfect, some DNA is oxidized. Oxidatively damaged DNA is repaired by enzymes that excise the lesions, which are then excreted in the urine. We have developed methods to assay several of these excised damaged bases in the urine of rodents and humans almost all of which appear as the free base from repair by glycosylases. We estimate that the number of oxidative hits to DNA per cell per day is about l00,000 in the rat and about l0,000 in the human. DNA repair enzymes efficiently remove most, but not all, of the lesions formed. Oxidative lesions in DNA accumulate with age, so that by the time a rat is old (2 years) it has about two million DNA lesions per cell, which is about twice that in a young rat. Mutations also accumulate with age . For example, the somatic mutation frequency in human lymphocytes, of which the contribution of oxidative DNA lesions is unknown, is about nine times greater in elderly people than in neonates. The importance of oxidative DNA lesions in cancer and aging is underscored by the existence of specific repair glycosylases that excise these lesions from DNA. In the case of 8-hydroxy-2'-deoxyguanosine, a lesion formed from oxidative damage to guanine residues in DNA, loss of a specific glycosylase activity leads to an appreciable increase in the spontaneous mutation rate, indicating the intrinsic mutagenic potential of this DNA lesion. Many other oxidative DNA lesions are likely to be important as well.

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Mitochondrial DNA (mtDNA) from rat liver has more than ten times the level of oxidative DNA damage than does nuclear DNA from the same tissue. This increase may be due to a lack of mtDNA repair enzymes, lack of histones protecting mtDNA, and the proximity of mtDNA to oxidants generated during oxidative phosphorylation. The cell defends itself against this high rate of damage by a constant turnover of mitochondria, thus presumably removing those damaged mitochondria that produce increased oxidants. Despite this turnover, oxidative lesions appear to accumulate with age in mtDNA at a higher rate than in nuclear DNA.

Oxidative damage could also account for the mutations in mtDNA that accumulate with age

Endogenous oxidants also damage proteins. Stadtman and his colleagues have shown that the proteolytic enzymes that hydrolyze oxidized proteins are not sufficient to prevent an age-associated accumulation of oxidized proteins. In two human diseases associated with premature aging, Werner's syndrome and progeria, oxidized proteins accumulate at a much higher rate than is normal. Fluorescent age pigments, which are thought to be due in part to cross-links between protein and lipid peroxidation products, also accumulate with aging.

Glutathione, oxidative stress and aging

The theory of aging proposes that the impairment in physiological performance associated with aging is caused by the detrimental effects of oxygen free radicals. This is interesting because it provides us with a theoretical framework to understand aging and because it suggests a rationale for intervention, i.e., antioxidant administration. Thus, the study of antioxidant systems of the cell may be very important in gerontological studies. Glutathione is one of the main nonprotein antioxidant in the cell which, together with its related enzymes, constitute the “Glutathione system.” The involvement of Glutathione in aging has been known since the early seventies. Several studies have reported that reduced Glutathione is decreased in cells from old animals, whereas oxidized Glutathione tends to be increased. Recent experiments from our laboratory have underscored the importance of cellular compartmentation of Glutathione. MitochondrialGlutathione plays a key role in the protection against free radical damage associated with aging. Oxidative damage to mitochondrial DNA is directly related to an oxidation of mitochondrialGlutathione. In fact, aging is associated with oxidative damage to proteins, nucleic acids, and lipids. These molecular lesions may be responsible for the low physiological performance of aged cells. Thus, antioxidant supplementation may be a rational way to partially protect against age-associated impairment in performance. Apoptosis, a programmed cell death, is an area of research which has seen an explosive growth. Glutathione is involved in apoptosis: apoptotic cells have lower levels of reduced Glutathione, and administration of Glutathione precursors prevent, or at least delay, apoptosis. Age-associated diseases constitute a major concern for researchers involved in aging. Free radicals are involved in many such diseases; for instance, cancer, diabetes or atherosclerosis. The key role of Glutathione and other antioxidant in the pathophysiology of aging and age-associated diseases is discussed in this review.

Juan Sastre1, Federico V. Pallardó1 and Jose Viña Department of Physiology, Faculty of Medicine, University of Valencia, Spain Dept. Fisiologia, Facultad de Medicina, Avenida Blasco Ibanez 17, 46010 Valencia, Spain

The role of glutathione in aging and cancer.

The incidence and mortality rates from most cancers increase exponentially with age. It is likely that this aging phenomenon is partially due to specific changes that occur in the host resulting in an increased susceptibility to neoplasia. Our hypothesis is that one such host factor is a deficiency in GSH, based on the importance of this compound in the detoxification of a wide variety of exogenous and endogenous carcinogens and free radicals, as well as in the maintenance of immune function. American Health Foundation, Valhalla, New York 10595.
PMID: 1426093 [PubMed - indexed for MEDLINE]

Antioxidants are well documented and known to possess vital roles in health maintenance and disease prevention. Glutathione is your cell's own major antioxidant. Maintaining elevated glutathione levels aids the body's natural antioxidant function.

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10 Ways to Detoxify Your Body

1. Eat plenty of fiber, including brown rice and organically-grown fresh fruits and vegetables. Beets, radishes, artichokes, cabbage, broccoli, spirulina, chlorella, and seaweed are excellent detoxifying foods.

2. Cleanse and protect the liver by taking herbs such as dandelion root, burdock and milk thistle, and drinking green tea.

3. Take vitamin C, which helps the body produce glutathione, a liver compound that drives away toxins.

4. Drink at least 2 quarts of water daily.

5. Breathe deeply to allow oxygen to circulate more completely through your system.

6. Transform stress by emphasizing positive emotions.

7. Practice hydrotherapy by taking a very hot shower for five minutes, allowing the water to run on your back. Follow with cold water for 30 seconds. Do this three times, and then get into bed for 30 minutes.

8. Sweat in a sauna so your body can eliminate wastes through perspiration.

9. Dry-brush your skin or try detoxifying patches or foot baths to remove toxins through your pores. Special brushes are available at natural products stores.

10. What is the most important way to detoxify? "Exercise," says Bennett. "Yoga or jump-roping are good. One hour every day." Also try qigong, a martial-arts based exercise system that includes exercises specifically for detoxifying or cleansing, as well as many other exercises with specific health benefits.

After a detoxification program, you can cleanse your body daily through diet, supplements and lifestyle practices.

Detoxifies your bodyAntioxidants are well documented and known to possess vital roles in health maintenance and disease prevention. Glutathione is your cell's own major antioxidant.

Glutathione and its benefits in an anti-aging

FACTS about Glutathione and its benefits in an anti-aging program:

• Glutathione is a material that is found naturally in the human body

• As we age our bodies levels of Glutathione start to decline, necessitating the need for supplementation

• Glutathione is the master antioxidant and plays an important role in our overall health

• As we age our body may accumulate toxins; Glutathione protects the body from many toxins we come into contact with every day

• As we age we are subjected to numerous heavy metals, in the food we eat and the air we breathe; Glutathione is known to rid the body of heavy metals such as Mercury

• When we exercise our body uses up its stores of antioxidants; Glutathione is known to improve athletic performance and to help us keep going longer

• As we age our immune system becomes weaker; Glutathione can keep the immune system functioning at its peek.

We also suggest to click here to read this article that will demonstrate to you why Glutathione is so important to your health and well-being.

Aging Phenomenon

The incidence and mortality rates from most cancers increase exponentially with age. It is likely that this aging phenomenon is partially due to specific changes that occur in the host resulting in an increased susceptibility to neoplasia. Our hypothesis is that one such host factor is a deficiency in GSH, based on the importance of this compound in the detoxification of a wide variety of exogenous and endogenous carcinogens and free radicals, as well as in the maintenance of immune function.
American Health Foundation, Valhalla, New York 10595.
PMID: 1426093 [PubMed - indexed for MEDLINE]