7-Methylguanine adducts in DNA are normally present at high levels and increase on aging: analysis by HPLC with electrochemical detection.

Park, Jeen‐Woo; Ames, Bruce N.

doi:10.1073/pnas.85.20.7467

Cited by 93 publications

(40 citation statements)

References 45 publications

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“…The main reasons for the implication of mitochondria are that the mitochondrion is the predominant site of ATP production and also the primary producer and target of reactive oxygen species (ROS) such as O 2 − and H 2 O 2 . This notion is supported by the findings that the rates of mitochondrial O 2 − /H 2 O 2 generation, and amounts of oxidative damage to macromolecules are elevated during aging in different species (Sheldahl and Tappel, 1974;Park and Ames, 1988;Stadtman, 1992;Orr and Sohal, 1994;Sohal and Weindruch, 1996). While it was originally thought that oxidative damage to macromolecules, particularly proteins, occurred randomly and ubiquitously (Harman, 1981), more recent studies indicate that such damage in vivo is highly selective (Yan et al, 1997;Yan and Sohal, 1998;Kanski et al, 2005).…”

Section: Introductionsupporting

confidence: 61%

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

Yarian

Toroser

Sohal

2006

Mechanisms of Ageing and Development

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The activities of the citric acid cycle enzymes were determined in mitochondria isolated from kidneys of relatively young, middle age, and old mice. Aconitase exhibited the most significant decrease in activity with age. The activity of α-ketoglutarate dehydrogenase exhibited a modest decrease in activity, while NADP + -isocitrate dehydrogenase (NADP + -ICD) activity increased moderately with age. Activities of citrate synthase, NAD + -isocitrate dehydrogenase (NAD + -ICD), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SD), fumarase (FUM), and malate dehydrogenase (MD) were not affected. The molar ratio of the intra-mitochondrial redox indicator, NADPH:NADP + , was higher in young compared to old animals, while the NADH:NAD + molar ratio remained unchanged. It is suggested that an age-related decrease in aconitase activity along with relatively subtle alterations in activities of some other citric acid cycle enzymes are likely to contribute to a decline in the overall efficiency of mitochondrial bioenergetics. The biological consequences of such alterations include age-related fluctuations in the citric acid cycle intermediates, which are precursors of protein synthesis, activators of fatty acid synthesis, and can also act as ligands for orphan G-protein coupled receptors.

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Section: Introductionsupporting

confidence: 61%

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

Yarian

Toroser

Sohal

2006

Mechanisms of Ageing and Development

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“…With respect to the effect of age, m 7 Gua may be increased due to lower glutathione (GSH) concentration in aged people, (56) because GSH may be involved in scavenging alkylating agents. Ames and collaborators (57) reported that the m 7 Gua levels in rat liver DNA were increased 2.5-fold in old rats (24 months old) as compared to the levels in young rats (6 months old). Our results are compatible with their data.…”

Section: Discussionmentioning

confidence: 99%

Effect of age, smoking and other lifestyle factors on urinary 7‐methylguanine and 8‐hydroxydeoxyguanosine

Tamae¹,

Kawai²,

Yamasaki³

et al. 2009

Cancer Science

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Urinary 8-hydroxydeoxyguanosine (8-OH-dG) and 7-methylguanine (m 7 Gua) were measured by a column-switching high performance liquid chromatography method as markers of oxidative and methylating DNA damage, respectively. We investigated the associations between urinary 8-OH-dG or m 7 Gua and various lifestyle and demographic factors, such as age and sex. The urinary 8-OH-dG excretion level was positively correlated with cigarette smoking, but inversely correlated with fruit consumption, physical activity and total energy consumed per day. A multiple regression analysis revealed that daily physical activity and healthy meal combinations decreased the urinary 8-OH-dG level, whereas alcohol consumption increased it. In terms of the urinary m 7 Gua measurement, cigarette smoking, age and consumption of meat, fish, egg, soybean, etc. were positively correlated with the urinary m 7 Gua level, whereas body weight, BMI, physical activity, and dietary index score, which indicates good nutritional balance, were negatively correlated with the amount of m 7 Gua. Based on a multiple regression analysis, cigarette smoking and age correlated with the m 7 Gua level, while high BMI and healthy meal combinations have significant reducing effects on m 7 Gua level. Therefore, the urinary m 7 Gua level is considered to be a useful marker of DNA methylation, not only from smoking, but also from aging and unhealthy dietary habits. (Cancer Sci 2009; 100: 715-721) O xygen radicals are formed in cells by oxygen metabolism and various environmental agents, and they damage DNA, RNA, and proteins.(1) Among the many types of oxidative DNA damage, 8-hydroxydeoxyguanosine (8-OH-dG) is a major product and is frequently analyzed as a marker of cellular oxidative stress related to carcinogenesis, (2,3) because 8-OH-dG induces mutations, (4,5) is excreted in the urine, and it has been analyzed by high performance liquid chromatography-electrochemical detection (HPLC-ECD), (6,7) liquid chromatography-tandem mass spectrometry (LC-MS), (8) gas chromatography-mass spectrometry (GC-MS),and enzyme linked immunosorbent assay (ELISA).(10) However, the reproducibility and accuracy of its measurement are much higher with the HPLC-ECD and LC-MS/MS methods, as compared to the ELISA method. (11,12) We have reported that higher 8-OH-dG levels were observed in the lung DNA of smokers, (13) the liver DNA of chronic hepatitis patients, (14) and in the stomach DNA of patients infected with Helicobacter pylori.(15) It has also been reported that the urinary 8-OH-dG level is higher in cancer patients than in healthy people, (16) higher in smokers than in nonsmokers, (17) and lower in people who exercise moderately. (17) In addition, the urinary 8-OH-dG level was higher in men than in women, (7) and it negatively correlated to body mass index (BMI).(7) As an explanation for the relationship between a lean BMI and high urinary 8-OH-dG excretion, it has been suggested that lean persons have a higher metabolic rate than obese persons, (18) and therefore have higher oxidat...

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“…Statistical significance of the difference between the ethanol-fed and paired-fed control groups (*P Ͻ 0.05 and **P Ͻ 0.01) was calculated using the paired t-test. formation of a number of deleterious adducts of mtDNA including products of lipid peroxidation (53,59), oxidation (16,52), and alkylation (46), all adducts likely to impede the progress of Taq polymerase in the polymerase inhibition assay (29). Additionally, evidence has shown that aging interferes with the import of two major mtDNA repair enzymes, i.e., 8-oxoguanine-DNA glycosylase and uracil-DNA glycosylase, into the mitochondrial matrix (58).…”

Section: Discussionmentioning

confidence: 99%

Ethanol feeding enhances age-related deterioration of the rat hepatic mitochondrion

Cahill

Hershman

Davies

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ethanol feeding enhances age-related deterioration of the rat hepatic mitochondrion. Am J Physiol Gastrointest Liver Physiol 289: G1115-G1123, 2005. First published July 14, 2005; doi:10.1152/ajpgi.00193.2005.-Chronic ethanol feeding damages the hepatic mitochondrion by increasing mitochondrial DNA (mtDNA) oxidation, lowering mtDNA yields and impairing mitochondrial respiration. These effects are also seen during aging. By employing a 21-day chronic feeding regimen, we investigated the effects of ethanol consumption on mtDNA content and mitochondrial respiration in 2-, 12-, and 24-mo-old male rats. Aging resulted in decreased mtDNA content, increased mtDNA damage (as indicated by inhibition of Taq polymerase progression), and a decline in state 3 respiration; effects that were further exacerbated by ethanol feeding. Additionally, ethanol consumption caused an increase in the levels of citrate synthase while not impacting mitochondrial protein content. In conclusion, ethanol and aging combine to cause deterioration in the structural and functional integrity of the hepatic mitochondrion. The additive effects of aging and ethanol feeding may have serious consequences for hepatic energy metabolism in aged animals, and their detrimental combination may serve as one of the molecular mechanisms underlying the progression of alcoholic liver disease. mitochondrial DNA; respiration; polymerase-blocking lesions; citrate synthase CHRONIC ETHANOL FEEDING results in a number of detrimental alterations to the structural and functional integrity of the hepatic mitochondrion, e.g., altered morphology (17, 20), impaired mitochondrial protein synthesis (8), decreased activity/ levels of electron transport chain components (14, 15), and potentiation of mitochondrial permeability transition (47). Additionally, ethanol feeding, both chronic and acute, leads to oxidative damage to, and decreased yields of, hepatic mitochondrial DNA (mtDNA) (9,10,38,39). Many of these ethanol-elicited deleterious effects on energy metabolism can also be seen during aging, e.g., altered mitochondrial morphology (52), impaired electron transport chain activity (43), increased susceptibility to mitochondrial permeability transition (22,40), and impaired structural integrity of hepatic mtDNA (6, 32). These observations lend themselves to the intriguing possibility that a similar molecular mechanism(s) may underlie both processes. Thus far, no studies have specifically investigated the potential interaction of ethanol treatment and the aging process and how such an interaction may compromise mitochondrial function. To that end, we present the following data showing how aging results in a gradual deterioration in the structural and functional integrity of the hepatic mitochondrion, and we demonstrate that ethanol feeding increases the rate of this deterioration. EXPERIMENTAL PROCEDURESReagents and chemicals. All reagents were molecular biology grade and obtained from Sigma (St. Louis, MO) or Fisher Scientific (Pittsburgh, PA).Animal experimentation and feed...

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7-Methylguanine adducts in DNA are normally present at high levels and increase on aging: analysis by HPLC with electrochemical detection.

Abstract: The 7-methylguanine adduct in the DNA of rat liver is determined as an indicator of exposure to exogenous and endogenous methylating agents. A method for the analysis of 7-methylguanine adducts has been developed by combining

Cited by 93 publications

References 45 publications

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

Effect of age, smoking and other lifestyle factors on urinary 7‐methylguanine and 8‐hydroxydeoxyguanosine

Ethanol feeding enhances age-related deterioration of the rat hepatic mitochondrion

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