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J Cereb Blood Flow Metab. 2008 Sep 10. [Epub ahead of print]
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New insights into central roles of cerebral oxygen metabolism in the resting and stimulus-evoked brain.
1Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
The possible role of oxygen metabolism in supporting brain activation remains elusive. We have used a newly developed neuroimaging approach based on high-field in vivo (17)O magnetic resonance spectroscopic (MRS) imaging to noninvasively image cerebral metabolic rate of oxygen (CMRO(2)) consumption in cats at rest and during visual stimulation. It was found that CMRO(2) increases significantly (32.3%+/-10.8%, n=6) in the activated visual cortical region as depicted in blood oxygenation level dependence functional maps; this increase is also accompanied by a CMRO(2) decrease in surrounding cortical regions, resulting a smaller increase (9.7%+/-1.9%) of total CMRO(2) change over a larger cortical region displaying either a positive or negative CMRO(2) alteration. Moreover, a negative correlation between stimulus-evoked percent CMRO(2) increase and resting CMRO(2) was observed, indicating an essential impact of resting brain metabolic activity level on stimulus-evoked percent CMRO(2) change and neuroimaging signals. These findings provide new insights into the critical roles of oxidative metabolism in supporting brain activation and function. They also suggest that in vivo (17)O MRS imaging should provide a sensitive neuroimaging modality for mapping CMRO(2) and its change induced by brain physiology and/or pathologic alteration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 September 2008; doi:10.1038/jcbfm.2008.97.
Archive for the ‘bioenergetics’ category
Artères et veines
septembre 11, 2008Paris, 20 mai 2008
Artères et veines, un mariage forcé
Une équipe pluridisciplinaire, composée de physiciens et de biologistes français et allemands(1), vient de découvrir comment, chez l’embryon, les artères et les veines se développent en paires parallèles. Grâce à des mesures physiques, des modèles théoriques et des simulations numériques, les chercheurs montrent comment la croissance des artères oriente directement celle des veines par un processus dépendant uniquement des forces mécaniques en présence. Ces travaux sont publiés en ligne sur le site de la revue Physical Review E(2).
Un réseau vasculaire extraordinairement complexe, composé d’artères, de capillaires et de veines, parcourt l’organisme des vertébrés. Il apporte à chaque cellule l’oxygène et les nutriments nécessaires et permet d’évacuer les déchets métaboliques produits. Ce réseau contient un si grand nombre de branches que les positions de chaque vaisseau ne peuvent pas être codées génétiquement. Cependant, la génétique est souvent évoquée pour expliquer le fait que, chez l’adulte, les artères et les veines cheminent très fréquemment par paires parallèles, une artère étant même souvent encadrée par deux veines qui lui sont strictement parallèles. Pendant le développement embryonnaire une «conversation génétique» artères/veines permettrait en effet d’interpréter ce phénomène.
Dans leur article paru dans Physical Review E, les chercheurs montrent comment des phénomènes physiques (mécaniques, hydrodynamiques et élastiques) conduisent à un développement parallèle des artères et des veines.
Une étude détaillée du développent spatial et temporel des artères et des veines au stade embryonnaire montre qu’une métamorphose de l’arborescence vasculaire se produit spontanément en cours de croissance. Au stade embryonnaire précoce, on observe une organisation spatiale en série, où les artères et les veines sont situées dans des régions distinctes de l’espace. Puis rapidement, après quelques jours de développement embryonnaire, de nouvelles veines se développent en parallèle des artères existantes et les territoires vasculaires s’entrelacent.
A partir de visualisations du réseau vasculaire et de la mesure de paramètres mécaniques locaux réalisées in situ, les chercheurs démontrent que cette métamorphose est initiée par la croissance des artères. A leur voisinage, on observe une réponse visco-élastique du tissu vivant, se traduisant par un gonflement. Cette réponse entraîne à son tour une augmentation de la perméabilité du lit capillaire, très localisée dans des zones parfaitement parallèles aux artères précédemment formées. Ces zones de forte conductivité sont sélectionnées par l’écoulement sanguin qui y circule plus favorablement, puis remodelées en veines, dès que le tissu atteint une taille critique, qui a été prédite théoriquement. Des simulations numériques de l’écoulement sanguin réalisées dans des réseaux vasculaires idéalisés d’organes, à différents stades de croissance, ont confirmé ces résultats.
Ce travail apporte un éclairage nouveau sur l’importance de la mécanique dans le développement embryonnaire. Il existe dans les embryons un paysage de forces mécaniques formant une dentelle de régions dures ou molles, qui évolue spontanément sous l’action des poussées exercées par les cellules. Analyser la composante physique des différents actes du scénario du développement embryonnaire permettra de comprendre la cause des aberrations du développement ou des pathologies causées par des gènes défectueux, qui altèrent les propriétés physiques du tissu.
© V.Fleury/CNRS (Ce visuel est disponible auprès de la photothèque du CNRS : phototheque©cnrs-bellevue.fr)
Formation des vaisseaux chez un embryon de 4 jours. On observe Le processus de formation des veines (indiquées par des flèches), en parallèle des artères (indiquées par des étoiles).
Notes :
1) Institut de physique de Rennes (CNRS/Université Rennes 1), Institut de mécanique des fluides de Toulouse (CNRS/INP Toulouse/Université Toulouse 3), Laboratoire de physique de la matière condensée (CNRS/Ecole Polytechnique, Palaiseau), Laboratory for Angiogenesis and Cardiovascular Pathology, Max Delbrück Centrum für Molekulare Medizin, Berlin-Buch, Germany.
Références :
A. Al-Kilani, S. Lorthois, T.-H. Nguyen, F. Le Noble, A. Cornelissen, M. Unbekandt, O. Boryskina, L. Leroy and V. Fleury. “During vertebrate development, arteries exert a morphological control over the venous pattern through physical factors”, Physical Review E (mai 2008)
Contacts :
Chercheurs
Sylvie Lorthois
Institut de mécanique des fluides de Toulouse
(CNRS/INP Toulouse/Université Toulouse 3)
T 05 61 28 58 74
sylvie.lorthois@imft.fr
pubmed Barja G; ROS , radical production, rate of aging, bird, mammals
juillet 30, 2008
Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver.Caro P, Gómez J, López-Torres M, Sánchez I, Naudi A, Portero-Otín M, Pamplona R, Barja G.
Department of Animal Physiology-II, Complutense University, Madrid, Spain.
It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected. It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR. Based on these facts, we have studied the effect of EOD DR on the rate of mitochondrial reactive oxygen species (ROS) production, oxygen consumption, and the percent free radical leak (FRL) of well-coupled liver mitochondria, the marker of mtDNA oxidative damage 8-oxo-7,8-dihydro-2’deoxyguanosine (8-oxodG), the content of complexes I to IV of the respiratory chain, the apoptosis inducing factor (AIF), PGC1-alpha, UCP2, five different markers of oxidative damage to proteins and the full fatty acid composition on C57BL/6 mice liver. It was found that EOD DR decreased ROS production in complex I but not in complex III without changes in oxygen consumption. As a result, FRL was decreased in complex I. Oxidative damage to mtDNA (8-oxodG) and protein oxidation, glycoxidation and lipoxidation were also lower in the EOD restricted group in comparison with the control one while the degree of fatty acid unsaturation was held constant. The EOD group also showed decreases in AIF, PGC1-alpha, and UCP2. These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.
Publication Types:
PMID: 18593280 [PubMed – in process]
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2: Biogerontology. 2008 Jun;9(3):183-96. Epub 2008 Feb 19.Related Articles, <!–
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Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver.Caro P, Gómez J, López-Torres M, Sánchez I, Naudí A, Jove M, Pamplona R, Barja G.
Departamento de Fisiología Animal-II, Facultad de Ciencias Biológicas, Complutense University, c/Jose Antonio Novais-2, Madrid 28040, Spain.
Dietary restriction (DR) lowers mitochondrial reactive oxygen species (ROS) generation and oxidative damage and increases maximum longevity in rodents. Protein restriction (PR) or methionine restriction (MetR), but not lipid or carbohydrate restriction, also cause those kinds of changes. However, previous experiments of MetR were performed only at 80% MetR, and substituting dietary methionine with glutamate in the diet. In order to clarify if MetR can be responsible for the lowered ROS production and oxidative stress induced by standard (40%) DR, Wistar rats were subjected to 40% or 80% MetR without changing other dietary components. It was found that both 40% and 80% MetR decrease mitochondrial ROS generation and percent free radical leak in rat liver mitochondria, similarly to what has been previously observed in 40% PR and 40% DR. The concentration of complexes I and III, apoptosis inducing factor, oxidative damage to mitochondrial DNA, five different markers of protein oxidation, glycoxidation or lipoxidation and fatty acid unsaturation were also lowered. The results show that 40% isocaloric MetR is enough to decrease ROS production and oxidative stress in rat liver. This suggests that the lowered intake of methionine is responsible for the decrease in oxidative stress observed in DR.
Publication Types:
PMID: 18283555 [PubMed – in process]
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3: Biochim Biophys Acta. 2008 Jan 18. [Epub ahead of print]Related Articles, <!–
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Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction Possible implications for humans.Department of Animal Physiology II, Faculty of Biological Sciences, Complutense University, Madrid 28040, Spain.
Available information indicates that long-lived mammals have low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, many studies have consistently shown that dietary restriction (DR) in rodents also decreases mitochondrial ROS (mtROS) production and oxidative damage to mitochondrial DNA and proteins. It has been observed that protein restriction also decreases mtROS generation and oxidative stress in rat liver, whereas neither carbohydrate nor lipid restriction change these parameters. This is interesting because protein restriction also increases maximum longevity in rodents (although to a lower extent than DR) and is a much more practicable intervention for humans than DR, whereas neither carbohydrate nor lipid restriction seem to change rodent longevity. Moreover, it has been found that isocaloric methionine restriction also decreases mtROS generation and oxidative stress in rodent tissues, and this manipulation also increases maximum longevity in rats and mice. In addition, excessive dietary methionine also increases mtROS generation in rat liver. These studies suggest that the reduced intake of dietary methionine can be responsible for the decrease in mitochondrial ROS generation and the ensuing oxidative damage that occurs during DR, as well as for part of the increase in maximum longevity induced by this dietary manipulation. In addition, the mean intake of proteins (and thus methionine) of Western human populations is much higher than needed. Therefore, decreasing such levels to the recommended ones has a great potential to lower tissue oxidative stress and to increase healthy life span in humans while avoiding the possible undesirable effects of DR diets.
PMID: 18252204 [PubMed – as supplied by publisher]
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4: Biogerontology. 2008 Feb;9(1):57-66. Epub 2007 Oct 31.Related Articles, <!–
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The gene cluster hypothesis of aging and longevity.Departamento de Fisiología Animal-II, Facultad de Ciencias Biológicas, Universidad Complutense, Madrid, Spain. gbarja@bio.ucm.es
The maximum longevity of different species can vary by 100-fold in mammals and by 1,000-fold or more from invertebrates to mammals. However, the life extension effect of single gene mutations or dietary restriction converges on a comparatively minute 1.3- to 1.6-fold difference with controls. It is proposed that this can be due to organization of genes affecting maximum life span in large clusters functionally linked by complex interactions analogously to homeotic genes during development. A relatively small number of master genes would control the activity of the structural target genes of the whole cluster, strongly facilitating changes in longevity during species evolution. Experimentally manipulating the expression of those master genes would have the potential to increase maximum longevity to a much higher extent than the options available nowadays. The present availability of the full genome sequence of various organisms including rats, mice and men can greatly help to discover such clustering and to identify those master genes. Fortunately for gerontology, the first highly reliable completed genomes were those of the laboratory rodents and humans, mammals with strongly different maximum longevities, 3-4 years and 122 years, respectively. Comparing them focusing on longevity will help to discover the longevity gene cluster and many other relevant aspects concerning aging rate, and should be encouraged. The gene cluster hypothesis of aging can be tested at least: (a) using bioinformatics tools allowing to look for common sequences in known genes that, based on the evidence available, are expected to be part of the longevity gene cluster; (b) looking for spatial clustering of some of these genes in particular chromosome regions. The huge benefits that could be obtained discovering the longevity gene cluster will amply outweigh the comparatively small research effort involved.
Publication Types:
PMID: 17972157 [PubMed – in process]
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5: Rejuvenation Res. 2007 Dec;10(4):473-84.Related Articles, <!–
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Methionine restriction decreases endogenous oxidative molecular damage and increases mitochondrial biogenesis and uncoupling protein 4 in rat brain.Naudí A, Caro P, Jové M, Gómez J, Boada J, Ayala V, Portero-Otín M, Barja G, Pamplona R.
Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA, c/Montserrat Roig 2, Lleida, Spain.
Aging plays a central role in the occurrence of neurodegenerative diseases. Caloric restriction (CR) mitigates oxidative stress by decreasing the rate of generation of endogenous damage, a mechanism that can contribute to the slowing of the aging rate induced by this intervention. Various reports have recently linked methionine to aging, and methionine restriction (MetR) without energy restriction also increases life span. We have thus hypothesized that MetR can be responsible, at least in part, for the decrease in endogenous oxidative damage in CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their life span. We have found that MetR: (1) decreases the mitochondrial complex I content and activity, as well as complex III content, while the complex II and IV, the mitochondrial flavoprotein apoptosis-inducing factor (AIF) and ATP content are unchanged; (2) increases the mitochondrial biogenesis factor PGC-1alpha; (3) increases the resistance of brain to metabolic and oxidative stress by increasing mitochondrial uncoupling protein 4 uncoupling protein 4 (UCP4); and (4) decreases mitochondrial oxidative DNA damage and all five different markers of protein oxidation measured and lowers membrane unsaturation in rat brain. No changes were detected for protein amino acid composition. These beneficial MetR-induced changes likely derived from metabolic reprogramming at the cellular and tissue level can play a key role in the protection against aging-associated neurodegenerative disorders.
Publication Types:
PMID: 17716000 [PubMed – indexed for MEDLINE]
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6: Ageing Res Rev. 2007 Oct;6(3):189-210. Epub 2007 Jul 13.Related Articles, <!–
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Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity.Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Lleida 25008, Spain.
Key characteristics relating oxidative damage to aging and longevity are reviewed. Available information indicates that the specific composition of tissue macromolecules (proteins, lipids and mitochondrial DNA) in long-lived animal species gives them an intrinsically high resistance to modification that likely contributes to the superior longevity of these species. This is obtained in the case of lipids by decreasing fatty acid unsaturation, and in the proteins by lowering their methionine content. Long-lived animals also show low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, dietary restriction decreases mitochondrial ROS production and oxidative damage to mitochondrial DNA and proteins. These changes are due to the decreased intake of dietary proteins (not of lipids or carbohydrates) of the dietary restricted animals. In turn, these effects of protein restriction seem to be specifically due to the lowered methionine intake of the protein and dietary restricted animals. It is emphasized that both a low rate of generation of endogenous damage and an intrinsically high resistance to modification of tissue macromolecules are key traits of animal longevity.
Publication Types:
PMID: 17702671 [PubMed – indexed for MEDLINE]
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7: Rejuvenation Res. 2007 Jun;10(2):215-24.Related Articles, <!–
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Mitochondrial oxygen consumption and reactive oxygen species production are independently modulated: implications for aging studies.Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, c/Antonio Novais-2, Madrid 28040, Spain. gbarja@bio.ucm.es
Various recent investigations relevant to the study of aging mechanisms have recently found that increases in longevity during dietary restriction can occur together with lack of decreases or even increases in O2 consumption. This is frequently interpreted as contradictory with the mitochondrial free radical theory of aging. But this is based on the erroneous assumption that increasing O2 consumption must increase the rate of mitochondrial oxygen radical generation. Here it is shown that the opposite occurs in many important situations. Strong decreases in absolute and relative (per unit of O2 consumed) mitochondrial oxygen radical production occur during aerobic exercise bouts, chronic exercise training, and hyperthyroidism, and notably, during dietary restriction. Mitochondrial oxygen radical generation is also lower in long-lived birds than in short-lived mammals of similar body size and metabolic rate. Total rates of reactive oxygen species generation can also vary between tissues in a way not linked to their differences in oxygen consumption. All this indicates that mitochondrial reactive oxygen species (ROS) production is not a simple byproduct of mitochondrial respiration. Instead, it is regulated independently of O2 consumption in many different physiologic situations, tissues, and animal species. Thus, the apparently paradoxical increases in O2 consumption observed in some models of dietary restriction do not discredit the mitochondrial free radical theory of aging, and they can further strengthen it.
Publication Types:
PMID: 17523876 [PubMed – indexed for MEDLINE]
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8: Biogerontology. 2007 Oct;8(5):555-66. Epub 2007 May 8.Related Articles, <!–
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Effect of 8.5% and 25% caloric restriction on mitochondrial free radical production and oxidative stress in rat liver.Gómez J, Caro P, Naudí A, Portero-Otin M, Pamplona R, Barja G.
Department of Animal Physiology-II, Complutense University, c/Antonio Novais-2, Madrid 28040, Spain.
Previous studies have consistently shown that 40% caloric restriction (CR) decreases the rate of mitochondrial ROS production and steady-state levels of markers of oxidative damage to macromolecules including mitochondrial DNA. However, few investigations have studied whether these changes also occur in lower CR regimes. This is of potential interest since moderate levels of dietary restriction are more practicable for humans. In this investigation male Wistar rats were subjected to 8.5% and 25% caloric restriction. Neither 8.5% nor 25% CR changed mitochondrial ROS production, oxygen consumption or mtDNA oxidative damage in rat liver mitochondria. However, both 8.5% and 25% CR significantly decreased the five different markers of protein oxidation, glycoxidation and lipoxidation measured, aminoadipic and glutamic semialdehyde, carboxyethyl-lysine, carboxymethyl-lysine, and malondialdehyde-lysine. The fatty acid composition of liver mitochondria was also affected and led to a moderate decrease in the degree of membrane unsaturation in both 8.5% and 25% CR. While 8.5% CR only affected complex I concentration (which was decreased), 25% CR decreased complexes I and IV and increased complexes II and III of the respiratory chain. Apoptosis-inducing factor (AIF) significantly decreased in 25% CR but not in 8.5% CR. The results show that moderate levels of caloric restriction can have beneficial effects including decreases in oxidative protein modification and a lower sensitivity of membranes to lipid peroxidation, in association with a reprogramming of the respiratory chain complexes and AIF content.
Publication Types:
PMID: 17486421 [PubMed – indexed for MEDLINE]
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9: J Gerontol A Biol Sci Med Sci. 2007 Apr;62(4):352-60.Related Articles, <!–
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Dietary protein restriction decreases oxidative protein damage, peroxidizability index, and mitochondrial complex I content in rat liver.Ayala V, Naudí A, Sanz A, Caro P, Portero-Otin M, Barja G, Pamplona R.
Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Spain.
Caloric restriction (CR) decreases oxidative damage, which contributes to the slowing of aging rate. It is not known if such decreases are due to calories themselves or specific dietary components. In this work, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls. After 7 weeks, the liver of the protein-restricted (PR) animals showed decreases in oxidative protein damage, degree of membrane unsaturation, and mitochondrial complex I content. The results and previous information suggest that the decrease in the rate of aging induced by PR can be due in part to decreases in mitochondrial reactive oxygen species production and DNA and protein oxidative modification, increases in fatty acid components more resistant to oxidative damage, and decreased expression of complex I, analogously to what occurs during CR. Recent studies suggest that those benefits of PR could be caused, in turn, by the lowered methionine intake of that dietary manipulation.
Publication Types:
PMID: 17452727 [PubMed – indexed for MEDLINE]
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10: J Bioenerg Biomembr. 2006 Dec;38(5-6):327-33.Related Articles, <!–
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Carbohydrate restriction does not change mitochondrial free radical generation and oxidative DNA damage.Sanz A, Gómez J, Caro P, Barja G.
Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, 28040, Spain.
Many previous investigations have consistently reported that caloric restriction (40%), which increases maximum longevity, decreases mitochondrial reactive species (ROS) generation and oxidative damage to mitochondrial DNA (mtDNA) in laboratory rodents. These decreases take place in rat liver after only seven weeks of caloric restriction. Moreover, it has been found that seven weeks of 40% protein restriction, independently of caloric restriction, also decrease these two parameters, whereas they are not changed after seven weeks of 40% lipid restriction. This is interesting since it is known that protein restriction can extend longevity in rodents, whereas lipid restriction does not have such effect. However, before concluding that the ameliorating effects of caloric restriction on mitochondrial oxidative stress are due to restriction in protein intake, studies on the third energetic component of the diet, carbohydrates, are needed. In the present study, using semipurified diets, the carbohydrate ingestion of male Wistar rats was decreased by 40% below controls without changing the level of intake of the other dietary components. After seven weeks of treatment the liver mitochondria of the carbohydrate restricted animals did not show changes in the rate of mitochondrial ROS production, mitochondrial oxygen consumption or percent free radical leak with any substrate (complex I- or complex II-linked) studied. In agreement with this, the levels of oxidative damage in hepatic mtDNA and nuclear DNA were not modified in carbohydrate restricted animals. Oxidative damage in mtDNA was one order of magnitude higher than that in nuclear DNA in both dietary groups. These results, together with previous ones, discard lipids and carbohydrates, and indicate that the lowered ingestion of dietary proteins is responsible for the decrease in mitochondrial ROS production and oxidative damage in mtDNA that occurs during caloric restriction.
Publication Types:
PMID: 17136610 [PubMed – indexed for MEDLINE]
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11: Exp Gerontol. 2007 Mar;42(3):173-82. Epub 2006 Nov 21.Related Articles, <!–
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Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice.Sanz A, Hiona A, Kujoth GC, Seo AY, Hofer T, Kouwenhoven E, Kalani R, Prolla TA, Barja G, Leeuwenburgh C.
Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid 28040, Spain. albsanz@bio.ucm.es
It has been postulated that the differences in longevity observed between organisms of different sexes within a species can be attributed to differences in oxidative stress. It is generally accepted that differences are due to the higher female estrogen levels. However, in some species males live the same or longer despite their lower estrogen values. Therefore, in the present study, we analyze key parameters of mitochondrial bioenergetics, oxidative stress and apoptosis in the B6 (C57Bl/6J) mouse strain. There are no differences in longevity between males and females in this mouse strain, although estrogen levels are higher in females. We did not find any differences in heart, skeletal muscle and liver mitochondrial oxygen consumption (State 3 and State 4) and ATP content between male and female mice. Moreover, mitochondrial H(2)O(2) generation and oxidative stress levels determined by cytosolic protein carbonyls and concentration of 8-hydroxy-2′-deoxyguanosine in mitochondrial DNA were similar in both sexes. In addition, markers of apoptosis (caspase-3, caspase-9 and mono- and oligonucleosomes: the apoptosis index) were not different between male and female mice. These data show that there are no differences in mitochondrial bioenergetics, oxidative stress and apoptosis due to gender in this mouse strain according with the lack of differences in longevity. These results support the Mitochondrial Free Radical Theory of Aging, and indicate that oxidative stress generation independent of estrogen levels determines aging rate.
Publication Types:
PMID: 17118599 [PubMed – indexed for MEDLINE]
PMCID: PMC1817668
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12: J Bioenerg Biomembr. 2006 Apr;38(2):121-7. Epub 2006 Jul 14.Related Articles, <!–
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Testing the vicious cycle theory of mitochondrial ROS production: effects of H2O2 and cumene hydroperoxide treatment on heart mitochondria.Sanz A, Caro P, Gómez J, Barja G.
Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid, 28040, Spain.
Vicious cycle theories of aging and oxidative stress propose that ROS produced by the mitochondrial electron transport chain damage the mitochondria leading exponentially to more ROS production and mitochondrial damage. Although this theory is widely discussed in the field of research on aging and oxidative stress, there is little supporting data. Therefore, in order to help clarify to what extent the vicious cycle theory of aging is correct, we have exposed mitochondria in vitro to different concentrations of hydrogen peroxide or cumene-hydroperoxide (0, 30, 100 and 500 muM). We have found that 30 muM hydrogen peroxide (or higher concentrations) inhibit oxygen consumption in state 3 and increase ROS production with pyruvate/malate but not with succinate as substrate, indicating that these effects occur specifically at complex I. Similar levels of cumene-OOH inhibit state 3 respiration with both kinds of substrates, and increase ROS production in both state 4 and state 3 with pyruvate/malate and with succinate. The effects of cumene-OOH on ROS generation are due to action of the peroxide in the complex III or in the complex III plus complex I ROS generators. In all cases, the increase in ROS production occurred at a threshold level of peroxide exposure without further exponential increase in ROS generation. These results are consistent with the idea that ROS production can contribute to increase oxidative stress in old animals, but the results do not fit with a vicious cycle theory in which peroxide generation leads exponentially to more and more ROS production with age.
Publication Types:
PMID: 16841200 [PubMed – indexed for MEDLINE]
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13: Biogerontology. 2007 Feb;8(1):1-11. Epub 2006 Jul 5.Related Articles, <!–
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Effect of graded corticosterone treatment on aging-related markers of oxidative stress in rat liver mitochondria.Caro P, Gómez J, Sanz A, Portero-Otín M, Pamplona R, Barja G.
Department of Animal Physiology-II, Facultad de Ciencias Biológicas, Complutense University, c/Antonio Novais-2, Madrid 28040, Spain.
Caloric restriction (CR) decreases aging rate and lowers the rate of reactive oxygen species (ROS) production at mitochondria in different organs, but the signal responsible for this last change is unknown. Glucocorticoids could constitute such a signal since it is well known that their levels increase during CR, and available studies failed to find consistent effects of insulin, the other better described hormone that varies during CR, on mitochondrial oxidative stress. In addition, there is almost no information on the possible in vivo effects of glucocorticoids on specific markers of mitochondrial and tissue oxidative stress. In this investigation, male Wistar rats were treated with corticosterone at doses of 150 and 400 mg/kg of diet during 4 weeks. After that time, oxidative stress-related parameters were measured in the liver. The corticosterone treatments did not change the rate of ROS production or the rate of oxygen consumption of rat liver mitochondria. The two lipoxidation protein markers measured (malondialdehyde-lysine and carboxymethyllysine) were decreased by both corticosterone treatments. These changes were associated with decreases in fatty acid unsaturation, especially with lowered levels of the highly unsaturated araquidonic and docosahexaenoic acids, which decrease the sensitivity to lipid peroxidation processes. The specific protein carbonyl glutamic semialdehyde, a marker of protein oxidation, was also lowered at 400 mg/kg corticosterone. The protein glycoxydation marker carboxyethyllysine and the level of oxidative damage to mtDNA (8-oxo-7,8-dihydro-2 9-deoxyguanosine) were increased by corticosterone. The results do not support the idea that corticosterone is the signal responsible for the decrease in mitochondrial ROS generation during CR. However, they show that this hormone modulates the level of oxidative stress both in proteins and in mtDNA. Some of these changes can contribute to the chronic effects of the hormone at tissue level.
Publication Types:
PMID: 16823605 [PubMed – indexed for MEDLINE]
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14: Ann N Y Acad Sci. 2006 May;1067:200-9.Related Articles, <!–
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Effect of lipid restriction on mitochondrial free radical production and oxidative DNA damage.Sanz A, Caro P, Sanchez JG, Barja G.
Department of Animal Physiology II, Faculty of Biological Sciences, Complutense University, Madrid, Spain.
Many studies have shown that caloric restriction (40%) decreases mitochondrial reactive oxygen species (ROS) generation in rodents. Moreover, we have recently found that 7 weeks of 40% protein restriction without strong caloric restriction also decreases ROS production in rat liver. This is interesting since it has been reported that protein restriction can also extend longevity in rodents. In the present study we have investigated the possible role of dietary lipids in the effects of caloric restriction on mitochondrial oxidative stress. Using semipurified diets, the ingestion of lipids in male Wistar rats was decreased by 40% below controls, while the other dietary components were ingested at exactly the same level as in animals fed ad libitum. After 7 weeks of treatment the liver mitochondria of lipid-restricted animals showed significant increases in oxygen consumption with complex I-linked substrates (pyruvate/malate and glutamate/malate). Neither mitochondrial H(2)O(2) production nor oxidative damage to mitochondrial or nuclear DNA was modified in lipid-restricted animals. Oxidative damage to mitochondrial DNA was one order of magnitude higher than that of nuclear DNA in both dietary groups. These results deny a role for lipids and reinforce the possible role of dietary proteins as being responsible for the decrease in mitochondrial ROS production and DNA damage in caloric restriction.
Publication Types:
PMID: 16803986 [PubMed – indexed for MEDLINE]
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15: FASEB J. 2006 Jun;20(8):1064-73.Related Articles, <!–
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Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins.Sanz A, Caro P, Ayala V, Portero-Otin M, Pamplona R, Barja G.
Department of Animal Physiology-II, Complutense University, Madrid, Spain.
Previous studies have consistently shown that caloric restriction (CR) decreases mitochondrial reactive oxygen species (ROS) (mitROS) generation and oxidative damage to mtDNA and mitochondrial proteins, and increases maximum longevity, although the mechanisms responsible for this are unknown. We recently found that protein restriction (PR) also produces these changes independent of energy restriction. Various facts link methionine to aging, and methionine restriction (MetR) without energy restriction increases, like CR, maximum longevity. We have thus hypothesized that MetR is responsible for the decrease in mitROS generation and oxidative stress in PR and CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their longevity. We have found, for the first time, that MetR profoundly decreases mitROS production, decreases oxidative damage to mtDNA, lowers membrane unsaturation, and decreases all five markers of protein oxidation measured in rat heart and liver mitochondria. The concentration of complexes I and IV also decreases in MetR. The decrease in mitROS generation occurs in complexes I and III in liver and in complex I in heart mitochondria, and is due to an increase in efficiency of the respiratory chain in avoiding electron leak to oxygen. These changes are strikingly similar to those observed in CR and PR, suggesting that the decrease in methionine ingestion is responsible for the decrease in mitochondrial ROS production and oxidative stress, and possibly part of the decrease in aging rate, occurring during caloric restriction.
Publication Types:
PMID: 16770005 [PubMed – indexed for MEDLINE]
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16: Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):582-99.Related Articles, <!–
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Is the mitochondrial free radical theory of aging intact?Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, Spain.
The present state of the mitochondrial free radical theory of aging is reviewed. Available studies do not support the hypothesis that antioxidants control the rate of aging because: (a) they correlate inversely with maximum longevity in vertebrates, and (b) increasing their concentration by different methods does not increase maximum lifespan. On the other hand, comparative studies consistently show that long-lived mammals and birds have low rates of mitochondrial reactive oxygen species (ROS) production and low levels of oxidative damage in their mitochondrial DNA. Furthermore, caloric restriction, which extends longevity, also decreases mitochondrial ROS production at complex I and lowers mtDNA oxidative damage. Recent data show that these changes can also be obtained with protein restriction without strong caloric restriction. Another trait of long-lived mammals and birds is the possession of low degrees of unsaturation in their cellular membranes. This is mainly due to minimizing the presence of highly unsaturated fatty acids such as 22:6n-3 and emphasizing the presence of less unsaturated fatty acids such as 18:2n-6 in long-lived animals, without changing the total amount of polyunsaturated fatty acids. This leads to lower levels of lipid peroxidation and lipoxidation-derived protein modification in long-lived species. Taken together, available information is consistent with the predictions of the mitochondrial free radical theory of aging, although definitive proof and many mechanistic details are still lacking.
Publication Types:
PMID: 16677102 [PubMed – indexed for MEDLINE]
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17: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):496-508. Epub 2006 Feb 24.Related Articles, <!–
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Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection.Department of Basic Medical Sciences, University of Lleida, Lleida 25008, Spain.
Caloric restriction (CR) decreases aging rate and mitochondrial ROS (MitROS) production and oxidative stress in rat postmitotic tissues. Low levels of these parameters are also typical traits of long-lived mammals and birds. However, it is not known what dietary components are responsible for these changes during CR. It was recently observed that 40% protein restriction without strong CR also decreases MitROS generation and oxidative stress. This is interesting because protein restriction also increases maximum longevity (although to a lower extent than CR) and is a much more practicable intervention for humans than CR. Moreover, it was recently found that 80% methionine restriction substituting it for l-glutamate in the diet also decreases MitROS generation in rat liver. Thus, methionine restriction seems to be responsible for the decrease in ROS production observed in caloric restriction. This is interesting because it is known that exactly that procedure of methionine restriction also increases maximum longevity. Moreover, recent data show that methionine levels in tissue proteins negatively correlate with maximum longevity in mammals and birds. All these suggest that lowering of methionine levels is involved in the control of mitochondrial oxidative stress and vertebrate longevity by at least two different mechanisms: decreasing the sensitivity of proteins to oxidative damage, and lowering of the rate of ROS generation at mitochondria.
Publication Types:
PMID: 16574059 [PubMed – indexed for MEDLINE]
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18: Free Radic Res. 2006 Apr;40(4):339-47.Related Articles, <!–
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Effects of fasting on oxidative stress in rat liver mitochondria.Sorensen M, Sanz A, Gómez J, Pamplona R, Portero-Otín M, Gredilla R, Barja G.
Danish Center for Molecular Gerontology, University of Aarhus, Department of Molecular Biology, 8000 Aarhus, Denmark.
While moderate caloric restriction has beneficial effects on animal health state, fasting may be harmful. The present investigation was designed to test how fasting affects oxidative stress, and to find out whether the effects are opposite to those previously found in caloric restriction studies. We have focused on one of the main determinants of aging rate: the rate of mitochondrial free radical generation. Different parameters related to lipid and protein oxidative damage were also analyzed. Liver mitochondria from rats subjected to 72 h of fasting leaked more electrons per unit of O(2) consumed at complex III, than mitochondria from ad libitum fed rats. This increased leak led to a higher free radical generation under state 3 respiration using succinate as substrate. Regarding lipids, fasting altered fatty acid composition of hepatic membranes, increasing the double bond and the peroxidizability indexes. In accordance with this, we observed that hepatic membranes from the fasted animals were more sensitive to lipid peroxidation. Hepatic protein oxidative damage was also increased in fasted rats. Thus, the levels of oxidative modifications, produced either indirectly by reactive carbonyl compounds (N(epsilon)-malondialdehyde-lysine), or directly through amino acid oxidation (glutamic and aminoadipic semialdehydes) were elevated due to the fasting treatment in both liver tissue and liver mitochondria. The current study shows that severe food deprivation increases oxidative stress in rat liver, at least in part, by increasing mitochondrial free radical generation during state 3 respiration and by increasing the sensitivity of hepatic membranes to oxidative damage, suggesting that fasting and caloric restriction have different effects on liver mitochondrial oxidative stress.
Publication Types:
PMID: 16517498 [PubMed – indexed for MEDLINE]
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19: Eur J Clin Invest. 2005 Jul;35(7):421-4.Related Articles, <!–
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International conference on the healthy effect of virgin olive oil.Perez-Jimenez F, Alvarez de Cienfuegos G, Badimon L, Barja G, Battino M, Blanco A, Bonanome A, Colomer R, Corella-Piquer D, Covas I, Chamorro-Quiros J, Escrich E, Gaforio JJ, Garcia Luna PP, Hidalgo L, Kafatos A, Kris-Etherton PM, Lairon D, Lamuela-Raventos R, Lopez-Miranda J, Lopez-Segura F, Martinez-Gonzalez MA, Mata P, Mataix J, Ordovas J, Osada J, Pacheco-Reyes R, Perucho M, Pineda-Priego M, Quiles JL, Ramirez-Tortosa MC, Ruiz-Gutierrez V, Sanchez-Rovira P, Solfrizzi V, Soriguer-Escofet F, de la Torre-Fornell R, Trichopoulos A, Villalba-Montoro JM, Villar-Ortiz JR, Visioli F.
Lipid and Atherosclerosis Unit, Reina Sofia University Hospital, Cordoba, Spain. franperezjimenez@yahoo.com
1. Ageing represents a great concern in developed countries because the number of people involved and the pathologies related with it, like atherosclerosis, morbus Parkinson, Alzheimer’s disease, vascular dementia, cognitive decline, diabetes and cancer. 2. Epidemiological studies suggest that a Mediterranean diet (which is rich in virgin olive oil) decreases the risk of cardiovascular disease. 3. The Mediterranean diet, rich in virgin olive oil, improves the major risk factors for cardiovascular disease, such as the lipoprotein profile, blood pressure, glucose metabolism and antithrombotic profile. Endothelial function, inflammation and oxidative stress are also positively modulated. Some of these effects are attributed to minor components of virgin olive oil. Therefore, the definition of the Mediterranean diet should include virgin olive oil. 4. Different observational studies conducted in humans have shown that the intake of monounsaturated fat may be protective against age-related cognitive decline and Alzheimer’s disease. 5. Microconstituents from virgin olive oil are bioavailable in humans and have shown antioxidant properties and capacity to improve endothelial function. Furthermore they are also able to modify the haemostasis, showing antithrombotic properties. 6. In countries where the populations fulfilled a typical Mediterranean diet, such as Spain, Greece and Italy, where virgin olive oil is the principal source of fat, cancer incidence rates are lower than in northern European countries. 7. The protective effect of virgin olive oil can be most important in the first decades of life, which suggests that the dietetic benefit of virgin olive oil intake should be initiated before puberty, and maintained through life. 8. The more recent studies consistently support that the Mediterranean diet, based in virgin olive oil, is compatible with a healthier ageing and increased longevity. However, despite the significant advances of the recent years, the final proof about the specific mechanisms and contributing role of the different components of virgin olive oil to its beneficial effects requires further investigations.
Publication Types:
PMID: 16008542 [PubMed – indexed for MEDLINE]
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20: Mech Ageing Dev. 2005 Oct;126(10):1106-14.Related Articles, <!–
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Protein methionine content and MDA-lysine adducts are inversely related to maximum life span in the heart of mammals.Ruiz MC, Ayala V, Portero-Otín M, Requena JR, Barja G, Pamplona R.
Department of Basic Medical Sciences, University of Lleida, Lleida 25198, Spain.
Aging affects all organisms and its basic mechanisms are expected to be conserved across species. Oxidation of proteins has been proposed to be one of the basic mechanisms linking oxygen radicals with the basic aging process. If oxidative damage to proteins is involved in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. However, this possibility has not been investigated yet. In this study, steady-state levels of markers of different kinds of protein damage–oxidation (glutamic and aminoadipic semialdehydes), mixed glyco- and lipoxidation (carboxymethyl- and carboxyethyllysine), lipoxidation (malondialdehydelysine) and amino acid composition–were measured in the heart of eight mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. Oxidation markers were directly correlated with MLSP across species. Mixed glyco- and lipoxidation markers did not correlate with MLSP. However, the lipoxidation marker malondialdehydelysine was inversely correlated with MLSP (r2=0.85; P<0.001). The amino acid compositional analysis revealed that methionine is the only amino acid strongly correlated MLSP and that such correlation is negative (r2=0.93; P<0.001). This trait may contribute to lower steady-state levels of oxidized methionine residues in cellular proteins. These results reinforce the notion that high longevity in homeothermic vertebrates is achieved in part by constitutively decreasing the sensitivity of both tissue proteins and lipids to oxidative damage. This is obtained by modifying the constituent structural components of proteins and lipids, selecting those less sensitive to oxidative modifications.
Publication Types:
PMID: 15955547 [PubMed – indexed for MEDLINE]
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21: Endocrinology. 2005 Sep;146(9):3713-7. Epub 2005 May 26.Related Articles, <!–
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Minireview: the role of oxidative stress in relation to caloric restriction and longevity.Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid, Spain.
Reduction of caloric intake without malnutrition is one of the most consistent experimental interventions that increases mean and maximum life spans in different species. For over 70 yr, caloric restriction has been studied, and during the last years the number of investigations on such nutritional intervention and aging has dramatically increased. Because caloric restriction decreases the aging rate, it constitutes an excellent approach to better understand the mechanisms underlying the aging process. Various investigations have reported reductions in steady-state oxidative damage to proteins, lipids, and DNA in animals subjected to restricted caloric intake. Most interestingly, several investigations have reported that these decreases in oxidative damage are related to a lowering of mitochondrial free radical generation rate in various tissues of the restricted animals. Thus, similar to what has been described for long-lived animals in comparative studies, a decrease in mitochondrial free radical generation has been suggested to be one of the main determinants of the extended life span observed in restricted animals. In this study we review recent reports of caloric restriction and longevity, focusing on mitochondrial oxidative stress and the proposed mechanisms leading to an extended longevity in calorie-restricted animals.
Publication Types:
PMID: 15919745 [PubMed – indexed for MEDLINE]
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22: J Bioenerg Biomembr. 2005 Apr;37(2):83-90.Related Articles, <!–
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Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain.Sanz A, Caro P, Ibañez J, Gómez J, Gredilla R, Barja G.
Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, c/Antonio Novais-2, Madrid 28040, Spain.
Previous studies in mammalian models indicate that the rate of mitochondrial reactive oxygen species ROS production and the ensuing modification of mitochondrial DNA (mtDNA) link oxidative stress to aging rate. However, there is scarce information concerning this in relation to caloric restriction (CR) in the brain, an organ of maximum relevance for ageing. Furthermore, it has never been studied if CR started late in life can improve those oxidative stress-related parameters. In this investigation, rats were subjected during 1 year to 40% CR starting at 24 months of age. This protocol of CR significantly decreased the rate of mitochondrial H(2)O(2) production (by 24%) and oxidative damage to mtDNA (by 23%) in the brain below the level of both old and young ad libitum-fed animals. In agreement with the progressive character of aging, the rate of H(2)O(2) production of brain mitochondria stayed constant with age. Oxidative damage to nuclear DNA increased with age and this increase was fully reversed by CR to the level of the young controls. The decrease in ROS production induced by CR was localized at Complex I and occurred without changes in oxygen consumption. Instead, the efficiency of brain mitochondria to avoid electron leak to oxygen at Complex I was increased by CR. The mechanism involved in that increase in efficiency was related to the degree of electronic reduction of the Complex I generator. The results agree with the idea that CR decreases aging rate in part by lowering the rate of free radical generation of mitochondria in the brain.
Publication Types:
PMID: 15906153 [PubMed – indexed for MEDLINE]
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23: Biogerontology. 2005;6(1):15-26.Related Articles, <!–
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Effect of insulin and growth hormone on rat heart and liver oxidative stress in control and caloric restricted animals.Sanz A, Gredilla R, Pamplona R, Portero-Otín M, Vara E, Tresguerres JA, Barja G.
Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid, Spain.
In order to know if insulin-like signalling is involved in the control of oxidative stress in mammalian tissues in relation to aging, ad libitum-fed and caloric restricted Wistar rats were treated during 2 weeks with GH and insulin. The most consistent effect of the hormonal treatments was an increase in plasma IGF-1 levels. Caloric restriction during 6 weeks decreased ROS generation and oxidative DNA damage in heart mitochondria and this was reversed by insulin treatment. The decrease in oxidative damage to liver nuclear DNA induced by caloric restriction was also reversed by GH and insulin. In the liver, however, insulin and GH decreased mitochondrial ROS generation while they increased oxidative damage to mitochondrial DNA. GH and insulin decreased three different markers of oxidative modification of liver proteins, while they increased lipoxidation-dependent markers. This last result is related to the increase in phospholipid unsaturation induced in the liver by both hormones. The results suggest that the idea that insulin-like signalling controls oxidative stress in mammals cannot be generalized since both prooxidant and protective effects of GH and insulin are observed depending on the particular parameter and tissue selected.
Publication Types:
PMID: 15834660 [PubMed – indexed for MEDLINE]
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24: J Bioenerg Biomembr. 2004 Dec;36(6):545-52.Related Articles, <!–
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]
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Protein restriction without strong caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat liver.Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, 28040, Spain.
Previous studies have shown that caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat organs, which can be linked to the slowing of aging rate induced by this regime. These two characteristics are also typical of long-lived animals. However, it has never been investigated if those decreases are linked to the decrease in the intake of calories themselves or to decreases in specific dietary components. In this study the possible role of the dietary protein was investigated. Using semipurified diets, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls while the other dietary components were ingested at the same level as in animals fed ad libitum. After seven weeks in this regime the liver of the protein restricted animals showed 30-40% decreases in mitochondrial production of reactive oxygen species (ROS) and in oxidative damage to nuclear and mitochondrial DNA. The decreases in ROS generation occurred specifically at complex I. They also occurred without changes in mitochondrial oxygen consumption. Instead, there was a decrease in the percent free radical leak (the percentage of total electron flow leading to ROS generation in the respiratory chain). These results are strikingly similar to those previously obtained after 40% caloric restriction in the liver of Wistar rats. Thus, the results suggest that part of the decrease in aging rate induced by caloric restriction can be due to the decreased intake of proteins acting through decreases in mitochondrial ROS production and oxidative DNA damage. Interestingly, these tissue oxidative stress-linked parameters can be lowered by restricting only the intake of dietary protein, probably a more feasible option than caloric restriction for adult humans.
Publication Types:
PMID: 15692733 [PubMed – indexed for MEDLINE]
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25: Trends Neurosci. 2004 Oct;27(10):595-600.Related Articles, <!–
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Free radicals and aging.Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid 28040, Spain. gbarja@bio.ucm.es <gbarja@bio.ucm.es>
Aging is characterized by decrements in maximum function and accumulation of mitochondrial DNA mutations, which are best observed in organs such as the brain that contain post-mitotic cells. Oxygen radicals are increasingly considered responsible for part of these aging changes. Comparative studies of animals with different aging rates have shown that the rate of mitochondrial oxygen radical generation is directly related to the steady-state level of oxidative damage to mitochondrial DNA and is inversely correlated with maximum longevity in higher vertebrates. The degree of unsaturation of tissue fatty acids also correlates inversely with maximum longevity. These are the two known traits connecting oxidative stress with aging. Furthermore, caloric restriction, which decreases the rate of aging, proportionately decreases mitochondrial oxygen radical generation, especially at complex I. These findings are reviewed, highlighting the results obtained in the brain.
Publication Types:
PMID: 15374670 [PubMed – indexed for MEDLINE]
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26: J Bioenerg Biomembr. 2000 Dec;32(6):609-15.Related Articles, <!–
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Localization of the Site of Oxygen Radical Generation inside the Complex I of Heart and Nonsynaptic Brain Mammalian Mitochondria.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
Mitochondrial production of oxygen radicals seems to be involved in many diseases and aging. Recent studies clearly showed that a substantial part of the free radical generation of rodent mitochondria comes from complex I. It is thus important to further localize the free radical generator site within this respiratory complex. In this study, superoxide production by heart and nonsynaptic brain submitochondrial particles from up to seven mammalian species, showing different longevities, were studied under different conditions. The results, taking together, show that rotenone stimulates NADH-supported superoxide generation, confirming that complex I is a source of oxygen radicals in mammals, in general. The rotenone-stimulated NADH-supported superoxide production of the heart and nonsynaptic brain mammalian submitochondrial particles was inhibited both by p-chloromercuribenzoate and by ethoxyformic anhydride. These results localize the complex I oxygen radical generator between the ferricyanide and the ubiquinone reduction site, making iron-sulfur centers possible candidates, although unstable semiquinones can not be discarded. The results also indicate that the previously described inverse correlation between rates of mitochondrial oxygen radical generation and mammalian longevity operates through mechanisms dependent on the presence of intact functional mitochondria.
PMID: 15254374 [PubMed – in process]
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27: Ann N Y Acad Sci. 2004 Jun;1019:333-42.Related Articles, <!–
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Short-term caloric restriction and sites of oxygen radical generation in kidney and skeletal muscle mitochondria.Gredilla R, Phaneuf S, Selman C, Kendaiah S, Leeuwenburgh C, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, 28040 Madrid, Spain.
Mitochondrial free radical generation is believed to be one of the principal factors determining aging rate, and complexes I and III have been described as the main sources of reactive oxygen species (ROS) within mitochondria in heart, brain, and liver. Moreover, complex I ROS generation of heart and liver mitochondria seems especially linked to aging rate both in comparative studies between animals with different longevities and in caloric restriction models. Caloric restriction (CR) is a well-documented manipulation that extends mean and maximum longevity. One of the factors that appears to be involved in such life span extension is the reduction in mitochondrial free radical generation at complex I. We have performed two parallel investigations, one studying the effect of short-term CR on oxygen radical generation in kidney and skeletal muscle (gastrocnemius) mitochondria and a second one regarding location of mitochondrial ROS-generating sites in these same tissues. In the former study, no effect of short-term caloric restriction was observed in mitochondrial free radical generation in either kidney or skeletal muscle. The latter study ruled out complex II as a principal source of free radicals in kidney and in skeletal muscle mitochondria, and, similar to previous investigations in heart and liver organelles, the main free radical generators were located at complexes I and III within the electron transport system.
Publication Types:
PMID: 15247039 [PubMed – indexed for MEDLINE]
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28: Biol Rev Camb Philos Soc. 2004 May;79(2):235-51.Related Articles, <!–
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Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism?Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
Oxygen is toxic to aerobic animals because it is univalently reduced inside cells to oxygen free radicals. Studies dealing with the relationship between oxidative stress and aging in different vertebrate species and in caloric-restricted rodents are discussed in this review. Healthy tissues mainly produce reactive oxygen species (ROS) at mitochondria. These ROS can damage cellular lipids, proteins and, most importantly, DNA. Although antioxidants help to control this oxidative stress in cells in general, they do not decrease the rate of aging, because their concentrations are lower in long- than in short-lived animals and because increasing antioxidant levels does not increase vertebrate maximum longevity. However, long-lived homeothermic vertebrates consistently have lower rates of mitochondrial ROS production and lower levels of steady-state oxidative damage in their mitochondrial DNA than short-lived ones. Caloric-restricted rodents also show lower levels of these two key parameters than controls fed ad libitum. The decrease in mitochondrial ROS generation of the restricted animals has been recently localized at complex I and the mechanism involved is related to the degree of electronic reduction of the complex I ROS generator. Strikingly, the same site and mechanism have been found when comparing a long- with a short-lived animal species. It is suggested that a low rate of mitochondrial ROS generation extends lifespan both in long-lived and in caloric-restricted animals by determining the rate of oxidative attack and accumulation of somatic mutations in mitochondrial DNA.
Publication Types:
PMID: 15191224 [PubMed – indexed for MEDLINE]
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29: Exp Gerontol. 2004 May;39(5):725-33.Related Articles, <!–
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]
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Modification of the longevity-related degree of fatty acid unsaturation modulates oxidative damage to proteins and mitochondrial DNA in liver and brain.Pamplona R, Portero-Otin M, Sanz A, Requena J, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Lleida 25198, Spain.
Previous studies have shown that tissue fatty acid unsaturation correlates inversely with maximum longevity. However, it is unclear if this is related to the effects of fatty acid unsaturation only on lipids, or also on proteins and DNA, specially on mitochondrial DNA (mtDNA) oxidative damage. In this investigation the degree of fatty acid unsaturation of liver and brain was successfully manipulated in Wistar rats by chronic feeding with specially designed semipurified diets rich in saturated or unsaturated fats. The brain, an organ of special relevance for aging, was most profoundly affected by the increase in fatty acid unsaturation, and showed significant increases in malondialdehyde (MDA)-lysine, aminoadipic semialdehyde (a protein carbonyl), N(epsilon)-(carboxymethyl)lysine, and N(epsilon)-(carboxyethyl)lysine in proteins, as well as in 8-oxo,7,8-dihydro-2′-deoxyguanosine (8-oxodG) in mtDNA without changes in nuclear DNA (nDNA). In the liver 8-oxodG was also increased in mtDNA and not in nDNA. These DNA results are consistent with the presence of a high density of mitochondrial inner membranes (rich in lipids and in reactive oxygen species generation capacity) near mtDNA but not near nDNA. Among the protein markers analyzed, MDA-lysine was most consistent and responsive to fatty acid unsaturation, since it increased in both organs and showed the highest increase. These results, together with previous data from our laboratories, show that increasing the degree of fatty unsaturation of postmitotic tissues in vivo can raise not only lipid but also protein and mtDNA oxidative damage. This is mechanistically relevant in relation to the constitutively low tissue fatty acid unsaturation of long-lived animals.
Publication Types:
PMID: 15130667 [PubMed – indexed for MEDLINE]
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30: Biogerontology. 2003;4(3):141-7.Related Articles, <!–
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Short-term caloric restriction and regulatory proteins of apoptosis in heart, skeletal muscle and kidney of Fischer 344 rats.Selman C, Gredilla R, Phaneuf S, Kendaiah S, Barja G, Leeuwenburgh C.
University of Florida, Biochemistry of Aging Laboratory, College of Health and Human Performance, Box 118206, Gainesville, FL 32611, USA.
Long-term caloric restriction reduces oxidative stress, increases mean and maximum lifespan in rodents and tends to enhance apoptosis, particularly in the liver. We investigated the effect of short-term (2 months) caloric restriction (40% reduction) in 6-month-old male Fischer 344 rats on various indicators of apoptosis (caspase-3, -7, -12, the inhibitor of apoptosis protein XIAP and cytoplasmic histone-associated DNA fragments) in the post-mitotic heart and gastrocnemius muscle, and the kidney that contains mitotic cells. Short-term caloric restriction significantly reduced body mass (30%), gastrocnemius muscle mass (22%), heart mass (25%) and kidney mass (32%) compared to ad libitum controls. The levels of procaspase-3 in gastrocnemius muscle and caspase-3 in kidney were significantly lower in the caloric restricted than in the ad libitum fed group. While caloric restriction did not alter DNA fragmentation levels (indicative of apoptosis), differences did exist amongst tissues with significantly elevated levels of fragmentation in the kidney compared to the heart and gastrocnemius muscle and significantly higher levels in the heart compared to gastrocnemius muscle. No differences were observed between groups in the levels of procaspase-7 or -12 or in XIAP (an endogenous inhibitor of apoptosis, particularly of caspase-3 and -7) in any tissue. The active forms of caspase-7 and -12 were present only in the kidney. These findings suggest that while the rate of apoptosis was higher in the kidney, which contains mitotic cells, compared to the post-mitotic heart and gastrocnemius muscle, short-term caloric restriction did not enhance the apoptosis rate in any tissue measured.
Publication Types:
PMID: 12815313 [PubMed – indexed for MEDLINE]
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31: Mech Ageing Dev. 2002 Sep;123(11):1437-46.Related Articles, <!–
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Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls.Pamplona R, Portero-Otín M, Requena J, Gredilla R, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, Lleida University, Lleida 25198, Spain.
In this investigation the effect of 4 months of 40% restriction of calories on defined markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins was studied. The protein markers assessed were N(epsilon)-(carboxyethyl)lysine (CEL), N(epsilon)-(carboxymethyl)lysine (CML), N(epsilon)-(malondialdehyde)lysine (MDA-lys), and the recently described (PNAS 98:69-74, 2001) main constituents of protein carbonyls glutamic and aminoadipic semialdehydes. All these markers were measured by gas chromatography/mass spectrometry. The results showed that glutamic semialdehyde was present in rat heart mitochondria at levels 20-fold higher than aminoadipic semialdehyde. After 4 months of caloric restriction, the levels of CEL, CML, MDA-lys and glutamic semialdehyde were significantly lower in the mitochondria from caloric restricted animals than in the controls. These decreases were not due to a lower degree of oxidative attack to mitochondrial proteins, since the rate of mitochondrial oxygen radical generation was not modified by 4 months of caloric restriction. The decreases in MDA-lys and CML were not due either to changes in the sensitivity of mitochondrial lipids to peroxidation since measurements of the fatty acid composition showed that the total number of fatty acid double bonds and the peroxidizability index were not changed by caloric restriction. The results globally indicate that caloric restriction during 4 months decreases oxidative stress-derived damage to heart mitochondrial proteins. They also suggest that these decreases are due to an increase in the capacity of the restricted mitochondria to decompose oxidatively modified proteins.
Publication Types:
PMID: 12425950 [PubMed – indexed for MEDLINE]
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32: Microsc Res Tech. 2002 Nov 15;59(4):273-7.Related Articles, <!–
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Effect of time of restriction on the decrease in mitochondrial H2O2 production and oxidative DNA damage in the heart of food-restricted rats.Gredilla R, López-Torres M, Barja G.
Department of Animal Biology-II, Faculty of Biology, Complutense University, Madrid 28040, Spain.
In the present study, the question if medium-term (4 months) caloric restriction (40%) decreases mitochondrial H2O2 production and oxidative DNA damage was investigated. Caloric restriction (CR) is the only experimental manipulation that increases maximum life span. Previous long-term CR studies have showed that CR decreases the mitochondrial rate of free radical production in diverse tissues and species. Those studies agree with the idea that the superior longevity of the restricted animals can be partly due to their lower mitochondrial rate of free radical generation. However, caloric restriction effects strongly depend on implementation time. Previous studies have shown that the decrease induced by CR on oxygen radical generation and oxidative damage to mitochondrial DNA occurs after 1 year but not after 6 weeks of restriction. In the present investigation, mitochondrial H2O2 production did not change in medium-term (4 months) caloric restricted animals, and, in agreement with that, no differences were found in either mitochondrial or nuclear oxidative DNA damage between restricted and ad libitum-fed animals. These results confirm the importance of the time of CR implementation, and show that time longer than 4 months is needed to decrease the mitochondrial rate of free radical generation and the oxidative damage to mtDNA in the rat heart. Copyright 2002 Wiley-Liss, Inc.
Publication Types:
PMID: 12424788 [PubMed – indexed for MEDLINE]
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33: Free Radic Biol Med. 2002 Nov 1;33(9):1167-72.Related Articles, <!–
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Rate of generation of oxidative stress-related damage and animal longevity.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain. gbarja@bio.ucm.es
Comparative studies about the relationship between endogenous antioxidant and pro-oxidant factors and maximum longevity of different animal species are reviewed. The majority of studies on antioxidant supplementation indicate that it can increase mean survival without changing maximum longevity. On the other hand, endogenous antioxidants are negatively correlated with maximum longevity. The same is true for the rates of mitochondrial oxygen radical generation, oxidative damage to mitochondrial DNA, and the degree of fatty acid unsaturation of cellular membranes in postmitotic tissues. The lower rate of mitochondrial oxygen radical generation of long-lived animals in relation to that of short-lived ones can be a primary cause of their slow aging rate. This is secondarily complemented in long-lived animals with low rates of lipid peroxidation due to their low degrees of fatty acid unsaturation. These two traits suggest that the rate of generation of endogenous oxidative damage determines, at least in part, the rate of aging in animals.
Publication Types:
PMID: 12398924 [PubMed – indexed for MEDLINE]
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34: Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R474-80. Epub 2002 Oct 3.Related Articles, <!–
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Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart.Drew B, Phaneuf S, Dirks A, Selman C, Gredilla R, Lezza A, Barja G, Leeuwenburgh C.
University of Florida, Biochemistry of Aging Laboratory, College of Health and Human Performance, Center for Exercise Science, Gainesville, Florida 32611, USA.
Mitochondria are chronically exposed to reactive oxygen intermediates. As a result, various tissues, including skeletal muscle and heart, are characterized by an age-associated increase in reactive oxidant-induced mitochondrial DNA (mtDNA) damage. It has been postulated that these alterations may result in a decline in the content and rate of production of ATP, which may affect tissue function, contribute to the aging process, and lead to several disease states. We show that with age, ATP content and production decreased by approximately 50% in isolated rat mitochondria from the gastrocnemius muscle; however, no decline was observed in heart mitochondria. The decline observed in skeletal muscle may be a factor in the process of sarcopenia, which increases in incidence with advancing age. Lifelong caloric restriction, which prolongs maximum life span in animals, did not attenuate the age-related decline in ATP content or rate of production in skeletal muscle and had no effect on the heart. 8-Oxo-7,8-dihydro-2′-deoxyguanosine in skeletal muscle mtDNA was unaffected by aging but decreased 30% with caloric restriction, suggesting that the mechanisms that decrease oxidative stress in these tissues with caloric restriction are independent from ATP availability. The generation of reactive oxygen species, as indicated by H2O2 production in isolated mitochondria, did not change significantly with age in skeletal muscle or in the heart. Caloric restriction tended to reduce the levels of H2O2 production in the muscle but not in the heart. These data are the first to show that an age-associated decline in ATP content and rate of ATP production is tissue specific, in that it occurs in skeletal muscle but not heart, and that mitochondrial ATP production was unaltered by caloric restriction in both tissues.
Publication Types:
PMID: 12388443 [PubMed – indexed for MEDLINE]
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35: J Bioenerg Biomembr. 2002 Jun;34(3):227-33.Related Articles, <!–
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The quantitative measurement of H2O2 generation in isolated mitochondria.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense Univesity, Madrid, Spain.
Adequate methods to measure the rate of mitochondrial oxygen radical generation are needed since oxygen radicals are involved in many pathologies. A fluorometric method appropriate to measure the rate of generation of H2O2 in intact mitochondria is described. Just after isolation of functional mitochondria from fresh tissues, rates of generation of H2O2 are kinetically measured by fluorometry in the presence of homovanillic acid and horseradish peroxidase. The method is specific for H2O2 and is sensitive enough to assay mitochondrial H2O2 generation in the presence of respiratory substrate without inhibitors of the respiratory chain. Simultaneous measurement of mitochondrial oxygen consumption allows calculation of the free radical leak: the percentage of electrons out of sequence which reduce oxygen to oxygen radicals along the mitochondrial respiratory chain instead of reducing oxygen to water at the terminal cytochrome oxidase. The method shows instantaneous response to H2O2. This makes it appropriate to study the quick effects of different inhibitors and modulators on the rate of mitochondrial oxygen radical production. Its application to the localization of the sites where caloric restriction decreases mitochondrial oxygen radical generation in heart mitochondria is described.
Publication Types:
PMID: 12171072 [PubMed – indexed for MEDLINE]
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36: Ageing Res Rev. 2002 Jun;1(3):397-411.Related Articles, <!–
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]
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Endogenous oxidative stress: relationship to aging, longevity and caloric restriction.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, 28040, Madrid, Spain.
Available studies are consistent with the possibility that oxygen radicals endogenously produced by mitochondria are causally involved in the determination of the rate of aging in homeothermic vertebrates. Oxidative damage to tissue macromolecules seems to increase during aging. The rate of mitochondrial oxygen radical generation of post-mitotic tissues is negatively correlated with animal longevity. In agreement with this, long-lived animals show lower levels of oxidative damage in their mitochondrial DNA (mtDNA) than short-lived ones, whereas this does not occur in nuclear DNA (nDNA). Caloric restriction, which decreases the rate of aging, also decreases mitochondrial oxygen radical generation and oxidative damage to mitochondrial DNA. This decrease in free radical generation occurs in complex I and is due to a decrease in the degree of electronic reduction of the complex I free radical generator, similarly to what has been described in various cases in long-lived animals. These results suggest that similar mechanisms have been used to extend longevity through decreases in oxidative stress in caloric restriction and during the evolution of species with different longevities.
Publication Types:
PMID: 12067594 [PubMed – indexed for MEDLINE]
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37: Free Radic Res. 2002 Jan;36(1):47-54.Related Articles, <!–
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Aging increases Nepsilon-(carboxymethyl)lysine and caloric restriction decreases Nepsilon-(carboxyethyl)lysine and Nepsilon-(malondialdehyde)lysine in rat heart mitochondrial proteins.
Pamplona R, Portero-Otín M, Bellmun MJ, Gredilla R, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, Lleida University, Spain.
The present investigation studies the effect of aging, short-term and long-term caloric restriction on four different markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins: protein carbonyls (measured by ELISA); Nepsilon-(carboxyethyl)lysine (CEL), Nepsilon-(carboxymethyl)lysine (CML), and Nepsilon-(malondialdehyde)lysine (MDA-lys) measured by gas chromatography/mass spectrometry. Aging increased the steady state level of CML in rat heart mitochondria without changing the levels of the other three markers of protein damage. Short-term caloric restriction (six weeks) did not change any of the parameters measured. However, long-term (one year) caloric restriction decreased CEL and MDA-lys in heart mitochondria and did not change protein carbonyls and CML levels. The decrease in MDA-lys was not due to changes in the sensitivity of mitochondrial lipids to peroxidation since the measurements of the fatty acid composition showed that the total number of fatty acid double bonds was not changed by caloric restriction. The decrease in CEL and MDA-lys in caloric restriction agrees with the previously and consistently described finding that caloric restriction agrees with the previously and consistently described finding that caloric restriction lowers the rate of generation of reactive oxygen species (ROS) in rodent heart mitochondria, although in the case of CEL a caloric restriction-induced lowering of glycaemia can also be involved. The CEL and MDA-lys results support the notion that caloric restriction decreases oxidative stress-derived damage to heart mitochondrial proteins.
Publication Types:
PMID: 11999702 [PubMed – indexed for MEDLINE]
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38: Free Radic Biol Med. 2002 May 1;32(9):882-9.Related Articles, <!–
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]
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Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria.López-Torres M, Gredilla R, Sanz A, Barja G.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain. mltorres@bio.ucm.es
The effect of long-term caloric restriction and aging on the rates of mitochondrial H2O2 production and oxygen consumption as well as on oxidative damage to nuclear (nDNA) and mitochondrial DNA (mtDNA) was studied in rat liver tissue. Long-term caloric restriction significantly decreased H2O2 production of rat liver mitochondria (47% reduction) and significantly reduced oxidative damage to mtDNA (46% reduction) with no changes in nDNA. The decrease in ROS production was located at complex I because it only took place with complex I-linked substrates (pyruvate/malate) but not with complex II-linked substrates (succinate). The mechanism responsible for that decrease in ROS production was not a decrease in mitochondrial oxygen consumption because it did not change after long-term restriction. Instead, the caloric restricted mitochondria released less ROS per unit electron flow, due to a decrease in the reduction degree of the complex I generator. On the other hand, increased ROS production with aging in state 3 was observed in succinate-supplemented mitochondria because old control animals were unable to suppress H2O2 production during the energy transition from state 4 to state 3. The levels of 8-oxodG in mtDNA increased with age in old animals and this increase was abolished by caloric restriction. These results support the idea that caloric restriction reduces the aging rate at least in part by decreasing the rate of mitochondrial ROS production and so, the rate of oxidative attack to biological macromolecules like mtDNA.
Publication Types:
PMID: 11978489 [PubMed – indexed for MEDLINE]
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39: Ann N Y Acad Sci. 2002 Apr;959:475-90.Related Articles, <!–
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Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation?Pamplona R, Barja G, Portero-Otín M.
Metabolic Physiopathology Research Group, Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Lleida 25198, Spain. manuel.portero@cmb.udl.es
Aging is a progressive and universal process originating endogenously that manifests during postmaturational life. Available comparative evidence supporting the mitochondrial free radical theory of aging consistently indicates that two basic molecular traits are associated with the rate of aging and thus with the maximum life span: the presence of low rates of mitochondrial oxygen radical production and low degrees of fatty acid unsaturation of cellular membranes in postmitotic tissues of long-lived homeothermic vertebrates in relation to those of short-lived ones. Recent research shows that steady-state levels of free radical-derived damage to mitochondrial DNA (mtDNA) and, in some cases, to proteins are lower in long- than in short-lived animals. Thus, nonenzymatic oxidative modification of tissue macromolecules is related to the rate of aging. The low degree of fatty acid unsaturation in biomembranes of long-lived animals may confer advantage by decreasing their sensitivity to lipid peroxidation. Furthermore, this may prevent lipoxidation-derived damage to other macromolecules. Taking into account the fatty acid distribution pattern, the origin of the low degree of membrane unsaturation in long-lived species seems to be the presence of species-specific desaturation pathways that determine membrane composition while an appropriate environment for membrane function is maintained. Mechanisms that prevent or decrease the generation of endogenous damage during the evolution of long-lived animals seem to be more important than trying to intercept those damaging agents or repairing the damage already inflicted. Here, the physiological meaning of these findings and the effects of experimental manipulations such as dietary stress, caloric restriction, and endocrine control in relation to aging and longevity are discussed.
Publication Types:
PMID: 11976221 [PubMed – indexed for MEDLINE]
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40: Toxicology. 2002 Jan 25;170(3):165-71.Related Articles, <!–
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]
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Deprenyl protects from MPTP-induced Parkinson-like syndrome and glutathione oxidation in rat striatum.Leret ML, San Millán JA, Fabre E, Gredilla R, Barja G.
Department Animal Biology-II (Animal Physiology), Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain. mantonio@bio.ucm.es
An intrastriatal injection with 18.8 nmoles of the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced in rats a progressive parkinsonism characterized by a major loss of striatum dopamine (DA) levels and an increased turnover of this neurotransmitter 96 h after the administration. In addition, the intrastriatal administration of MPTP produced an alteration in various behavioral markers of motor activity. Loss of DA was accompanied by a significant decrease of reduced glutathione (GSH) and an increase in GSH oxidation in the striatum. When deprenyl (10 mg/kg) was i.p. administered 2 h before the intrastriatal injection of MPTP, DA, GSH, glutathione redox status and the indexes of motor activity were not altered. These results show that MPTP increases striatum oxidative stress leading to cellular and in vivo degenerative changes which are prevented by pretreatment with deprenyl.
Publication Types:
PMID: 11788154 [PubMed – indexed for MEDLINE]
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41: J Bioenerg Biomembr. 2001 Aug;33(4):279-87.Related Articles, <!–
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]
–>Links
Effect of short-term caloric restriction on H2O2 production and oxidative DNA damage in rat liver mitochondria and location of the free radical source.Gredilla R, Barja G, López-Torres M.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Oxygen free radicals (ROS) of mitochondrial origin seem to be involved in aging. Whereas in other tissues complexes I or III of the respiratory chain contain the ROS generators, in this study we find that rat liver mitochondria generate oxygen radicals at complexes I, II, and III. Short-term (6 weeks) caloric restriction significantly decreased H2O2 production in rat liver mitochondria. This decrease in ROS production was located at complex I because it occurred with complex I-linked substrates (pyruvate/malate), but did not reach statistical significance with the complex II-linked substrate succinate. The mechanism responsible for the lowered ROS production was not a decrease in oxygen consumption. Instead, the mitochondria of caloric-restricted animals released less ROS per unit electron flow. This was due to a decrease in the degree of reduction of the complex I generator. Furthermore, oxidative damage to mitochondrial and nuclear DNA was also decreased in the liver by short-term caloric restriction. The results agree with the idea that caloric restriction delays aging, at least in part, by decreasing the rate of mitochondrial ROS generation and thus the rate of attack to molecules, like DNA, highly relevant for the accumulation of age-dependent changes.
Publication Types:
PMID: 11710804 [PubMed – indexed for MEDLINE]
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42: Free Radic Res. 2001 Oct;35(4):417-25.Related Articles, <!–
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–>Links -
Thyroid hormone-induced oxidative damage on lipids, glutathione and DNA in the mouse heart.
Gredilla R, Barja G, López-Torres M.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
Oxygen radicals of mitochondrial origin are involved in oxidative damage. In order to analyze the possible relationship between metabolic rate, oxidative stress and oxidative damage, OF1 female mice were rendered hyper- and hypothyroid by chronic administration of 0.0012% L-thyroxine (T4) and 0.05% 6-n-propyl-2-thiouracil (PTU), respectively, in their drinking water for 5 weeks. Hyperthyroidism significantly increased the sensitivity to lipid peroxidation in the heart, although the endogenous levels of lipid peroxidation were not altered. Thyroid hormone-induced oxidative stress also resulted in higher levels of GSSG and GSSG/GSH ratio. Oxidative damage to mitochondrial DNA was greater than that to genomic DNA. Hyperthyroidism decreased oxidative damage to genomic DNA. Hypothyroidism did not modify oxidative damage in the lipid fraction but significantly decreased GSSG and GSSG/GSH ratio and oxidative damage to mitochondrial DNA. These results indicate that thyroid hormones modulate oxidative damage to lipids and DNA, and cellular redox potential in the mouse heart. A higher oxidative stress in the hyperthyroid group is presumably neutralized in the case of nuclear DNA by an increase in repair activity, thus protecting this key molecule. Treatment with PTU, a thyroid hormone inhibitor, reduced oxidative damage in the different cell compartments.
Publication Types:
PMID: 11697138 [PubMed – indexed for MEDLINE]
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43: Mol Cell Biochem. 2001 May;221(1-2):41-8.Related Articles, <!–
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Influence of hyper- and hypothyroidism on lipid peroxidation, unsaturation of phospholipids, glutathione system and oxidative damage to nuclear and mitochondrial DNA in mice skeletal muscle.Gredilla R, López Torres M, Portero-Otín M, Pamplona R, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
While the biochemical literature on free radical metabolism is extensive, there is little information on the endocrine control of tissue oxidative stress, and in the case of thyroid hormones it is mainly limited to liver tissue and to short-term effects on a few selected biochemical parameters. In this investigation, chronic hypothyroidism and hyperthyroidism were successfully induced in mice, and various oxidative-stress-related parameters were studied in skeletal muscle. In vivo and in vitro lipid peroxidation significantly increased in hyperthyroidism and did not change in the hypothyroid state. The fatty acid composition of the major phospholipid classes was affected by thyroid hormones, leading to a significant decrease in total fatty acid unsaturation both in hypothyroid and hyperthyroid muscle in phosphatidylcholine and phosphatidylethanolamine fractions. In cardiolipin, however, the double bond content significantly increased as a function of thyroid status, leading to a 2.7 fold increase in the peroxidizability index from euthyroid to hyperthyroid muscle. Cardiolipin content was also directly and significantly related to thyroid state across the three groups. Glutathione system was not modified by thyroid state. The oxidative damage marker 8-oxo-7,8-dihydro-2′-deoxyguanosine did not change in mitochondrial DNA, and decreased in genomic DNA both in hypothyroid and hyperthyroid muscle. The results indicate that chronic alterations in thyroid status specially affect oxidative damage to lipids in skeletal muscle, with a probably stronger effect on mitochondrial membranes, whereas the cytosolic redox potential and DNA are better protected possibly due to homeostatic compensatory reactions on the long-term.
Publication Types:
PMID: 11506185 [PubMed – indexed for MEDLINE]
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44: Lipids. 2001 May;36(5):491-8.Related Articles, <!–
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Correlation of fatty acid unsaturation of the major liver mitochondrial phospholipid classes in mammals to their maximum life span potential.
Portero-Otín M, Bellmunt MJ, Ruiz MC, Barja G, Pamplona R.
Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Spain. manuel.portero@cmb.udl.es
Free radical damage is considered a determinant factor in the rate of aging. Unsaturated fatty acids are the tissue macromolecules that are most sensitive to oxidative damage. Therefore, the presence of low proportions of fatty acid unsaturation is expected in the tissues of long-lived animals. Accordingly, the fatty acid compositions of the major liver mitochondrial phospholipid classes from eight mammals, ranging in maximum life span potential (MLSP) from 3.5 to 46 yr, show that the total number of double bonds is inversely correlated with MLSP in both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) (r = 0.757, P < 0.03, and r = 0.862, P < 0.006, respectively), but not in cardiolipin (P = 0.323). This is due not to a low content of unsaturated fatty acids in long-lived animals, but mainly to a redistribution between kinds of fatty acids on PtdCho and PtdEtn, shifting from arachidonic (r = 0.911, P < 0.002, and r = 0.681, P = 0.05, respectively), docosahexaenoic (r = 0.931 and r = 0.965, P < 0.0001, respectively) and palmitic (r = 0.944 and r = 0.974, P < 0.0001, respectively) acids to linoleic acid (r = 0.942, P < 0.0001, for PtdCho; and r = 0.957, P < 0.0001, for PtdEtn). For cardiolipin, only arachidonic acid showed a significantly inverse correlation with MLSP (r = 0.904, P < 0.002). This pattern strongly suggests the presence of a species-specific desaturation pathway and deacylation-reacylation cycle in determining the mitochondrial membrane composition, maintaining a low degree of fatty acid unsaturation in long-lived animals.
Publication Types:
PMID: 11432462 [PubMed – indexed for MEDLINE]
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45: FASEB J. 2001 Jul;15(9):1589-91.Related Articles, <!–
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Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart.Gredilla R, Sanz A, Lopez-Torres M, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
PMID: 11427495 [PubMed – indexed for MEDLINE]
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46: Mech Ageing Dev. 2001 Apr 15;122(4):427-43.Related Articles, <!–
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]
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Effect of the degree of fatty acid unsaturation of rat heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage.Herrero A, Portero-Otín M, Bellmunt MJ, Pamplona R, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
Previous comparative studies have shown that long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts. Basal rates of mitochondrial oxygen radical generation were not modified by the degree of fatty acid unsaturation, but the rates of H2O2 generation stimulated by antimycin A were higher in UNSAT than in SAT mitochondria. These results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen radical generation in situations in which the degree of reduction of Complex III is higher than normal. These observations strengthen the notion that the relatively low double bond content of the membranes of long-lived animals could have evolved to protect them from oxidative damage.
Publication Types:
PMID: 11240164 [PubMed – indexed for MEDLINE]
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47: Aging (Milano). 2000 Oct;12(5):342-55.Related Articles, <!–
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]
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The flux of free radical attack through mitochondrial DNA is related to aging rate.
Department of Animal Biology-II, Faculty of Biology, Complutense University, Madrid, Spain.
Aging is a progressive and universal process originated endogenously which manifests best in post-mitotic cells. Available data indicate that the relation between oxidative stress and aging is due to the presence of low rates of mitochondrial free radical production and low degrees of fatty acid unsaturation of cellular membranes in the post-mitotic tissues of long-lived animals in relation to those of short-lived ones. Recent research shows that long-lived animals also have lower steady-state levels of oxidative damage in the mitochondrial DNA (mtDNA) of post-mitotic cells than short-lived species. This study shows that the flux of free radical attack to mtDNA is higher in short- than in long-lived animals, and proposes that this is a main determinant of the rate of accumulation of mtDNA mutations, and thus the rate of aging. This implies that aging has been slowed evolutionarily by mechanisms that decrease the generation of endogenous damage rather than try to intercept damaging agents, or to repair the damage already inflicted. The first kind of mechanisms are more efficient and less energetically expensive. Free radicals of mitochondrial origin, oxidative damage to DNA, evolution of aging rate, and possibilities and consequences of their future modification are also discussed.
Publication Types:
PMID: 11126520 [PubMed – indexed for MEDLINE]
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48: Mol Cell Endocrinol. 2000 Oct 25;168(1-2):127-34.Related Articles, <!–
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Effect of thyroid hormones on mitochondrial oxygen free radical production and DNA oxidative damage in the rat heart.López-Torres M, Romero M, Barja G.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, 28040, Madrid, Spain. mltorres@bio.ucm.es
Mitochondria seem to be involved in oxygen radical damage and aging. However, the possible relationships between oxygen consumption and oxygen radical production by functional mitochondria, and oxidative DNA damage, have not been studied previously. In order to analyze these relationships, male Wistar rats of 12 weeks of age were rendered hyper- and hypothyroid by chronic T(3) and 6-n-propyl-2-thiouracil treatments, respectively. Hypothyroidism decreased heart mitochondrial H(2)O(2) production in States 4 (to 51% of controls; P<0.05) and 3 (to 21% of controls; P<0.05). In agreement with this, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) decreased in the heart genomic DNA of hypothyroid animals to 40% of controls (P<0.001). Studies with respiratory inhibitors showed that the decrease in oxygen radical generation observed in hypothyroidism occurred at Complex III (mainly) and at Complex I; that decrease was due to the presence of a lower free radical leak in the respiratory chain (P<0.05). Hyperthyroidism did not significantly change heart mitochondrial H(2)O(2) production since the increase in State 4 oxygen consumption in comparison with control and hypothyroid animals (P<0.05) was compensated by a decrease in the free radical leak in relation to control animals (P<0.05). In agreement with this, heart 8-oxodG was not changed in hyperthyroid animals. The lack of increase in H(2)O(2) production per unit of mitochondrial protein will protect mitochondria themselves against self-inflicted damage during hyperthyroidism.
Publication Types:
PMID: 11064159 [PubMed – indexed for MEDLINE]
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49: J Gerontol A Biol Sci Med Sci. 2000 Jun;55(6):B286-91.Related Articles, <!–
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Low fatty acid unsaturation: a mechanism for lowered lipoperoxidative modification of tissue proteins in mammalian species with long life spans.Pamplona R, Portero-Otín M, Riba D, Requena JR, Thorpe SR, López-Torres M, Barja G.
Department of Basic Medical Science, University of Lleida, Spain.
Carbonyl compounds generated by the nonenzymatic oxidation of polyunsaturated fatty acids react with nucleophilic groups in proteins, leading to their modification. It has not been tested whether fatty acid unsaturation is related to steady-state levels of lipoxidation-derived protein modification in vivo. A low fatty acid unsaturation, hence a low protein lipoxidation, in tissues of longevous animals would be consistent with the free radical theory of aging, because membrane lipids increase their sensitivity to oxidative damage as a function of their degree of unsaturation. To evaluate the relationship between fatty acid composition, protein lipoxidation, and maximum life span (MLSP), we analyzed liver fatty acids and proteins from seven mammalian species, ranging in MLSP from 3.5 to 46 years. The results show that the peroxidizability index of fatty acids and the sensitivity to in vitro lipid peroxidation are negatively correlated with the MLSP. Based on gas chromatography and mass spectroscopy analyses, liver proteins of all these species contain malondialdehyde-lysine and Nepsilon-carboxymethyllysine adducts, two biomarkers of protein lipoxidation. The steady-state levels of malondialdehyde-lysine and Nepsilon-carboxymethyl lysine are directly related to the peroxidizability index and inversely related to the MLSP. We propose that a low degree of fatty acid unsaturation may have been selected in longevous mammals to protect their tissue lipids and proteins against oxidative damage while maintaining an appropriate environment for membrane function.
Publication Types:
PMID: 10843345 [PubMed – indexed for MEDLINE]
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50: J Physiol Biochem. 1999 Dec;55(4):325-31.Related Articles, <!–
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]
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Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum.
Fabre E, Monserrat J, Herrero A, Barja G, Leret ML.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University of Madrid, Spain.
An experimental rat model of Parkinson’s disease was established by injecting rats directly in the striatum with the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study the action mechanism of this neurotoxic agent, MPTP and its main metabolite 1-methyl-4-phenylpyridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemented nonsynaptic brain mitochondria, and the rates of hydrogen peroxide and ATP production were measured. Intrastriatal administration of MPTP produced a pronounced decrease in striatal dopamine levels (p < 0.005) and a strong increase in 3,4-hydroxiphenylacetic acid/dopamine ratio (an indicator of dopamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydrogen peroxide production by 90%, from 1.37+/-0.35 to 2.59+/-0.48 nanomoles of H2O2/minute . mg of protein (p < 0.01). The metabolite MPP+ produced a marked decrease on the rate of ATP production of brain mitochondria (p < 0.005). These findings support the mitochondria-oxidative stress-energy failure hypothesis of MPTP-induced brain neurotoxicity.
Publication Types:
PMID: 10731084 [PubMed – indexed for MEDLINE]
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51: Mech Ageing Dev. 2000 Jan 10;112(3):169-83.Related Articles, <!–
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]
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Double bond content of phospholipids and lipid peroxidation negatively correlate with maximum longevity in the heart of mammals.Pamplona R, Portero-Otín M, Ruiz C, Gredilla R, Herrero A, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, Lleida University, Spain.
Free radical damage is currently considered a main determinant of the rate of aging. Unsaturated fatty acids are the tissue macromolecules most sensitive to oxidative damage. Therefore, the presence of relatively low degrees of fatty acid unsaturation is expected in the tissues of longevous animals. In agreement with this prediction, fatty acid analyses of heart phospholipids in eight mammals ranging in maximum life span (MLSP) from 3.5 to 46 years showed that their total number of double bonds is negatively correlated with MLSP (r = -0.78, P < 0.02). The low double content of longevous mammals was not due to a low polyunsaturated fatty acid content. Instead, it was mainly due to a redistribution between types of polyunsaturated fatty acids from the highly unsaturated docosahexaenoic acid (22:6n-3) to the less unsaturated linoleic acid (18:2n-6) in longevous animals (r = -0.89, P < 0.003 for 22:6n-3 and r = 0.91, P < 0.002 for 18:2n-6 versus MLSP), where n = number of different animals in each species. This redistribution suggests that one of the mechanisms responsible for the low number of fatty acid double bonds is the presence of low desaturase activities in longevous animals, although other causing factors must be involved. In agreement with the low degree of fatty acid unsaturation of longevous mammals, the sensitivity to lipid peroxidation (r = -0.87; P < 0.005) and the in vivo lipid peroxidation (r = -0.86, P < 0.005) in the heart were also negatively correlated with MLSP across species. These results, together with previous ones obtained in rodents, birds, and humans, suggest that the low degree of tissue fatty acid unsaturation of longevous homeothermic animals could have been selected during evolution to protect the tissues against oxidative damage.
Publication Types:
PMID: 10687923 [PubMed – indexed for MEDLINE]
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52: J Bioenerg Biomembr. 1999 Aug;31(4):347-66.Related Articles, <!–
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Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Studies in heart and nonsynaptic brain mitochondria from two mammals and three birds show that complex I generates oxygen radicals in heart and nonsynaptic brain mitochondria in States 4 and 3, whereas complex III does it only in heart mitochondria and only in State 4. The increase in oxygen consumption during the State 4 to 3 transition is not accompanied by a proportional increase in oxygen radical generation. This will protect mitochondria and tissues during bursts of activity. Comparisons between young and old rodents do not show a consistent pattern of variation in mitochondrial oxygen radical production during aging. However, all the interspecies comparisons performed to date between different mammals, and between mammals and birds, agree that animals with high maximum longevities have low rates of mitochondrial oxygen radical production, irrespective of the value of their basal specific metabolic rate. The sites and mechanisms allowing this, the recently described low degree of membrane fatty acid unsaturation of longevous animals, and their relation to longevity and aging are discussed.
Publication Types:
PMID: 10665525 [PubMed – indexed for MEDLINE]
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53: FASEB J. 2000 Feb;14(2):312-8.Related Articles, <!–
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Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.
DNA damage is considered of paramount importance in aging. Among causes of this damage, free radical attack, particularly from mitochondrial origin, is receiving special attention. If oxidative damage to DNA is involved in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. However, this possibility has not heretofore been investigated. In this study, steady-state levels of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG) referred to deoxyguanosine (dG) were measured by high performance liquid chromatography (HPLC) in the mitochondrial (mtDNA) and nuclear (nDNA) DNA from the heart of eight and the brain of six mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. Exactly the same digestion of DNA to deoxynucleosides and HPLC protocols was used for mtDNA and nDNA. Significantly higher (three- to ninefold) 8-oxodG/dG values were found in mtDNA than in nDNA in all the species studied in both tissues. 8-oxodG/dG in nDNA did not correlate with MLSP across species either in the heart (r=-0.68; P<0.06) or brain (r = 0.53; P<0.27). However, 8-oxodG/dG in mtDNA was inversely correlated with MLSP both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016) tissues following the power function y = a(.)x(b), where y is 8-oxodG/dG and x is the MLSP. This agrees with the consistent observation that mitochondrial free radical generation is also lower in long-lived than in short-lived species. The results obtained agree with the notion that oxygen radicals of mitochondrial origin oxidatively damage mtDNA in a way related to the aging rate of each species.-Barja, G., Herrero, A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals.
Publication Types:
PMID: 10657987 [PubMed – indexed for MEDLINE]
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54: Aging (Milano). 1999 Oct;11(5):294-300.Related Articles, <!–
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8-oxo-deoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of two mammals and three birds in relation to their different rates of aging.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Previous studies found that the rate of mitochondrial oxygen radical generation is lower in long-lived birds than in short-lived mammals. In the present study, the oxidative DNA damage marker 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) in heart and brain mitochondrial (mtDNA) and nuclear DNA (nDNA) was compared between mammals and birds of approximately similar body size and metabolic rates; rats (maximum life span, MLSP = 4 years) vs pigeons (MLSP = 35 years), and mice (MLSP = 3.5 years) vs parakeets (MLSP = 21 years) or canaries (MLSP = 24 years). Lower steady-state 8-oxodG values were observed in all cases in the heart mtDNA in birds than in mammals. 8-oxodG levels were also lower in brain mtDNA in pigeons than in rats, in brain nDNA in canaries than in mice, and in heart nDNA in parakeets compared with mice. The rest of the comparisons did not show significant differences between species. These results taken together indicate that oxidative damage to DNA tends to be lower in birds (highly long-lived species) than in short-lived mammals, specially in the case of mtDNA. This is consistent with the low rate of mitochondrial oxygen radical generation observed in all long-lived species investigated up to date, birds or mammals, including the bird species studied here. The results also show that 8-oxodG steady-state levels are much higher in mtDNA than in nDNA in all the tissues (heart and brain) and species (birds and mammals) studied.
Publication Types:
PMID: 10631878 [PubMed – indexed for MEDLINE]
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55: Free Radic Biol Med. 1999 Oct;27(7-8):901-10.Related Articles, <!–
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Thyroid status modulates glycoxidative and lipoxidative modification of tissue proteins.
Pamplona R, Portero-Otín M, Ruiz C, Bellmunt MJ, Requena JR, Thorpe SR, Baynes JW, Romero M, López-Torres M, Barja G.
Metabolic Physiopathology Research Group, Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Spain. manuel.portero@cmb.udl.es
Steady state protein modification by carbonyl compounds is related to the rate of carbonyl adduct formation and the half-life of the protein. Thyroid hormones are physiologic modulators of both tissue oxidative stress and protein degradation. The levels of the glycation product N(epsilon)-fructoselysine (FL) and those of the oxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and malondialdehyde-lysine (MDA-lys), identified by GC/MS in liver proteins, decreased significantly in hyperthyroid rats, as well as (less acutely) in hypothyroid animals. Immunoblotting of liver proteins for advanced glycation end-products (AGE) is in agreement with the results obtained by GC/MS. Cytosolic proteolytic activity against carboxymethylated foreign proteins measured in vitro was significantly increased in hypo- and hyperthyroidism. Oxidative damage to DNA, estimated as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8oxodG), did not show significant differences between groups. The results suggests that the steady state levels of these markers depend on the levels of thyroid hormones, presumably through their combined effects on the rates of protein degradation and oxidative stress, whereas DNA is more protected from oxidative damage.
Publication Types:
PMID: 10515595 [PubMed – indexed for MEDLINE]
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56: Free Radic Biol Med. 1999 Jun;26(11-12):1531-7.Related Articles, <!–
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Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Free radical scavengers can protect against the genotoxicity induced by chemical carcinogens by decreasing oxidative damage. The protective effect of the antioxidants melatonin, resveratrol, vitamin E, butylated hydroxytoluene and 2-mercaptoethylamine, and the spin-trapping compound alpha-phenyl-N-tert-butyl nitrone (PBN) against oxidative DNA damage was studied in the kidney of rats treated with the kidney-specific carcinogen potassium bromate (KBrO3). KBrO3 was given to rats previously treated with melatonin, resveratrol, PBN, vitamin E, butylated hydroxytoluene, or 2-mercaptoethylamine. Oxidative damage to kidney DNA was estimated 6 hours afterwards by measuring 8-oxo-7,8-dihydro-2′-deoxyguanosine (oxo8dG) referred to deoxyguanosine (dG) by means of high performance liquid chromatography with electrochemical-coulometric and ultraviolet detection. Levels of oxo8dG in the renal genomic DNA significantly increased by more than 100% after the KBrO3 treatment. This increase was completely abolished by the treatment with resveratrol and was partially prevented by melatonin, PBN and vitamin E. Resveratrol and PBN also prevented the increase in relative kidney weight induced by KBrO3. These results show that various different antioxidants and a free radical trap, working in either the water-soluble or the lipid-soluble compartments, can prevent the oxidative DNA damage induced in the kidney by the carcinogen KBrO3.
Publication Types:
PMID: 10401619 [PubMed – indexed for MEDLINE]
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57: Aging (Milano). 1999 Feb;11(1):44-9.Related Articles, <!–
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Heart fatty acid unsaturation and lipid peroxidation, and aging rate, are lower in the canary and the parakeet than in the mouse.
Pamplona R, Portero-Otín M, Riba D, Ledo F, Gredilla R, Herrero A, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, Lleida University, Spain.
Despite their high metabolic rates, birds have a much higher maximum longevity (MLSP) than mammals of similar body size, and thus represent ideal models for identifying longevity characteristics not linked to low metabolic rates. This study shows that the fatty acid double bond content of both canary (MLSP = 24 years) and parakeet (MLSP = 21 years) hearts is intrinsically lower than in mouse (MLSP = 3.5 years) heart. This is caused by a redistribution between types of unsaturated fatty acids, mainly due to a lower content of the most highly unsaturated docosahexaenoic acid (22:6n-3) in the two birds in relation to the mammal. The lower double bond content leads to a lower sensitivity to lipid peroxidation, and to a lower level of in vivo lipid peroxidation in the heart of parakeets and canaries than in that of mice. Similar results have been previously found comparing liver mitochondria of rats and pigeons and tissues of different mammalian species. All these results taken together suggest that a low degree of fatty acid unsaturation is a general characteristic of longevous homeothermic vertebrate animals, both when they have low metabolic rates (mammals of large body size) or high metabolic rates (the studied birds); this constitutive trait protects their tissues and organelles against free radical mediated lipid peroxidation, and can contribute to their slow aging rate.
Publication Types:
PMID: 10337442 [PubMed – indexed for MEDLINE]
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58: Mech Ageing Dev. 1999 Jan 15;106(3):283-96.Related Articles, <!–
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]
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A low degree of fatty acid unsaturation leads to lower lipid peroxidation and lipoxidation-derived protein modification in heart mitochondria of the longevous pigeon than in the short-lived rat.Pamplona R, Portero-Otín M, Requena JR, Thorpe SR, Herrero A, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, Lleida University, Spain.
Birds have a maximum longevity (MLSP) much greater than mammals of similar metabolic rate and body size. Thus, they are ideal models to identify longevity characteristics not linked to low metabolic rates. In this investigation, we show that the fatty acid double bond content of total lipids and phosphatidylcholine, phosphatidylethanolamine and cardiolipin fractions of heart mitochondria is intrinsically lower in pigeons (MLSP = 35 years) than in rats (MLSP = 4 years). This is mainly due to a lower content of the most highly unsaturated docosahexaenoic acid (22:6n-3) and in some fractions arachidonic acid (20:4n-6). The lower double bond content leads to a lower sensitivity to in vitro lipid peroxidation, and is associated with a lower concentration of lipid peroxidation products in vivo, and a lower level of malondialdehyde-lysine protein adducts in heart mitochondria of pigeons than rats. These results, together with those previously obtained in other species or tissues, suggest that a low degree of fatty acid unsaturation is a general characteristic of longevous homeothermic vertebrate animals both when they have low metabolic rates (mammals of large body size) or high metabolic rates (small sized birds). This constitutive trait helps to protect their tissues and mitochondria against lipid peroxidation and oxidative protein modification and can be a factor contributing to their slow rate of aging. The results also show, for the first time in a physiological model, that lipid peroxidizability is related to lipoxidative protein damage.
Publication Types:
PMID: 10100156 [PubMed – indexed for MEDLINE]
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59: Ann N Y Acad Sci. 1998 Nov 20;854:224-38.Related Articles, <!–
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]
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Mitochondrial free radical production and aging in mammals and birds.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
The mitochondrial rate of oxygen radical (ROS) production is negatively correlated with maximum life span potential (MLSP) in mammals following the rate of living theory. In order to know if this relationship is more than circumstantial, homeothermic vertebrates with MLSP different from that predicted by the body size and metabolic rate of the majority of mammals (like birds and primates) must be studied. Birds are unique because they combine a high rate of basal oxygen consumption with a high MLSP. Heart, brain, and lung mitochondrial ROS production and free radical leak (percent of total electron flow directed to ROS production) are lower in three species of birds of different orders than in mammals of similar body size and metabolic rate. This suggests that the capacity to show a low rate of ROS production is a general characteristic of birds. Using substrates and inhibitors specific for different segments of the respiratory chain, the main ROS generator site (responsible for those bird-mammalian differences) in state 4 has been localized at complexes I and III in heart mitochondria and only at complex I in nonsynaptic brain mitochondria. In state 3, complex I is the only generator in both tissues. The results also suggest that the iron-sulphur centers are the ROS generators of complex I. A general mechanism that allows pigeon mitochondria to show a low rate of ROS production can be the capacity to maintain a low degree of reduction of the ROS generator site. In heart mitochondria, this is supplemented with a low rate of oxygen consumption physiologically compensated with a comparatively higher heart size. A low rate of free radical production near DNA, together with a high rate of DNA repair, can be responsible for the slow rate of accumulation of DNA damage and thus the slow aging rate of longevous animals.
Publication Types:
PMID: 9928433 [PubMed – indexed for MEDLINE]
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60: Free Radic Biol Med. 1999 Jan;26(1-2):73-80.Related Articles, <!–
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]
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Effect of thyroid status on lipid composition and peroxidation in the mouse liver.Guerrero A, Pamplona R, Portero-Otín M, Barja G, López-Torres M.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
In order to analyze the possible relationship between metabolic rate and oxidative stress, OF1 female mice were rendered hyper- or hypothyroid for 4-5 weeks by administration of 0.0012% L-thyroxine (T4) or 0.05% 6-n-propyl-2-thiouracil (PTU), respectively, in their drinking water. Treatment with T4 resulted in increased basal metabolic rate measured by oxygen consumption and liver cytochrome oxidase activity without altering the glutathione redox system. Endogenous lipid peroxidation, sensitivity to lipid peroxidation and fatty acid unsaturation were decreased in the hyperthyroid group. Hypothyroidism also decreased phosphatidylcholine and cardiolipin fatty acid unsaturation but not in total lipids, and thus lipid peroxidation was not altered. Cardiolipin, a mainly mitochondrial lipid, was the most profoundly altered fraction by both hyper- and hypothyroidism. It is suggested that the lipid changes observed in hyperthyroid animals can protect them against an increased oxidative attack to tissue lipids due to their increased mitochondrial activities.
Publication Types:
PMID: 9890642 [PubMed – indexed for MEDLINE]
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61: J Lipid Res. 1998 Oct;39(10):1989-94.Related Articles, <!–
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]
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Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals.Pamplona R, Portero-Otín M, Riba D, Ruiz C, Prat J, Bellmunt MJ, Barja G.
Department of Basic Medical Sciences, Faculty of Medicine, University of Lleida, Spain.
The oxidative stress theory of aging predicts a low degree of fatty acid unsaturation in tissues of longevous animals, because membrane lipids increase their sensitivity to oxidative damage as a function of their unsaturation. Accordingly, the fatty acids analyses of liver mitochondria from eight mammals, ranging in maximum life span from 3.5 to 46 years, show that the total number of double bonds and the peroxidizability index are negatively correlated with maximum life span (r = -0. 88, P < 0.003; r = -0.87, P < 0.004, respectively). This is not due to a low content of unsaturated fatty acids in longevous animals, but mainly to a redistribution between kinds of the polyunsaturated n-3 fatty acids series, shifting from the highly unsaturated docosahexaenoic acid (r = -0.89, P < 0.003) to the less unsaturated linolenic acid (r = 0.97, P < 0.0001). This redistribution pattern strongly suggests the presence of a constitutively low delta6-desaturase activity in longevous animals (r = -0.96, P < 0.0001). Thus, it may be proposed that, during evolution, a low degree of fatty acid unsaturation in liver mitochondria may have been selected in longevous mammals in order to protect the tissues against oxidative damage, while maintaining an appropriate environment for membrane function.
Publication Types:
PMID: 9788245 [PubMed – indexed for MEDLINE]
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62: J Bioenerg Biomembr. 1998 Jun;30(3):235-43.Related Articles, <!–
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]
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Localization at complex I and mechanism of the higher free radical production of brain nonsynaptic mitochondria in the short-lived rat than in the longevous pigeon.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Free radical production and leak of brain nonsynaptic mitochondria were higher with pyruvate/malate than with succinate in rats and pigeons. Rotenone, antimycin A, and myxothiazol maximally stimulated free radical production with pyruvate/malate but not with succinate. Simultaneous treatment with myxothiazol plus antimycin A did not decrease the stimulated rate of free radical production brought about independently by any of these two inhibitors with pyruvate/malate. Thenoyltrifluoroacetone did not increase free radical production with succinate. No free radical production was detected at Complex IV. Free radical production and leak with pyruvate/malate were higher in the rat (maximum longevity 4 years) than in the pigeon (maximum longevity 35 years). These differences between species disappeared in the presence of rotenone. The results localize the main free radical production site of nonsynaptic brain mitochondria at Complex I. They also suggest that the low free radical production of pigeon brain mitochondria is due to a low degree of reduction of Complex I in the steady state in this highly longevous species.
Publication Types:
PMID: 9733090 [PubMed – indexed for MEDLINE]
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63: Mech Ageing Dev. 1998 Jun 15;103(2):133-46.Related Articles, <!–
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–>Links
H2O2 production of heart mitochondria and aging rate are slower in canaries and parakeets than in mice: sites of free radical generation and mechanisms involved.Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Birds have a maximum longevity (MLSP) much higher than mammals of similar body size in spite of their high metabolic rates. In this study, State 4 and State 3 rates of H2O2 production were lower in canary (MLSP = 24 years) and parakeet (MLSP = 21 years) than in mouse (MLSP = 3.5 years) heart mitochondria. Studies using specific inhibitors of the respiratory chain indicate that free radical generation sites at Complexes I and III are responsible for these differences. Main mechanisms lowering H2O2 production in these birds are a low rate of mitochondrial oxygen consumption in the parakeet and a low mitochondrial free radical leak in the canary. Strong increases in H2O2 production during active respiration (State 3) released by addition of ADP to pyruvate/malate-supplemented mitochondria are avoided in three species because the free radical leak decreases during the transition from State 4 to State 3 respiration. These results, together with those previously obtained in pigeons and in various mammalian species, suggest that the rate of mitochondrial free radical production correlates better with the rate of aging and the MLSP than the metabolic rate. They also suggest that a low rate of mitochondrial H2O2 production is a general characteristic of birds, animals showing very slow aging rates.
Publication Types:
PMID: 9701767 [PubMed – indexed for MEDLINE]
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64: J Comp Physiol [B]. 1998 Apr;168(3):149-58.Related Articles, <!–
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The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach.
Perez-Campo R, López-Torres M, Cadenas S, Rojas C, Barja G.
Departamento de Fisiología Animal, Facultad de Biología, Universidad Complutense, Madrid, Spain.
The relationship of oxidative stress with maximum life span (MLSP) in different vertebrate species is reviewed. In all animal groups the endogenous levels of enzymatic and non-enzymatic antioxidants in tissues negatively correlate with MLSP and the most longevous animals studied in each group, pigeon or man, show the minimum levels of antioxidants. A possible evolutionary reason for this is that longevous animals produce oxygen radicals at a low rate. This has been analysed at the place where more than 90% of oxygen is consumed in the cell, the mitochondria. All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds. Birds have low rates of mitochondrial oxygen radical production, frequently due to a low free radical leak in their respiratory chain. Possibly the low rate of mitochondrial oxygen radical production of longevous species can decrease oxidative damage at targets important for aging (like mitochondrial DNA) that are situated near the places of free radical generation. A low rate of free radical production can contribute to a low aging rate both in animals that conform to the rate of living (metabolic) theory of aging and in animals with exceptional longevities, like birds and primates. Available research indicates there are at least two main characteristics of longevous species: a high rate of DNA repair together with a low rate of free radical production near DNA. Simultaneous consideration of these two characteristics can explain part of the quantitative differences in longevity between animal species.
Publication Types:
PMID: 9591361 [PubMed – indexed for MEDLINE]
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65: Pharmacol Toxicol. 1998 Jan;82(1):11-8.Related Articles, <!–
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]
–>Links -
Endotoxin increases oxidative injury to proteins in guinea pig liver: protection by dietary vitamin C.
Department of Animal Biology-II (Animal Physiology), Complutense University, Madrid, Spain.
Current information suggests that oxidative damage plays a key role in septic shock induced by endotoxin. This raises the possibility that dietary antioxidant vitamins could protect against endotoxin damage. In this study, the effects of endotoxin administration on protein and lipid oxidative damage and endogenous antioxidants were studied in the liver of guinea pigs previously supplemented with marginal or optimum levels of dietary vitamin C, vitamin E or both. Vitamins C and E inhibited in vitro lipid peroxidation in endotoxin-treated animals. Endotoxin significantly increased oxidative damage to liver proteins in animals receiving low doses of both vitamins, a result described here for the first time. This increase was totally prevented in guinea pigs supplemented with vitamin C alone or in combination with vitamin E, a treatment which strongly increased liver ascorbate. Vitamin C caused small significant increases in superoxide dismutase and glutathione, increased uric acid, and synergically increased alpha-tocopherol levels in vitamin E-supplemented animals treated with endotoxin. The results show that dietary vitamin C protects against endotoxin-induced oxidative damage to proteins in the guinea pig liver. This seems mainly due to a direct protective effect of the increased hepatic ascorbate levels present in vitamin C-supplemented animals.
Publication Types:
PMID: 9527640 [PubMed – indexed for MEDLINE]
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66: Carcinogenesis. 1997 Dec;18(12):2373-7.Related Articles, <!–
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–>Links 
Oxidative DNA damage estimated by oxo8dG in the liver of guinea-pigs supplemented with graded dietary doses of ascorbic acid and alpha-tocopherol.Cadenas S, Barja G, Poulsen HE, Loft S.
Department of Pharmacology, Panum Institute, University of Copenhagen, Copenhagen N, Denmark.
Dietary antioxidants may influence cancer risk and aging by modifying oxidative damage. The effect of graded dietary doses of the antioxidant vitamins C and E on oxidative DNA damage was studied in the liver of guinea-pigs under normal conditions. Like human beings, guinea-pigs cannot synthesize ascorbate and alpha-tocopherol. In one experiment, three groups of 6-8 guinea-pigs were fed diets containing 15 mg of vitamin E/kg chow and three different amounts of vitamin C (33,660 or 13,200 mg/kg) for 5 weeks. In a second experiment, three groups of seven guinea-pigs were fed diets containing 660 mg of vitamin C/kg and three different amounts of vitamin E (15, 150 or 1500 mg/kg) for 5 weeks. The three graded levels of each vitamin respectively represent marginal deficiency, an optimum supplementation and a megadose. Oxidative damage to liver DNA was estimated by measuring 8-oxo-7,8-dihydro-2′-deoxyguanosine (oxo8dG) referred to deoxyguanosine (dG) by means of high-performance liquid chromatography with simultaneous electrochemical-coulometric and ultraviolet detection. The level of ascorbate in the liver was 0.034 +/- 0.051, 1.63 +/- 1.06 and 1.99 +/- 0.44 micromol/g in the low, medium and high dose ascorbate groups (59-fold variation). The liver concentration of alpha-tocopherol was 28 +/- 11, 63 +/- 18 and 187 +/- 34 nmol/g in the low, medium and high dose alpha-tocopherol groups (7-fold variation). The level of oxo8dG in the liver DNA was 1.89 +/- 0.32, 1.94 +/- 0.78 and 1.93 +/- 0.65 per 10(5) dG in the low, medium and high dose ascorbate groups (no effect: P > 0.05). In the low, medium and high dose alpha-tocopherol groups oxo8dG level in the liver DNA was 2.85 +/- 0.70, 2.74 +/- 0.66 and 2.61 +/- 0.92 per 10(5) dG (no effect: P > 0.05). It is concluded that even very large variations in the content of the antioxidant vitamins C and E in the diet and liver have no influence on the steady-state level of oxidative damage to guanine in the liver DNA of normal unstressed guinea-pigs.
Publication Types:
PMID: 9450484 [PubMed – indexed for MEDLINE]
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67: Mech Ageing Dev. 1997 Nov;98(2):95-111.Related Articles, <!–
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Sites and mechanisms responsible for the low rate of free radical production of heart mitochondria in the long-lived pigeon.Department of Animal Biology-II (Animal Physiology) Faculty of Biology, Complutense University, Madrid, Spain.
Basal (substrate alone) and maximum rates of H2O2 production, oxygen consumption and free radical leak in the respiratory chain were higher in heart mitochondria of the short-lived rat (4 years) than in the long-lived pigeon (35 years). This suggests that the low free radical production of pigeon heart mitochondria is due in part to both a low electron flow and a low percent leak of electrons out of sequence in the respiratory chain. Thenoyltrifluoroacetone did not increase H2O2 production with succinate either in rats or pigeons. Mitochondrial H2O2 production was higher with pyruvate/malate than with succinate in both animal species. Rotenone and antimycin A increased H2O2 production with pyruvate/malate to the maximum levels observed in each species. Addition of myxothiazol to antimycin A-treated mitochondria supplemented with pyruvate/malate decreased H2O2 production in both species. All the combinations of inhibitors added with pyruvate/malate resulted in higher rates of H2O2 production in rats than in pigeons. When succinate instead of pyruvate/malate was used as substrate, rotenone and thenoyltrifluoroacetone decreased mitochondrial H2O2 production in the rat and did not change it in the pigeon. The results indicate that Complexes I and III are the main H2O2 generators of heart mitochondria in rats and pigeons and that both Complexes are responsible for the low H2O2 production of the bird. p-Chloromercuribenzoate and ethoxyformic anhydride strongly inhibited the H2O2 production induced by rotenone with pyruvate/malate in both species. This suggests that the free radical generator of Complex I is located after the ferricyanide reduction site, between the ethoxyformic and the rotenone-sensitive sites.
Publication Types:
PMID: 9379714 [PubMed – indexed for MEDLINE]
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68: J Bioenerg Biomembr. 1997 Jun;29(3):241-9.Related Articles, <!–
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]
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ADP-regulation of mitochondrial free radical production is different with complex I- or complex II-linked substrates: implications for the exercise paradox and brain hypermetabolism.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
In agreement with classic studies, succinate-supplemented rat and pigeon heart and nonsynaptic brain mitochondrial free radical production is stopped by ADP additions causing the stimulation of respiration from State 4 to State 3. Nevertheless, with Complex I-linked substrates, mitochondria produce free radicals in State 3 at rates similar or somewhat higher than during resting respiration. The absence of sharp increases in free radical production during intense respiration is possible due to strong decreases of free radical leak in State 3. The results indicate that Complex I is the main mitochondrial free radical generator in State 3, adding to its already known important generation of active oxygen species in State 4. The observed rate of mitochondrial free radical production with Complex I-linked substrates in the active State 3 can help to explain two paradoxes: (a) the lack of massive muscle oxidative damage and shortening of life span due to exercise, in spite of up to 23-fold increases of oxygen consumption together with the very low levels of antioxidants present in heart, skeletal muscle, and brain; (b) the presence of some degree of oxidative stress during exercise and hyperactivity in spite of the stop of mitochondrial free radical production by ADP with succinate as substrate.
Publication Types:
PMID: 9298709 [PubMed – indexed for MEDLINE]
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69: Pharmacol Toxicol. 1996 Nov;79(5):247-53.Related Articles, <!–
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]
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Vitamin E decreases urine lipid peroxidation products in young healthy human volunteers under normal conditions.
Cadenas S, Rojas C, Méndez J, Herrero A, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
An experimental study on the effects of supplementation with antioxidant vitamins on urine lipid peroxidation products was performed in 21 young healthy men. The subjects ingested placebo, 1 g of vitamin C, or 100 mg of vitamin E per day just after the midday meal during 30 days. Urine samples were obtained 0, 15 and 30 days after the beginning of the study. These samples were analyzed by spectrophotometry or fluorometry after reaction with thiobarbituric acid. Prescan fluorometric studies of the thiobarbituric acid reactive substances in both malondialdehyde standards and urine samples indicated 503 nm and 548 nm as optimum excitation and emission wavelengths. The fluorescence measurements proved to be superior both in terms of selectivity and capacity of detection of antioxidant effects in relation to spectrophotometry. Identical emission peaks were obtained with malondialdehyde standards and urine samples, showing the specificity of the fluorometric method. When measured by fluorometry, the urine of the subjects supplemented with vitamin E showed significantly and progressively smaller lipid peroxidation products as the time of supplementation increased, reaching a 27% decrease at the end of the longitudinal trial. The results indicate the usefulness of the fluorescent measurement of urine thiobarbituric acid reactive substances to easily and rapidly detect variations in whole body oxidative stress in humans. They also show the capacity of safe vitamin E dietary doses to decrease endogenous oxidative stress in healthy humans routinely performing their normal activities.
Publication Types:
PMID: 8936558 [PubMed – indexed for MEDLINE]
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70: Lipids. 1996 Sep;31(9):963-70.Related Articles, <!–
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]
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Effect of dietary vitamin E levels on fatty acid profiles and nonenzymatic lipid peroxidation in the guinea pig liver.
Barja G, Cadenas S, Rojas C, Pérez-Campo R, López-Torres M, Prat J, Pamplona R.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Guinea pigs were fed for five weeks with three diets containing different levels of vitamin E: LOW (but nondeficient, 15 mg of vitamin E/kg diet), MEDIUM (150 mg/kg diet), and HIGH (1,500 mg/kg diet). Dietary vitamin E supplementation did not change oxidative stress indicators in the hydrophilic compartment but increased liver alpha-tocopherol in a dose-dependent way and strongly decreased sensitivity to nonenzymatic in vitro liver lipid peroxidation. This last effect was already observed in group MEDIUM, and no further decrease in in vitro lipid peroxidation occurred from group MEDIUM to group HIGH. The protective effect of vitamin E against in vitro lipid peroxidation was observed even though an optimum dietary concentration of vitamin C for this animal model was present in the three different vitamin E diets. Both HIGH and LOW vitamin E decreased percentage fatty acid unsaturation in all phospholipid fractions from membrane origin in relation to group MEDIUM. The results, together with previous information, show that both vitamin E and vitamin C at intermediate concentrations are needed for optimal protection against lipid peroxidation and loss of fatty acid unsaturation even in normal nonstressful conditions. These protective concentrations are higher than those needed to avoid deficiency syndromes.
Publication Types:
PMID: 8882976 [PubMed – indexed for MEDLINE]
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71: Free Radic Res. 1996 Jun;24(6):485-93.Related Articles, <!–
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]
–>Links -
Phospholipid hydroperoxides and lipid peroxidation in liver and plasma of ODS rats supplemented with alpha-tocopherol and ascorbic acid.
Cadenas S, Lertsiri S, Otsuka M, Barja G, Miyazawa T.
Department of Applied Biological Chemistry, Faculty of Agriculture, Tohoku University, Sendai, Japan.
Forty-five mutant male ODS rats, unable to synthesize ascorbic acid, were fed nine diets containing 5, 50 or 250 mg of vitamin E/kg diet and 150, 300 or 900 mg of vitamin C/kg diet for 21 days. The concentrations of vitamins C and E increased in liver and plasma in relation to the level of these vitamins in the diet. Vitamin C dietary supplementation increased the plasma vitamin E content at low levels of vitamin E intake, supporting the concept of an in vivo synergism between both antioxidant vitamins. Vitamin C, at the dietary levels studied, did not affect the lipid peroxidation. Vitamin E decreased liver and plasma endogenous levels of thiobarbituric acid-reactive substances and liver sensitivity to non-enzymatic lipid peroxidation. This was confirmed by a highly specific assay of lipid hydroperoxides using high performance liquid chromatography with chemiluminescence detection. The hepatic concentration of both phosphatidylcholine and phosphatidylethanolamine hydroperoxides decreased as the vitamin E content of the diet increased. The results show for the first time the capacity of vitamin E to protest against peroxidation of major phospholipids in vivo under basal unstressed conditions.
Publication Types:
PMID: 8804991 [PubMed – indexed for MEDLINE]
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72: Mech Ageing Dev. 1996 Jan 5;86(1):53-66.Related Articles, <!–
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Low fatty acid unsaturation protects against lipid peroxidation in liver mitochondria from long-lived species: the pigeon and human case.
Pamplona R, Prat J, Cadenas S, Rojas C, Pérez-Campo R, López Torres M, Barja G.
Department of Animal Biology-II, Complutense University, Madrid, Spain.
Birds have a much higher maximum longevity (MLSP) than mammals of similar metabolic rate. Recent data showed that pigeon mitochondria produce oxygen radicals at a rate much slower than rat mitochondria, in spite of showing similar levels of oxygen consumption (Free Rad. Res., 21 (1994) 317-328). Since oxidative damage from and to mitochondria seems important in relation to aging and longevity, and mitochondrial membranes are situated at the place where oxygen radicals are generated, we studied protein and lipid peroxidation and fatty acid composition of the three main membrane phospholipids of liver mitochondria from rats (MLSP = 4 years) and pigeons (MLSP = 35 years). It was found that pigeon mitochondria show lower levels of fatty acid unsaturation than rat mitochondria in the three lipid fractions, mainly due to a substitution of highly unsaturated fatty acids (20:4 and 22:6) by linoleic acid (18:2), and that these mitochondria are more resistant to lipid peroxidation. Previous research has also obtained exactly the same major difference in fatty acid composition in human mitochondria when compared to those of rat. Thus, present information suggests that the liver mitochondrial membranes of especially long-lived species show both a low level of free radical production and a low degree of fatty acid unsaturation as important constitutive protective traits to slow down aging.
Publication Types:
PMID: 8866736 [PubMed – indexed for MEDLINE]
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73: Free Radic Biol Med. 1996;21(7):907-15.Related Articles, <!–
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–>Links
Increase in heart glutathione redox ratio and total antioxidant capacity and decrease in lipid peroxidation after vitamin E dietary supplementation in guinea pigs.Rojas C, Cadenas S, López-Torres M, Pérez-Campo R, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Dietary treatment with three diets differing in vitamin E, Low E (15 mg of vitamin E/kg diet), Medium E (150 mg/kg), or High E (1,500 mg/kg), resulted in guinea pigs with low (but nondeficient), intermediate, or high heart alpha-tocopherol concentration. Neither the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and reductase, nor the nonenzymatic antioxidants, GSH, ascorbate, and uric acid were homeostatically depressed by increases in heart alpha-tocopherol. Protection from both enzymatic (NADPH dependent) and nonenzymatic (ascorbate-Fe2+) lipid peroxidation was strongly increased by vitamin E supplementation from Low to Medium E whereas no additional gain was obtained from the Medium E to the High E group. The GSH/GSSG and GSH/total glutathione ratios increased as a function of the vitamin E dietary concentration closely resembling the shape of the dependence of heart alpha-tocopherol on dietary vitamin E. The results show the capacity of dietary vitamin E to increase the global antioxidant capacity of the heart and to improve the heart redox status in both the lipid and water-soluble compartments. This capacity occurred at levels six times higher than the minimum daily requirement of vitamin E, even in the presence of optimum dietary vitamin C concentrations and basal unstressed conditions. The need for vitamin E dietary supplementation seems specially important in this tissue due to the low constitutive levels of endogenous enzymatic and nonenzymatic antioxidants present of the mammalian heart in comparison with those of other internal organs.
Publication Types:
PMID: 8937878 [PubMed – indexed for MEDLINE]
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74: Subcell Biochem. 1996;25:157-88.Related Articles, <!–
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–>Links -
Ascorbic acid and aging.
Department of Animal Biology-II, Complutense University, Madrid, Spain.
Publication Types:
PMID: 8821974 [PubMed – indexed for MEDLINE]
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75: Life Sci. 1996;59(8):649-57.Related Articles, <!–
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]
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Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress.Rojas C, Cadenas S, Herrero A, Méndez J, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology Complutense University, Madrid, Spain.
The effect of acute endotoxin-induced septic shock on myocardium oxidative stress after low or high vitamin C and/or E dietary supplementation was studied in guinea pigs, laboratory animals which, like human, do not have capacity for ascorbate synthesis. Neither the antioxidant enzymes or GSH were modified by endotoxin and vitamin treatments. Vitamin E showed a strong capacity to protect the myocardium against both enzymatic and non-enzymatic lipid peroxidation even in the presence of endotoxin. Vitamin C supplementation increased heart ascorbate whereas endotoxic shock totally depleted the heart ascorbate of vitamin C supplemented animals without changing vitamin E. Endotoxin significantly increased myocardium uric acid, a marker of ischemia induced oxidative stress, in animals fed with low vitamin C levels. This increase was totally prevented in vitamin C supplemented, but not in vitamin E supplemented animals. Strongly depressed levels of plasma vitamin C have been recently described in sepsis in human patients. The results suggest that ascorbate is a primary antioxidant target in the heart of endotoxin treated mammals lacking the capacity to synthesize ascorbate and that ascorbate can have a protective value against endotoxin-induced free radical damage in the myocardium. Implications of these results for the possible preventive role of vitamin C in humans during sepsis are discussed.
Publication Types:
PMID: 8761015 [PubMed – indexed for MEDLINE]
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76: Int J Biochem Cell Biol. 1995 Nov;27(11):1175-81.Related Articles, <!–
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]
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Vitamin E protects guinea pig liver from lipid peroxidation without depressing levels of antioxidants.Cadenas S, Rojas C, Pérez-Campo R, López-Torres M, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Oxidative stress is considered a pathogenic factor in many disorders. The capacity of dietary vitamin E to increase global antioxidant capacity and to decrease lipid peroxidation was studied in the guinea pig, an animal that cannot synthesize ascorbate. Male guinea pigs were subjected for 5 weeks to three diets differing in vitamin E content in the presence of optimum levels of vitamin C: group 15 (15 mg vitamin E/kg diet), group 150 (150 mg/kg), and group 1500 (1500 mg/kg). Hepatic vitamin E increased in the three groups in relation to the level of vitamin E in the diet. The increase in vitamin E between groups 15 and 150 was accompanied by a reduction in sensitivity to enzymatic lipid peroxidation. This did not occur between groups 150 and 1500. The different liver vitamin E concentrations did not affect the antioxidant enzymes superoxide dismutase, catalase, GSH-peroxidase and GSH-reductase, nor the non-enzymatic antioxidants vitamin C, GSH and ascorbate. It is concluded that dietary supplementation with vitamin E, at a level 6 times higher than the minimum daily requirement for guinea pigs, increases protection against hepatic lipid peroxidation without depressing endogenous antioxidant defences. Further increases in vitamin E to megadose levels did not provide additional protection from oxidative stress. The results also suggest that optimum levels of both vitamin C and vitamin E, simultaneously needed for protection against oxidative stress, are much higher than the minimum daily requirements.
Publication Types:
PMID: 7584603 [PubMed – indexed for MEDLINE]
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77: J Nutr Sci Vitaminol (Tokyo). 1994 Oct;40(5):411-20.Related Articles, <!–
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]
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Effect of vitamin C on antioxidants, lipid peroxidation, and GSH system in the normal guinea pig heart.
Rojas C, Cadenas S, Pérez-Campo R, López-Torres M, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Male guinea pigs were fed during 5 weeks with diets differing only in vitamin C content: low (33 mg/kg diet), medium (660 mg/kg), and high (13,200 mg/kg). Heart vitamin C was strongly dependent on dietary vitamin C and heart vitamin E showed a trend to increase as a function of the vitamin C level in the diet. The low vitamin C diet decreased body weight gain, food intake, and heart malondialdehyde without changing lipid peroxidation, whereas the high vitamin C increased oxidized glutathione and glutathione peroxidase and decreased body growth. A tendency to show higher levels of all the first-line antioxidants reduced glutathione, uric acid, superoxide dismutase, catalase, and glutathione peroxidase at extreme (high or low) dietary levels of vitamin C was observed. The guinea pig heart showed capacity for enzymatic but not for non-enzymatic in vitro lipid peroxidation. It is concluded that dietary vitamin C supplementation is able to increase the global antioxidant capacity of the heart tissue.
Publication Types:
PMID: 7891202 [PubMed – indexed for MEDLINE]
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78: Free Radic Res. 1994 Oct;21(5):317-27.Related Articles, <!–
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Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds.
Barja G, Cadenas S, Rojas C, Pérez-Campo R, López-Torres M.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Birds are unique since they can combine a high rate of oxygen consumption at rest with a high maximum life span (MLSP). The reasons for this capacity are unknown. A similar situation is present in primates including humans which show MLSPs higher than predicted from their rates of O2 consumption. In this work rates of oxygen radical production and O2 consumption by mitochondria were compared between adult male rats (MLSP = 4 years) and adult pigeons (MLSP = 35 years), animals of similar body size. Both the O2 consumption of the whole animal at rest and the O2 consumption of brain, lung and liver mitochondria were higher in the pigeon than in the rat. Nevertheless, mitochondrial free radical production was 2-4 times lower in pigeon than in rat tissues. This is possible because pigeon mitochondria show a rate of free radical production per unit O2 consumed one order of magnitude lower than rat mitochondria: bird mitochondria show a lower free radical leak at the respiratory chain. This result, described here for the first time, can possibly explain the capacity of birds to simultaneously increase maximum longevity and basal metabolic rate. It also suggests that the main factor relating oxidative stress to aging and longevity is not the rate of oxygen consumption but the rate of oxygen radical production. Previous inconsistencies of the rate of living theory of aging can be explained by a free radical theory of aging which focuses on the rate of oxygen radical production and on local damage to targets relevant for aging situated near the places where free radicals are continuously generated.
Publication Types:
PMID: 7842141 [PubMed – indexed for MEDLINE]
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79: Free Radic Biol Med. 1994 Aug;17(2):105-15.Related Articles, <!–
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]
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Dietary vitamin C decreases endogenous protein oxidative damage, malondialdehyde, and lipid peroxidation and maintains fatty acid unsaturation in the guinea pig liver.
Barja G, López-Torres M, Pérez-Campo R, Rojas C, Cadenas S, Prat J, Pamplona R.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Guinea pigs were fed during 5 weeks with three different levels of vitamin C in the diet: 33 (marginal deficiency), 660, or 13,200 mg of vitamin C per kg of diet. The group fed 660 mg of vitamin C/kg of diet showed strongly reduced levels of protein carbonyls (46% decrease), malondialdehyde (HPLC; 72% decrease), and in vitro production of TBARS (both stimulated with ascorbate-Fe2+ and with NADPH-ADP-Fe2+; 68% and 71% decrease), increased glutathione reductase activity, and increased vitamin C content (48 times higher) in the liver in relation to the group fed 33 mg/kg. The treatment with 660 mg of vitamin C/kg did not decrease any of the antioxidant defenses studied: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, GSH, vitamin E, or uric acid. Further supplementation with 13,200 mg vitamin C/kg also reduced protein and lipid peroxidation, but decreased hepatic glutathione reductase and uric acid and resulted in a lower body weight of the animals. Both low (33 mg/kg) and very high (13,200 mg/kg) levels of vitamin C decreased body weight, glutathione reductase, and unsaturation of fatty acids in membrane lipids. The results show that a diet supplying an amount of vitamin C 40 times higher than the minimum daily requirement to avoid scurvy increases the global antioxidant capacity and is of protective value against endogenous lipid and protein oxidation in the liver under normal nonstressful conditions.
Publication Types:
PMID: 7959171 [PubMed – indexed for MEDLINE]
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80: Comp Biochem Physiol Biochem Mol Biol. 1994 Aug;108(4):501-12.Related Articles, <!–
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]
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A decrease of free radical production near critical targets as a cause of maximum longevity in animals.
Barja G, Cadenas S, Rojas C, López-Torres M, Pérez-Campo R.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
A comprehensive study was performed on the brains of various vertebrate species showing different life energy potentials in order to find out if free radicals are important determinants of species-specific maximum life span. Brain superoxide dismutase, catalase, Se-dependent and independent GSH-peroxidases, GSH-reductase, and ascorbic acid showed significant inverse correlations with maximum longevity, whereas GSH, uric acid, GSSG/GSH, in vitro peroxidation (thiobarbituric acid test), and malondialdehyde (measured by HPLC), did not correlate with maximum life span. Superoxide dismutase, catalase, GSH-peroxidase, GSH and ascorbate results agree with those previously reported in various independent works using different animal species. GSSG/GSH, and true malondialdehyde (HPLC) results are reported for the first time in relation to maximum longevity. The results suggest that longevous species simultaneously show low antioxidant concentrations and low levels of in vivo free radical production (a low free radical turnover) in their tissues. The « free radical production hypothesis of aging » is proposed: a decrease in oxygen radical production per unit of O2 consumption near critical DNA targets (mitochondria or nucleus) increases the maximum life span of extraordinarily long-lived species like birds, primates, and man. Free radical production near these DNA sites would be a main factor responsible for aging in all the species, in those following Pearl’s (Rubner’s) metabolic rule as well as in those not following it.
Publication Types:
PMID: 7953069 [PubMed – indexed for MEDLINE]
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81: Free Radic Res. 1994 Aug;21(2):109-18.Related Articles, <!–
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]
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Effect of dietary vitamin C and catalase inhibition of antioxidants and molecular markers of oxidative damage in guinea pigs.
Cadenas S, Rojas C, Pérez-Campo R, López-Torres M, Barja G.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Guinea pigs were fed for five weeks with two diets with different levels of vitamin C, low (33 mg of Vit C/Kg diet) and high (13,200 mg of Vit C/Kg of diet). Catalase was inhibited with 3-amino-1,2,4-triazole (AT) in half of the animals from each dietary group. AT caused an almost complete depletion of liver catalase activity (90%) in both dietary groups. Vitamin C supplementation increased total glutathione peroxidase activity and tissue vitamin C level and decreased levels of protein carbonyls and malondialdehyde (MDA) in both treated and non-treated animals. This vitamin C supplementation did not change any of the other antioxidant defences studied. Our results show that dietary vitamin C supplementation increases global antioxidant capacity and decreases endogenous oxidative damage in the guinea pig liver under normal non-stressful conditions. This supports the protective value of dietary antioxidant supplementation.
Publication Types:
PMID: 7921163 [PubMed – indexed for MEDLINE]
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82: J Comp Physiol [B]. 1994;163(8):682-9.Related Articles, <!–
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]
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Longevity and antioxidant enzymes, non-enzymatic antioxidants and oxidative stress in the vertebrate lung: a comparative study.
Pérez-Campo R, López-Torres M, Rojas C, Cadenas S, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
It has been proposed that antioxidants can be longevity determinants in animals. However, no comprehensive study has been conducted to try to relate free radicals with maximum life span. This study compares the lung tissue of various vertebrate species–amphibia, mammals and birds–showing very different and well known maximum life spans and life energy potentials. The lung antioxidant enzymes superoxide dismutase, catalase, Se-dependent and non-Se-dependent glutathione peroxidases, and glutathione reductase showed significantly negative correlations with maximum life span. The same was observed for the lung antioxidants, reduced glutathione and ascorbate. It is concluded that a generalized decrease in tissue antioxidant capacity is a characteristic of longevous species. It is suggested that a low rate of free radical recycling (free-radical generation and scavenging) can be an important factor involved in the evolution of high maximum animal longevities. A low free-radical production could be responsible for a low rate of damage at critical sites such as mitochondrial DNA.
Publication Types:
PMID: 8195472 [PubMed – indexed for MEDLINE]
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83: Exp Gerontol. 1994 Jan-Feb;29(1):77-88.Related Articles, <!–
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]
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Caloric and carbohydrate restriction in the kidney: effects on free radical metabolism.
Cadenas S, Rojas C, Pérez-Campo R, López-Torres M, Barja G.
Department of Animal Biology-II (Animal Physiology) Faculty of Biology, Complutense University, Madrid, Spain.
Carbohydrate restriction and caloric restriction (60% restriction of calories in relation to controls in both cases) were imposed on OF1 mice during 8 weeks in their growing phase. The three groups of animals ingested the same amount of vitamins and minerals. Kidney ascorbate strongly decreased in both restriction groups. Nevertheless, global caloric restriction significantly increased kidney antioxidant glutathione (GSH)/oxidized glutathione (GSSG) ratio, a sign of a reduced kidney oxidative stress. Increased glutathione peroxidase and cytochrome oxidase activities and decreased in vivo peroxidation were found in the kidney when the restriction was performed by substituting carbohydrates by nonnutritive bulk. No significant changes were observed for superoxide dismutase, catalase, glutathione reductase, glutathione, uric acid, malondialdehyde (HPLC), or in vitro sensitivity to peroxidation in the kidney. The results, reported for the first time in this tissue, show that short-term caloric restriction can increase the capacity for enzymatic decomposition of hydroperoxides and can decrease oxidative stress in the kidney, thus suggesting a role for free radical metabolism in the caloric restriction phenomenon.
Publication Types:
PMID: 8187843 [PubMed – indexed for MEDLINE]
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84: Methods Enzymol. 1994;234:331-7.Related Articles, <!–
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Vitamin C, dehydroascorbate, and uric acid in tissues and serum: high-performance liquid chromatography.
Department of Animal Biology-II (Animal Physiology), Complutense University, Madrid, Spain.
PMID: 7808304 [PubMed – indexed for MEDLINE]
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85: Arch Biochem Biophys. 1993 Oct;306(1):59-64.Related Articles, <!–
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Relationship between lipid peroxidation, fatty acid composition, and ascorbic acid in the liver during carbohydrate and caloric restriction in mice.Rojas C, Cadenas S, Pérez-Campo R, López-Torres M, Pamplona R, Prat J, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Growing OF1 mice were treated on a short-term basis with ad libitum, caloric-restricted, or carbohydrate-restricted diets, maintaining the same intake of vitamins and minerals in the three groups. Caloric intake was 60% of controls both in the caloric-restricted and in the carbohydrate-restricted groups. Neither global nor carbohydrate restriction changed liver superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, cytochrome oxidase, GSH, uric acid, or malondialdehyde (HPLC). Ascorbate was decreased in both restricted groups. Carbohydrate restriction, but not caloric restriction, increased unsaturation indexes of fatty acids in all lipid classes analyzed and increased sensitivity to peroxidation by one order of magnitude. It is concluded that short-term caloric restriction does not seem to increase antioxidants and decrease peroxidation in the mouse liver whereas long-term restriction can avoid decreases of antioxidants and increases of peroxidation during aging. Our experiments support the prevailing view that the caloric restriction phenomenon is due to a reduction in calories themselves instead of to a reduction in carbohydrates. This last manipulation strongly increases sensitivity to peroxidative damage in the liver. The results show that in vivo fatty acid unsaturation is a main factor in determining the sensitivity to lipid peroxidation.
Publication Types:
PMID: 8215421 [PubMed – indexed for MEDLINE]
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86: Exp Lung Res. 1993 Sep-Oct;19(5):533-43.Related Articles, <!–
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]
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Effect of early maternal adrenalectomy on antioxidant enzymes, GSH, ascorbate, and uric acid in the rat fetal lung at term.
Arahuetes RM, Madrid R, Cadenas S, Rojas C, Pérez-Campo R, López-Torres M, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Previous studies have shown that the increase of the enzymatic antioxidant defense that takes place in the fetal rat lung at the end of gestation can be accelerated by the synthetic glucocorticoid dexamethasone and diminished by metyrapone, a blocker of glucocorticoid synthesis. Since it is known that the fetal adrenal does not start to synthesize corticosterone until the last 20% of gestation, pregnant rats were bilaterally adrenalectomized on the first day of gestation in order to clarify the role of the endogenous maternal hormone on the development of the enzymatic and nonenzymatic antioxidant systems of fetal lung. This early adrenalectomy did not change fetal lung catalase, glutathione peroxidase, glutathione reductase, cytochrome oxidase, GSH, ascorbate, and uric acid at term. The presence of the maternal glands is not essential for lung antioxidant development in the fetus and that the stimulus of fetal corticosterone during the last 20% of gestation is enough to achieve a normal maturation of the fetal lung enzymatic and nonenzymatic antioxidant systems.
Publication Types:
PMID: 8253057 [PubMed – indexed for MEDLINE]
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87: Mech Ageing Dev. 1993 Aug 15;70(3):177-99.Related Articles, <!–
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Maximum life span in vertebrates: relationship with liver antioxidant enzymes, glutathione system, ascorbate, urate, sensitivity to peroxidation, true malondialdehyde, in vivo H2O2, and basal and maximum aerobic capacity.
Lopez-Torres M, Perez-Campo R, Rojas C, Cadenas S, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
In order to help clarify whether free radicals are implicated or not in the evolution of maximum life span (MLSP) of animals, a comprehensive study was performed in the liver of various vertebrate species. Strongly significant negative correlations against MLSP were found for hepatic catalase, Se-dependent and -independent glutathione peroxidases, and GSH, whereas superoxide dismutase, glutathione reductase, ascorbate, uric acid, GSSG/GSH, in vitro peroxidation (TBA-RS), and in vivo steady-state H2O2 concentration in the liver did not correlate with MLSP. Superoxide dismutase, catalase, glutathione peroxidase, and GSH results were in agreement with those independently reported by other authors, whereas the rest of our data are reported for the first time. Potential limitations arising from the use of animals of different vertebrate Classes were counterbalanced by the possibility to study animals with very different MLSPs and life energy potentials. Furthermore, the results agreed with previous data obtained using only mammals. Since liver GSSG/GSH, peroxidation, and specially H2O2 concentration were similar in species with widely different MLSPs, it is suggested that the decrease in enzymatic H2O2 detoxifying capacity of longevous species represents an evolutionary co-adaptation with a smaller in vivo rate of free radical generation. We propose the possibility that maximum longevity was increased during vertebrate evolution by lowering the rate of free radical recycling in the tissues.
Publication Types:
PMID: 8246633 [PubMed – indexed for MEDLINE]
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88: Free Radic Biol Med. 1993 Aug;15(2):133-42.Related Articles, <!–
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]
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Simultaneous induction of sod, glutathione reductase, GSH, and ascorbate in liver and kidney correlates with survival during aging.
López-Torres M, Pérez-Campo R, Rojas C, Cadenas S, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
Catalase was continuously inhibited with aminotriazole in the liver and kidney during 33 months in large populations of old and young frogs in order to study the effects of the modification of the tissue antioxidant/prooxidant balance on the life span of a vertebrate species showing an oxygen consumption rate similar to that of humans. Free-radical-related parameters were measured during three consecutive years at 2.5, 14.5, and 26.5 months of experimentation. Aging per se did not decrease antioxidant enzymes and did not increase peroxidation (thiobarbituric acid positive substances, or high-pressure liquid chromatography [HPLC]-malondialdehyde), either cross sectionally or longitudinally. Long-term catalase inhibition leads to time-dependent increases (100-900%) of endogenous superoxide dismutase, GSH, ascorbate, and especially glutathione reductase at 2.5 and 14.5 months of experimentation. This was positively correlated with a higher survival of treated animals (91% in treated versus 46% in controls at 14.5 months of experimentation). The loss of those inductions after 26.5 months leads to a sharp increase in mortality rate. The results show for the first time that simultaneous induction of various tissue antioxidant enzymes and nonenzymatic antioxidants can increase the mean life span of a vertebrate animal. It is concluded that the tissue antioxidant/prooxidant balance is a strong determinant of mean life span.
Publication Types:
PMID: 8375690 [PubMed – indexed for MEDLINE]
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89: Comp Biochem Physiol B. 1993 Jul-Aug;105(3-4):749-55.Related Articles, <!–
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]
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A comparative study of free radicals in vertebrates–I. Antioxidant enzymes.
Pérez-Campo R, López-Torres M, Rojas C, Cadenas S, Barja G.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
1. Five antioxidant enzymes and cytochrome oxidase were measured in three vital organs of seven animal species of different vertebrate classes. 2. Minimal superoxide dismutase activities were found in the brain of homeotherms and in the lung of amphibia. Catalase (CAT) was maximal in liver and minimal in brain. 3. Possession of both Se dependent and independent glutathione peroxidase (GPx) is widespread in vertebrate organs. Similarities in tissue distribution were found among enzymes which use hydroperoxides (Se and non-Se GPx and CAT) or glutathione (both GPx and glutathione reductase) as substrates. 4. The results also suggest that the high aerobic capacity of the liver strongly influences the activities of the antioxidant enzymes in this tissue across vertebrate species, whereas other factors such as tissue pO2 can be more important in the lung.
Publication Types:
PMID: 8395990 [PubMed – indexed for MEDLINE]
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90: Comp Biochem Physiol B. 1993 Jul-Aug;105(3-4):757-63.Related Articles, <!–
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]
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A comparative study of free radicals in vertebrates–II. Non-enzymatic antioxidants and oxidative stress.
López-Torres M, Pérez-Campo R, Cadenas S, Rojas C, Barja G.
Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, Madrid, Spain.
1. The three main non-enzymatic endogenous soluble antioxidants and three estimators of oxidative stress were measured in the liver, lung and brain of seven animal species of different vertebrate classes. 2. The more concentrated antioxidant was GSH, followed by ascorbate and finally by uric acid. Liver showed higher levels of GSH and uric acid than the other two organs in the majority of the species. 3. GSSG/GSH ratio was highest in lung, probably due to the high pO2 prevalent in the tissue. Nevertheless, this did not result in higher tissue peroxidation, suggesting that the lung antioxidants are capable of coping with a high tissue pO2. 4. Tissue peroxidation was maximal in the brain when assayed by the TBA test, but this was not confirmed by HPLC of malondialdehyde (MDA). HPLC resulted in much lower MDA values than TBA.
Publication Types:
PMID: 8365120 [PubMed – indexed for MEDLINE]
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91: Free Radic Res Commun. 1993;18(2):63-70.Related Articles, <!–
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Oxygen radicals, a failure or a success of evolution?
Department of Animal Biology II Animal Physiology, Faculty of Biology, Complutense University, Madrid, Spain.
Oxygen radicals are no doubt involved in the development of many pathological states. Nevertheless, the possibility that oxygen radical production was selected for during biological evolution in order to perform useful roles in relation to cellular metabolism is contemplated; previous data on this subject are briefly reviewed. The concept of an « oxygen radical cycle » is proposed as a useful theoretical model.
Publication Types:
PMID: 8386685 [PubMed – indexed for MEDLINE]
Social brain & ATLAS of Zebra Finch Brain 