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THE FOUR RULES OF AGING 1) AGING IS UNIVERSAL 2) AGING IS PROGRESSIVE 3) AGING IS ENDOGENOUS 4) AGING-POSTMITOTIC (DELETEREOUS)
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SOD, CAT, GPx, GR, GSH, ASC (%) 051520253540 MAXIMUM LONGEVITY (YEARS) VERTEBRATES 0 100 80 60 40 20 1030 PIGEON 204060801001200 MAXIMUM LONGEVITY (YEARS) MAMMALS 0 100 80 60 40 20 CAT, GPx, GR, GSH, ASC (%) HUMAN From other four different independent laboratories From: López-Torres et al. Mech Ageing Dev 70 (1993) Barja et al Free Radic Res 21 (1994) Pérez-Campo et al J Comp Physiol [B] 163 (1994) Barja et al Comp Biochem Physiol Biochem Mol Biol 108 (1994)
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LOW ANTIOXIDANT LEVELS LOW RATE OF MITOCHONDRIAL OXYGEN RADICAL PRODUCTION (LONG-LIVED ANIMAL SPECIES) (HYPOTHESIS) 1993 (Barja & cols.: MAD 1993; CBP1994; JCP, 1994; Free Rad. Res. 94, Review (written in 1994, passed through 4 journals & finally published in J. Comp. Physiol. In 1998
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COMPARATIVE STUDIES OF MITOCHONDRIAL H 2 O 2 PRODUCTION IN MAMMALS AND BIRDS WITH DIFFERENT MAXIMUM LONGEVITIES (MLSP)
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PIGEON MLSP= 35 YEARS RAT MLSP= 4 YEARS
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H2O2 GENERATION. HEART MITOCHONDRIA
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MOUSE MLSP= 3.5 YEARS PARAKEET MLSP= 21 YEARS (Melopsittacus undulatus) CANARY MLSP= 24 YEARS (Serinus canarius)
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S S S ROS NO ROS O2O2 O2O2 O2O2
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Cx I Cx IVCx III Cx II Q Succinate Pyruvate/ Malate O2O2 H2OH2O c ROT TTFA AA
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LOW RATE OF MITOCHONDRIAL OXYGEN RADICAL PRODUCTION LOW OXIDATIVE DAMAGE IN MITOCHONDRIAL DNA (LONG-LIVED ANIMAL SPECIES) (HYPOTHESIS)
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8-oxoGua O H 2 N O N H HN HNHN N
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8-oxodG/ 10 5 dG in heart mt DNA Rat Mouse Guinea pig Horse Pig Rabbit Sheep Cow 1040302050 1212 0 1010 8 6 4 2 MAXIMUM LONGEVITY (YEARS) G.Barja & A. Herrero. FASEB J. 14: 312-318 (2000) r=-0.92 p<0.000 (HEART) (SAME RESULT IN BRAIN)
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1040302050 0 2 1 0 8-oxodG/ 10 5 dG in nDNA MLSP (YEARS) Rat Mouse Guinea Pig Horse Rabbit Cow (BRAIN) (SIMILAR RESULTS IN HEART)
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H 2 O 2 PRODUCTION HEART MITOCHONDRIA * 0.0 0.2 0.4 0.6 0.8 1.0 1.2 nmoles H 2 O 2 / min· mg prot AC OC OR Pyruvate/ malate Long-term Caloric Restriction (1 year)
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0.0 0.5 1.0 1.5 2.0 2.5 H 2 O 2 PRODUCTION HEART MITOCHONDRIA nmoles H 2 O 2 / min· mg prot Succinate (+ Rotenone) Long-term Caloric Restriction (1 year) AC OC OR
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Cx I Cx IVCx III Cx II Q Succinate Pyruvate/ Malate O2O2 H2OH2O c ROT TTFA AA
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Mitochondrial matrix Intermembrane space NADH NAD + +H + FMN nxFeS FeCN O 2 O 2 ·- QH 2 Q H 2 O 2 H + ROT Q Complex III Complex I Pyr/ mal H + e - Q ·- Fe SN-2 C. Krebs
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1,2-NAPHTOQUINONE ROTENONE FERRICYANIDE MENADIONE p-ClHg BENZOATE ETHOXYFORMIC ANHYDRIDE NADH Q Cx I
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O 2 CONSUMPTION HEART MITOCHONDRIA Pyruvate/ malate Long-term Caloric Restriction (1 year) 0 8 16 24 32 nmoles O 2 / min· mg prot AC OC OR
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0.0 0.5 1.0 1.5 2.0 2.5 FREE RADICAL LEAK HEART MITOCHONDRIA Pyruvate/ malate Long-term Caloric Restriction (1 year) AC OC OR (%) **
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Age of animals at time of analysis: adult (7 months), old (24 months). Results are means ± SEM (n). No significant differences due to age or restriction were observed. Effect of long-term caloric restriction (1 year) on the steady-state levels of oxidative damage (8-oxodG/10 5 dG) in rat heart nuclear DNA Adult control 0.61 ± 0.09 (6) Old control 0.49 ± 0.04 (6) Old restricted 0.54 ± 0.05 (6) 8-oxodG/10 5 dG in nuclear DNA
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8-oxodG in HEART mtDNA Long-term Caloric Restriction (1 year) 0 1 2 3 4 5 6 7 8-oxodG/ 10 5 dG AC OC OR *
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MITOCHONDRIAL ROS PRODUCTION RATE AGING RATE RATE OF ACCUMULATION OF mtDNA MUTATIONS MITOCHONDRIAL DNA CALORIC RESTRICTION LONG-LIVED ANIMALS (-)
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Survival plots of dwarf mice. Left panel: Snell dwarf mice and normal controls. Right panel: Ames dwarf mice and normal controls. Reproduced from Bartke and Turyn 2001.
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8-oxodG/10 5 dG in mtDNA HEART BRAIN 0.0 1.0 2.0 3.0 4.0 5.0 * * WILD TYPE AMES DWARF
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LOW [8-oxodG] Low repair ? Long-lived animals Restricted animals Low attack HIGH [8-oxodG] High (8-oxo mtDNA repair ? (post.mitot.) Short-lived animals Ad libitum animals High attack (Low mitoch. ROS product.) (High mitoch. ROS product.) Low 8-oxodG mtDNA repair ? (post.mitot.)
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DOUBLE BOND INDEX OF FATTY ACIDS HEART MAX. LONGEVITY (YEARS) (MOUSE) (G. pig) (Horse) (Pig) (Cow) (Sheep) (Rabbit) (Rat)
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Maximum longevity (years) % LINOLEIC ACID (18:2n-6) Horse Cow Pig Sheep Rabbit Guinea Pig Mouse 10 20 30 40 10010 Rat 0 100 Horse 30 20 10 Mouse Guinea pig Sheep Pig Rabbit Cow Rat Maximum longevity (years) % DOCOSAHEXAENOIC ACID (22:6n-3) Relationship between maximum longevity and linoleic acid (18:2n-6) and docosahexanoic acid (22:6n-3) contents in heart phospholipids of 8 mammalian species
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MITOCHONDRIAL ROS PRODUCTION RATE AGING RATE RATE OF ACCUMULATION OF mtDNA MUTATIONS MITOCHONDRIAL DNA CALORIC RESTRICTION LONG-LIVED ANIMALS (-) DBI ? MDA Prot. ox. ?
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OXYGEN RADICAL PRODUCTION IS NOT NECCESSARILY PROPORTIONAL TO OXYGEN CONSUMPTION FRL DECREASES FROM MAMMALS TO BIRDS FROM STATE 4 TO STATE 3 FROM EU- TO HYPERTHYROIDISM
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Cx ICx IIICx IV STATE 4 (RESTING RESPIRATION) High rate of electron flux ROS +ADP STATE 3 (ACTIVE, ATP is being generated at complex V) Cx ICx IIICx IV Low rate of electron flux ROS O2O2 H2OH2O O2O2 H2OH2O
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mtc DNA 1/2 O 2 e-e- S H 2 O 2 H2O2H2O2 HOMOVANILLIC ACID HORSERADISH PEROXIDASE DIMER FLUORESCENCE 312 nm EXC 420nm EM Positive fluorescent metod Specific for H 2 O 2 Sensitive Does not alter mitochondria Instantaneous response to H 2 O 2 No antioxidant interference (Barja G. (2002) J. Bioenerg. Biomembr. 33:227-233
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UNIVERSAL ++ PROGRESSIVE ++ ENDOGENOUS ++ POST-MITOTIC ++ RATE MIT. ROS PROD. FATTY ACID UNSATURATION (DBI) (Endogenous generation of oxidative damage)
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THE RATE OF GENERATION OF ENDOGENOUS DAMAGE IS THE CAUSE OF AGING
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COLLABORATION IS MUCH BETTER THAN COMPETITION (A L S O I N S C I E N C E)
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