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THE FOUR RULES OF AGING

THE FOUR RULES OF AGING. 1) AGING IS UNIVERSAL 2) AGING IS PROGRESSIVE 3) AGING IS ENDOGENOUS 4) AGING-POSTMITOTIC (DELETEREOUS). SOD, CAT, GPx, GR, GSH, ASC (%). CAT, GPx, GR, GSH, ASC (%). 100. 100. VERTEBRATES. MAMMALS. 80. 80. 60. 60. 40. 40. 20. 20. HUMAN. PIGEON. 0. 0.

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THE FOUR RULES OF AGING

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  1. THE FOUR RULES OF AGING 1) AGING IS UNIVERSAL 2) AGING IS PROGRESSIVE 3) AGING IS ENDOGENOUS 4) AGING-POSTMITOTIC (DELETEREOUS)

  2. SOD, CAT, GPx, GR, GSH, ASC (%) CAT, GPx, GR, GSH, ASC (%) 100 100 VERTEBRATES MAMMALS 80 80 60 60 40 40 20 20 HUMAN PIGEON 0 0 0 5 10 15 20 25 30 35 40 0 20 40 60 80 100 120 MAXIMUM LONGEVITY (YEARS) MAXIMUM LONGEVITY (YEARS) 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) From other four different independent laboratories

  3. (LONG-LIVED ANIMAL SPECIES) (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 LOW ANTIOXIDANT LEVELS (HYPOTHESIS) 1993 LOW RATE OF MITOCHONDRIAL OXYGEN RADICAL PRODUCTION

  4. COMPARATIVE STUDIES OF MITOCHONDRIAL H2O2 PRODUCTION IN MAMMALS AND BIRDS WITH DIFFERENT MAXIMUM LONGEVITIES (MLSP)

  5. PIGEON MLSP= 35 YEARS RAT MLSP= 4 YEARS

  6. H2O2 GENERATION. HEART MITOCHONDRIA

  7. CANARY MLSP= 24 YEARS (Serinus canarius) PARAKEET MLSP= 21 YEARS (Melopsittacus undulatus) MOUSE MLSP= 3.5 YEARS

  8. O2 ROS O2 ROS O2 NO ROS S S S

  9. Succinate Cx II Pyruvate/ Malate TTFA AA O2 c Cx III Cx IV Q Cx I ROT H2O

  10. (LONG-LIVED ANIMAL SPECIES) LOW RATE OF MITOCHONDRIAL OXYGEN RADICAL PRODUCTION (HYPOTHESIS) LOW OXIDATIVE DAMAGE IN MITOCHONDRIAL DNA

  11. O H N HN O H N N N 2 H 8-oxoGua

  12. 12 r=-0.92 p<0.000 (HEART) 10 8 Mouse (SAME RESULT IN BRAIN) 6 8-oxodG/ 105dG in heart mt DNA Guinea pig Rat 4 Rabbit Pig 2 Sheep Horse Cow 0 10 20 30 40 50 MAXIMUM LONGEVITY (YEARS) G.Barja & A. Herrero. FASEB J. 14: 312-318 (2000)

  13. 2 (BRAIN) 1 Horse 8-oxodG/ 105dG in nDNA Mouse Guinea Pig Rat Cow Rabbit 0 0 10 20 30 40 50 MLSP (YEARS) (SIMILAR RESULTS IN HEART)

  14. H2O2 PRODUCTION HEART MITOCHONDRIA 1.2 AC OC 1.0 OR 0.8 * nmoles H2O2/ min· mg prot 0.6 0.4 0.2 0.0 Pyruvate/ malate Long-term Caloric Restriction (1 year)

  15. H2O2 PRODUCTION HEART MITOCHONDRIA 2.5 AC OC OR 2.0 1.5 nmoles H2O2/ min· mg prot 1.0 0.5 0.0 Succinate (+ Rotenone) Long-term Caloric Restriction (1 year)

  16. Succinate Cx II Pyruvate/ Malate TTFA AA O2 c Cx III Cx IV Q Cx I ROT H2O

  17. + + NAD +H NADH Complex I - e C. Krebs FMN O 2 nxFeS FeCN Mitochondrial matrix Pyr/ mal + H ·- O 2 QH 2 ·- Q Fe SN-2 Q Complex III Q ROT H O + H 2 2 Pyr/ mal Intermembrane space

  18. Cx I NADH 1,2-NAPHTOQUINONE p-ClHg BENZOATE FERRICYANIDE ETHOXYFORMIC ANHYDRIDE ROTENONE MENADIONE Q

  19. O2 CONSUMPTION HEART MITOCHONDRIA 32 AC OC OR 24 nmoles O2/ min· mg prot 16 8 0 Pyruvate/ malate Long-term Caloric Restriction (1 year)

  20. FREE RADICAL LEAK HEART MITOCHONDRIA 2.5 AC OC 2.0 OR 1.5 ** (%) 1.0 0.5 0.0 Pyruvate/ malate Long-term Caloric Restriction (1 year)

  21. Effect of long-term caloric restriction (1 year) on the steady-state levels of oxidative damage (8-oxodG/105dG) in rat heart nuclear DNA 8-oxodG/105dG in nuclear DNA Adult control 0.61 ± 0.09 (6) Old control 0.49 ± 0.04 (6) Old restricted 0.54 ± 0.05 (6) 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.

  22. 7 AC OC 6 OR 5 * 4 8-oxodG/ 105 dG 3 2 1 0 8-oxodG in HEART mtDNA Long-term Caloric Restriction (1 year)

  23. CALORIC RESTRICTION LONG-LIVED ANIMALS (-) (-) MITOCHONDRIAL ROS PRODUCTION RATE MITOCHONDRIAL DNA RATE OF ACCUMULATION OF mtDNA MUTATIONS AGING RATE

  24. 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.

  25. 5.0 WILD TYPE AMES DWARF 4.0 * 3.0 8-oxodG/105dG in mtDNA * 2.0 1.0 0.0 HEART BRAIN

  26. Short-lived animals Ad libitum animals HIGH [8-oxodG] (High mitoch. ROS product.) High (8-oxo mtDNA repair ? (post.mitot.) High attack Long-lived animals Restricted animals LOW [8-oxodG] Low 8-oxodG mtDNA repair ? (post.mitot.) (Low mitoch. ROS product.) Low attack Low repair ?

  27. DOUBLE BOND INDEX OF FATTY ACIDS HEART (MOUSE) (Rat) (Pig) (G. pig) (Horse) (Rabbit) (Cow) (Sheep) MAX. LONGEVITY (YEARS)

  28. 30 40 Mouse Cow 30 Rat Rabbit 20 Horse Guinea Pig Pig % DOCOSAHEXAENOIC ACID (22:6n-3) 20 % LINOLEIC ACID (18:2n-6) Sheep 10 Rat 10 Sheep Pig Mouse Guinea pig Horse Cow 0 Rabbit 10 100 100 10 Maximum longevity (years) Maximum longevity (years) Relationship between maximum longevity and linoleic acid (18:2n-6) and docosahexanoic acid (22:6n-3) contents in heart phospholipids of 8 mammalian species

  29. CALORIC RESTRICTION LONG-LIVED ANIMALS  DBI (-) (-) MITOCHONDRIAL ROS PRODUCTION RATE ?  MDA MITOCHONDRIAL DNA ?  Prot. ox. RATE OF ACCUMULATION OF mtDNA MUTATIONS AGING RATE

  30. FROM MAMMALS TO BIRDS FROM STATE 4 TO STATE 3 FROM EU- TO HYPERTHYROIDISM FRL DECREASES OXYGEN RADICAL PRODUCTION IS NOT NECCESSARILY PROPORTIONAL TO OXYGEN CONSUMPTION

  31. STATE 4 (RESTING RESPIRATION) Cx I Cx III Cx IV O2 H2O +ADPSTATE 3 (ACTIVE, ATP is being generated at complex V) Cx I Cx III Cx IV O2 H2O Low rate of electron flux ROS ROS High rate of electron flux ROS

  32. S H2 O2 mtc DNA e- 1/2 O2 Positive fluorescent metod Specific for H2O2 Sensitive Does not alter mitochondria Instantaneous response to H2O2 No antioxidant interference (Barja G. (2002) J. Bioenerg. Biomembr. 33:227-233 HOMOVANILLIC ACID H2O2 HORSERADISH PEROXIDASE DIMER FLUORESCENCE 312 nm EXC 420nm EM

  33. RATE MIT. ROS PROD. FATTY ACID UNSATURATION + + UNIVERSAL + + PROGRESSIVE + + ENDOGENOUS + + POST-MITOTIC (Endogenous generation of oxidative damage) (DBI)

  34. THE RATE OF GENERATION OF ENDOGENOUS DAMAGE IS THE CAUSE OF AGING

  35. COLLABORATION IS MUCH BETTER THAN COMPETITION (A L S O I N S C I E N C E)

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