the four rules of aging 1) aging is universal 2) aging is progressive 3) aging is endogenous 4)...

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  • From other four different independent laboratories From: Lpez-Torres et al. Mech Ageing Dev 70 (1993)Barja et al Free Radic Res 21 (1994) Prez-Campo et al J Comp Physiol [B] 163 (1994)Barja et al Comp Biochem Physiol Biochem Mol Biol 108 (1994)

  • LOW ANTIOXIDANT LEVELSLOW RATE OF MITOCHONDRIALOXYGEN 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 inJ. Comp. Physiol. In 1998

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

  • PIGEONMLSP= 35 YEARSRATMLSP= 4 YEARS

  • SSS

  • Cx ICx IVCx IIICx IIQSuccinatePyruvate/MalateO2H2OcROTTTFAAA

  • LOW RATE OF MITOCHONDRIALOXYGEN RADICAL PRODUCTIONLOW OXIDATIVE DAMAGE IN MITOCHONDRIAL DNA(LONG-LIVED ANIMAL SPECIES)(HYPOTHESIS)

  • 8-oxoGua

  • 8-oxodG/ 105dG in heart mt DNARatMouseGuinea pigHorsePigRabbitSheepCow1040302050120108642MAXIMUM LONGEVITY (YEARS)G.Barja & A. Herrero. FASEB J. 14: 312-318 (2000)r=-0.92p
  • 104030205002108-oxodG/ 105dG in nDNAMLSP (YEARS)RatMouse Guinea PigHorseRabbitCow(BRAIN)(SIMILAR RESULTS IN HEART)

  • H2O2 PRODUCTION HEART MITOCHONDRIA*0.00.20.40.60.81.01.2nmoles H2O2/ min mg protACOCORPyruvate/ malateLong-term Caloric Restriction (1 year)

  • 0.00.51.01.52.02.5H2O2 PRODUCTION HEART MITOCHONDRIAnmoles H2O2/ min mg protSuccinate (+ Rotenone)Long-term Caloric Restriction (1 year)ACOCOR

  • Cx ICx IVCx IIICx IIQSuccinatePyruvate/MalateO2H2OcROTTTFAAA

  • 1,2-NAPHTOQUINONE

    ROTENONEFERRICYANIDEMENADIONEp-ClHg BENZOATEETHOXYFORMIC ANHYDRIDENADHQCx I

  • O2 CONSUMPTION HEART MITOCHONDRIAPyruvate/ malateLong-term Caloric Restriction (1 year)08162432nmoles O2/ min mg protACOCOR

  • 0.00.51.01.52.02.5FREE RADICAL LEAK HEART MITOCHONDRIAPyruvate/ malateLong-term Caloric Restriction (1 year)ACOCOR(%)**

  • 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.

  • 8-oxodG in HEART mtDNALong-term Caloric Restriction (1 year)

  • MITOCHONDRIAL ROS PRODUCTION RATE AGING RATERATE OF ACCUMULATION OF mtDNA MUTATIONS MITOCHONDRIAL DNACALORIC RESTRICTIONLONG-LIVEDANIMALS(-) (-)

  • 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.

  • 8-oxodG/105dG in mtDNA HEARTBRAIN0.01.02.03.04.05.0**WILD TYPEAMES DWARF

  • LOW [8-oxodG]Low repair ?Long-lived animalsRestricted animalsLow attackHIGH [8-oxodG]High (8-oxo mtDNArepair ? (post.mitot.)Short-lived animalsAd libitum animalsHigh attack(Low mitoch. ROS product.)(High mitoch. ROS product.)Low 8-oxodG mtDNArepair ? (post.mitot.)

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

  • Relationship between maximum longevity and linoleic acid (18:2n-6)and docosahexanoic acid (22:6n-3) contents in heart phospholipids of 8 mammalian species

  • MITOCHONDRIAL ROS PRODUCTION RATE AGING RATERATE OF ACCUMULATION OF mtDNA MUTATIONS MITOCHONDRIAL DNACALORIC RESTRICTIONLONG-LIVEDANIMALS(-) (-) DBI? MDA Prot. ox.?

  • OXYGEN RADICAL PRODUCTION IS NOT NECCESSARILY PROPORTIONAL TO OXYGEN CONSUMPTION

  • High rateof electron fluxROSLow rate of electron fluxROSROS

  • H2O2HOMOVANILLIC ACIDHORSERADISH PEROXIDASEDIMERFLUORESCENCE312 nm EXC420nm EMPositive fluorescent metodSpecific for H2O2SensitiveDoes not alter mitochondriaInstantaneous response to H2O2No antioxidant interference(Barja G. (2002) J. Bioenerg. Biomembr. 33:227-233

  • (DBI)(Endogenous generation of oxidative damage)

  • THE RATE OF GENERATION OF ENDOGENOUS DAMAGE IS THE CAUSE OF AGING

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

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