Source: Professor Daniel Ziegler of the Diabetes Research Institute, ... Minerals.
Vitamins. * USDA What we Eat in America (NHANES 2001-2002) Sept. 2005 ...
Delaying the Degenerative Diseases of Aging
O2
e-
O2-
e-
H2O2
e-
•OH
Bruce N. Ames Children‟s Hospital Oakland Research Institute Professor, University of California, Berkeley
e-
H 2O
5 August „07 DDP Oakland
Estimated oxidative DNA adducts per rat liver cell 70,000
Old (26-mo)
60,000
67,000
50,000
40,000 30,000 20,000 10,000 0
Young (4-mo)
24,000
carbonyl content (nmol/mg protein)
carbonyl content (nmol/mg protein)
6
2
5 4
1
3 0
2 0
20
40
60 Years
80
100
3
12
20
26 *
Months
Source: E. Stadtman, Science 257, 1220-1224 (1992)
160
MDA (pmol/mg protein) 140
Young
*
Old
*
120
100 80 60
*
40 20
*
*
0
Brain
Liver
Heart
Kidney
Lung
6
Proc. Natl. Acad. Sci. USA Vol. 91, pp. 10771-10778, November 1994
Review Oxidative damage and mitochondrial decay in aging (bioenergetics / mitochondrial DNA / cardiolipin / acetyl-L-carnitine / neurodegeneration)
Mark K. Shigenaga, Tory M. Hagen, and Bruce N. Ames* Division of Biochemistry and Molecular Biology, 401 Barker Hall, University of California, Berkeley, CA 94720
Contributed by Bruce N. Ames, July 27, 1994
H+
Cellular Cytoplasm
H+
H+
H+
H+
H+
Mitochondrial Outer Membrane H+
Intermembrane Space
Mitochondrial Matrix H+
H+
CoQ
I
Inner Membrane
H+
NAD+
H+
H+
FAD
CytC
H+ Succinate
Fumarate L-Malate
NADH Pyruvate NADH Oxaloacetate Dehydrogenase complex Acetyl-Co-A Citrate Synthase
ATP CITRIC ACID CYCLE Citrate
H+
H+
V
IV
H+ FADH2
H+
H+
III
II
NADH
H+
O2
H2O
H+
ADP + ATP H
Succinyl-Co-A NADH
-Ketoglutarate Dehydrogenase
-Ketoglutarate Isocitrate
NADH
Complex
H+
H+
9
Mitochondria from old rats compared to those from young rats: 1) Lower Cardiolipin
2) Lower Membrane Potential 3) Lower Oxygen Utilization
4) Increased Oxidant Leakage
Cardiolipin (µg per 106 Cells)
Cardiolipin Levels in 3 and 24 Month Old Rat Hepatocytes 30
20 **
10
0
Young
Old 10
R123 Fluorescence in old and young rat hepatocytes 0.03
Normal cell number
Old
0.02
Young
0.01
0.00 10
100
1000
Fluorescence/cell 11
L-Carnitine/Acetyl-L-Carnitine (ALCAR) • Transports long-chain fatty acids into mitochondria • Removes short- and medium-chain fatty acids that accumulate
• Mediates the ratio of acetyl-CoA/CoA • Decreases with age in plasma and in brain • Improves cognitive function in rats 12
Cardiolipin (µg per 10 cells)
Effect of ALCAR Supplementation on Cardiolipin Levels 30
20
+ ALCAR
** 10
0 Young
Old 14
Normalized Cell Number Normalized Cell Number
NO ALCAR
YOUNG
WITH ALCAR
OLD
NO ALCAR
WITH ALCAR
R123 Fluorescence in Young and Old Rat Hepatocytes
R--Lipoic Acid (LA) in mitochondria • LA reduced to dihydrolipoic acid, a potent antioxidant, & chelator of Fe & Cu • Coenzyme of pyruvate and -ketoglutarate dehydrogenases • Involved with carbohydrate utilization for ATP production
15
Fl. Units/O2 Consumed per Minute
Lipoic Acid Lowers Mitochondrial Oxidants in Old Rats
**
20
10 + LA + LA 0 Young
Old
80 70
***p
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