Delaying the Mitochondrial Decay of Aging
Bruce N. Ames
U.C., Berkeley/CHORI, 5700 MLK, Jr. Way, Oakland, CA 94609, USA
Mitochondria decay with age due to oxidation of RNA/DNA, proteins, and
lipids. Oxidative mitochondrial decay is a major contributor to aging.
We are making progress in reversing some of this decay in old rats by
feeding them normal mitochondrial metabolites (acetyl carnitine and
lipoic acid) at high levels (1-3). The principle behind this effect
appears to be that with age increased oxidative damage to protein
causes a deformation of structure of key enzymes, with a consequent
lessening of affinity (Km) for the enzyme substrate. The effect of age
on the enzyme binding affinity can be mimicked by reacting it with
malondialdehyde (a lipid peroxidation product). Feeding the substrate
(acetyl carnitine) with lipoic acid, a mitochondrial antioxidant,
restores the velocity of the reaction, Km for acyl carnitine
transferase, and mitochondrial function. In old rats (vs. young rats)
mitochondrial membrane potential, cardiolipin level, respiratory
control ratio, and cellular O2 uptake are lower; oxidants/02, neuron
RNA oxidation, and mutagenic aldehydes from lipid peroxidation are
higher. Ambulatory activity and cognition declines with age. Feeding
old rats acetyl carnitine and lipoic acid for a few weeks restores
mitochondrial function; lowers oxidants, neuron RNA oxidation, and
mutagenic aldehydes; and increases rat ambulatory activity and
cognition (as assayed with the Skinner box and Morris water maze).
Common vitamin and mineral deficiencies accelerate mitochondrial decay.
Heme biosynthesis is predominantly in the mitochondria. Interfering
with heme synthesis causes specific loss of Complex IV with consequent
release of oxidants and mitochondrial decay (4) in the brain complex IV
inactivation mimics the neurodegeneration of aging and Alzheimer's
disease. Iron deficiency (2 billion women in the world; 25% of U.S.
menstruating women are <50% of the RDA) also causes release of oxidants
and mitochondrial decay (5) presumably through lack of heme (4). Other
common vitamin and mineral deficiencies also cause a heme deficiency
and will be discussed.
1. Liu, J., Killilea, D. & Ames, B. N. (2002) Proc Natl Acad Sci U S A 99, 1876-1881.
2. Liu, J., Head, E., Gharib, A. M., Yuan, W., Ingersoll, R. T., Hagen, T. M., Cotman, C. W. & Ames, B. N. (2002) Proc Natl Acad Sci U S A 99, 2356-2361.
3. Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., Bartholomew, J. C. & Ames, B. N. (2002) Proc Natl Acad Sci U S A 99, 1870-1875.
4. Atamna, H., Killilea, D.W., Killilea, A.N., & Ames, B.N. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 14807-14812.
5. Walter, P. W., Knutson, M. D., Paler-Martinez, A., Lee, S., Xu, Y., Viteri, F. E. & Ames, B. N. (2002) Proc Natl Acad Sci U S A 99, 2264-2269.
Key words:
Problems or questions regarding this site should be directed to
the organiser