Authors: 
B.N. Ames
Category: 
Invited
Conference: 
Abstract: 

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.