 | INCREASING HEALTHY LIFE SPAN: CONVENTIONAL MEASURES AND SLOWING THE INNATE AGING PROCESS
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 959:133-166 (2002)
© 2002 New York Academy of Sciences
Delaying Brain Mitochondrial Decay and Aging with Mitochondrial Antioxidants and Metabolites
JIANKANG LIUa,
HANI ATAMNAa,
HIROHIKO KURATSUNEb AND
BRUCE N. AMESa
aDivision of Biochemistry and Molecular Biology, University of California, Berkeley, California 94720, USA and Children's Hospital Oakland Research Institute, Oakland, California 94609, USA
bDepartment of Hematology and Oncology, Osaka University, Osaka 565-0871, Japan
Address for correspondence: Professor Bruce Ames, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Voice: 510-450-7625; fax: 510-597-7128.
bnames{at}uclink4.berkeley.edu
Ann. N.Y. Acad. Sci. 959: 133-166 (2002).
Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (  -phenyl- N-t-butyl nitrone and N-t-butyl hydroxylamine) on the age-associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltrasferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant-induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.
Key Words: acetyl-l-carnitine • aging • brain • N-t-butyl hydroxylamine • lipoic acid • memory • mitochondria • neurotoxicity • oxidative damage • -phenyl- N-t-butyl nitrone
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