Delaying the mitochondrial decay of aging with acetylcarnitine.
Oxidative mitochondrial decay is a major contributor to aging. Some of this decay can be reversed in old rats by feeding them normal mitochondrial metabolites, acetylcarnitine (ALC) and lipoic acid (LA), at high levels. Feeding the substrate ALC with LA, a mitochondrial antioxidant, restores the velocity of the reaction (K(m)) for ALC transferase and mitochondrial function. The principle 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 (K(m)) 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 that increases with age). In old rats (vs. young rats), mitochondrial membrane potential, cardiolipin level, respiratory control ratio, and cellular O(2) uptake are lower; oxidants/O(2), neuron RNA oxidation, and mutagenic aldehydes from lipid peroxidation are higher. Ambulatory activity and cognition decline with age. Feeding old rats ALC with LA 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). A recent meta-analysis of 21 double-blind clinical trials of ALC in the treatment of mild cognitive impairment and mild Alzheimer's disease showed significant efficacy vs. placebo. A meta-analysis of 4 clinical trials of LA for treatment of neuropathic deficits in diabetes showed significant efficacy vs. placebo.
Ames
Bruce N
BN
Nutritional Genomics Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA. bames@chori.org
Liu
Jiankang
J
D000108:Acetylcarnitine / Q000494:pharmacology*; D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000187:drug effects; D002331:Carnitine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats
D018697:Nootropic Agents; D000108:Acetylcarnitine; D002331:Carnitine