Delaying the mitochondrial decay of aging in the brain

Abstract

Oxidative mitochondrial decay is a major contributor to aging and neural degeneration. 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 declines with age. Feeding old rats for a few weeks with acetyl- l-carnitine (ALCAR), a mitochondrial metabolite, plus R-lipoic acid (LA), a mitochondrial coenzyme and antioxidant, restores mitochondrial function; lowers oxidants, neuronal RNA oxidation, and mutagenic aldehydes; and increases rat ambulatory activity and cognition (Skinner box/Morris water maze). The mechanism 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 substrate. The loss with age of carnitine acetyl transferase binding affinity can be mimicked by reacting it with malondialdehyde (a lipid peroxidation product which increases with age). Feeding the substrate ALCAR with LA restores the velocity of the reaction, K m for ALCAR and CoA, and mitochondrial function. Heme biosynthesis is predominantly in the mitochondria. Interfering with heme synthesis causes specific loss of complex IV with consequent release of oxidants and neuronal degeneration. Iron deficiency (25% of menstruating women in the US ingest <50% of the RDA) also causes release of oxidants and mitochondrial decay, presumably through lack of heme, accelerating brain aging. Vitamin B6 or zinc inadequacy (10% of Americans ingest <50% of each RDA) should also cause a heme deficiency.