Senior Scholar Award in Aging
Children's Hospital, Oakland Research Institute
Reversal of Mitochondrial Decay: From Rats to Humans
Our major interest is the decay of mitochondria with age due to the oxidative damage of mtDNA, proteins, and lipids. We are making progress in reversing some of this mitochondrial decay in old rats by the feeding of normal mitochondrial metabolites at high levels; we now wish to extend this work to humans. Our second major interest is to determine the optimum micronutrient intake for minimizing damage to human DNA, including mtDNA, as a step toward delaying aging and preventing cancer and other degenerative diseases associated with aging.
Mitochondrial decay in Aging.
Aging appears to be due in good part to the oxidants produced by mitochondria as by-products of normal metabolism. In old rats mitochondrial membrane potential, cardiolipin levels, respiratory control ratio, and cellular O2 consumption are lower than in young rats, whereas oxidant-leakage/O2 consumed, and level of mutagenic aldehydes from lipid peroxidation are higher. Ambulatory activity also declines markedly in old rats. Feeding old rats the mitochondrial metabolites acetyl carnitine and lipoic acid for a few weeks, restores mitochondrial function, lowers oxidants to the level of a young rat, and increases ambulatory activity. Thus, for rats at least, acetyl carnitine and lipoic acid can be considered necessary for health in old age and are therefore "conditional" micronutrients. The mitochondrial restoration suggests a plausible mechanism for the reversal of decay: with age, increased oxidative damage to proteins and lipid membranes causes a deformation of structure of key enzymes, with a consequent lessening of affinity (KM) for the enzyme substrate; an increased level of the substrate restores the velocity of the reaction and thus function. We wish to investigate both the mechanism and the effect on brain function in rats. We propose to extend this work to humans using DNA microarrays as an assay. We will compare lymphocytes in young and old rats and humans for measuring the age-associated gene transcription changes that are reversed in rats by carnitine and lipoate supplementation as a guide for assaying humans.
Micronutrients and the Degenerative Diseases of Aging.
Deficiencies of folic acid, niacin, iron, zinc, or vitamins B12, B6, C, or E appear to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative base lesions, or both. The percentage of the U.S. population that has a low intake (< 50% of the RDA) for each of these eight micronutrients ranges from 2% to 20%; half of the population may be deficient in at least one of these micronutrients. We have shown that folate deficiency breaks chromosomes due to massive incorporation of uracil in human DNA (4 million/cell) with subsequent single strand breaks in DNA formed during base excision repair: two nearby single strand breaks on opposite strands cause a chromosome break. The level of folate intake at which we detected high uracil in DNA and chromosome breaks was present in 10% of the U.S. population and close to half of poor urban minorities. Deficiency of vitamin B12 (14% of elderly) and B6 (10% of U.S.) also causes high uracil in human DNA, as indicated by unpublished evidence from our laboratory and as expected from mechanistic considerations. We are currently attempting to determine the levels of various micronutrients that minimize both nuclear and mitochondrial DNA damage in humans.