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RESEARCH INTERESTS

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Introduction
The decay of mitochondria with age due to oxidation of RNA/DNA, proteins, and lipids is a major interest; we are making progress in reversing some of this decay in old rats by feeding them normal mitochondrial metabolites at high levels and are extending the work to humans. Another major interest is determining optimum micronutrient intakes for minimizing human DNA damage as an aid in the prevention of cancer and other degenerative diseases associated with aging.

Delaying the Mitochondrial Decay of Aging
Oxidative mitochondrial decay is a major contributor to aging [1-5]. 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 [3, in prep.] Ambulatory activity and cognition declines with age. Feeding old rats the normal mitochondrial metabolites 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) [6-9, 10, in prep.]. With age, increased oxidative damage to protein and mitochondrial membranes and the loss of cardiolipin causes a deformation of structure of key enzymes, with a consequent lessening of affinity (Km) for the enzyme substrate [11]; increasing the level of the substrate (acetyl carnitine) restores the velocity of the reaction, membranes, Km for acyl carnitine transferase, and function [in prep.].



DNA Damage Increases with Age
Apurinic/apyrimidinic (AP) sites are common DNA lesions that arise from spontaneous depurination or by base excision repair (BER) of modified bases. A biotin-containing aldehyde-reactive probe (ARP) is used to measure AP sites in living cells [12]. The assay was applied to living cells and nuclei. The number of AP sites in old human fibroblasts (IMR90 cells) was about two to three times higher than that in young cells, and the number in human leukocytes from old donors was about seven times that in young donors. The repair of AP sites was slower in senescent cells compared with young IMR90 cells. An age-dependent decline is shown in the activity of the glycosylase that removes methylated bases in IMR90 cells and in human leukocytes. The decline in excision of methylated bases from DNA suggests an age-dependent decline in 3-methyladenine DNA glycosylase, a BER enzyme responsible for removing alkylated bases.



Micronutrients and DNA Damage
Approximately forty micronutrients are required in the human diet. Deficiency of vitamins B12, folic acid, B6, niacin, C, or E, or iron, or zinc, appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both [11]. The percentage of the U.S. population that has a low intake (<50 percent of the RDA) for each of these eight micronutrients ranges from 2 percent to 20+ percent; half of the population may be deficient in at least one of these micronutrients [11]. We have shown [13] 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 the chromosome to fall apart. The level of folate where we see high uracil and breaks was present in 10percent of the U.S. population and close to half of poor urban minorities, due to poor diets. Vitamin B12 (14 percent elderly) and B6 (10 percent of U.S.) deficiencies also cause high uracil in human DNA and chromosome breaks as indicated by our new evidence and as expected from mechanistic considerations. We are currently attempting to determine the level of these three vitamins that minimizes both nuclear and mitochondrial DNA damage in humans. We have evidence that inadequate iron (19 percent of women of menstruating age in the U.S.) causes oxidative damage to mtDNA in rats. Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions a day is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake [11]. A number of other degenerative diseases of aging are also associated with low fruit and vegetable intake. Eighty percent of American children and adolescents and 68 percent of adults do not eat five portions a day [11]. Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important, and should be compared for perspective [11, 14, 15].



Micronutrients and Cognitive Function
We are studying the role of micronutrient inadequacy, particularly folate, B12, B6, iron, and zinc on neuronal damage and cognitive function in rats. Considerable epidemiological evidence in humans shows an association between low intakes and cognitive dysfunction. Much circumstantial evidence supports the plausibility of a direct causal relationship.



Micronutrients and Sperm
We are investigating the effect of inadequate micronutrient intake on genetic damage to sperm [11]. We have shown that folic acid deficiency decreases the sperm count in the rat by 90 percent, and that uracil is found in the sperm DNA of men on low fruit and vegetable diets. Our recent work in humans [16] shows an inverse association between the level of the non-methyl THF pool, but not the methyl-THF pool, with both sperm count and quality, consistent with a uracil misincorporation mechanism. We had previously shown that men with low vitamin C intake had more oxidative damage to their sperm DNA and that male smokers (smoking depletes the vitamin C level markedly) had more oxidative damage to their sperm [11]. Recent epidemiology supports the notion that smoking males have more offspring with childhood cancer.



The Metabolic Tune-up
Tuning-up human metabolism, which varies with genetic constitution and changes with age, is likely to be a major way to minimize DNA damage, improve health, and prolong healthy lifespan.

 

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