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Christopher Driver

Publications and source records attributed to Christopher Driver.

5 recordsLinked to original sources

What the papers say: where is the somatic mutation that causes aging?

It has been proposed that somatic mutations make major contributions to aging. The first paper, based on a gene knock-in mouse, supports a contributory role for mutation in mtDNA in aging, but does not support a damaged-mtDNA-producing-more-damaged-mtDNA hypothesis. The second paper indicates some GC-rich sequences in the nuclear DNA are more sensitive to oxidative damage than mtDNA. As a result, key genes involved in brain function and mitochondrial function are progressively inactivated with age. Failure in these nucleus-encoded mitochondrial genes may be a primary reason for mitochondrial failure in old age.

Aging↗

The contribution by mitochondrially induced oxidative damage to aging in Drosophila melanogaster.

Strains of Drosophila melanogaster have been generated that vary in the mitochondrial genome and have a common nuclear genome. Tetracycline was used to cure the strains of the endocommensal bacteria, Wolbachia, which is transmitted maternally. Variation in the tetracycline responsive agent contributed substantially to variation in longevity and production of metabolic oxidants. Changes in diurnal cycle of activity have been investigated: such changes should be responsive to metabolism-related damage because of the role of the very active neurons, retinal cells and muscle. The metabolic oxidant model predicts that longevity and production of metabolic oxidants should be negatively correlated, and that deterioration of behavior with age and metabolic oxidant production should be positively correlated. Only the first prediction was verified: rate of change in behavior correlated with metabolic oxidants, consistent with a role of metabolic oxidants in this age-related change. However, the data indicates a role for mitochondria in determination longevity, other than by production of metabolic oxidants.

Animals↗

Variable effects of vitamin E on Drosophila longevity.

Vitamin E has been used widely in invertebrate experiments where it usually acts to prolong life span. Conversely in vertebrates it has been less successful. In some cases, experiments in rodents show no effect of vitamin E on longevity. Consequently, the suggestion has been made that anti-oxidants do not effect ageing in vertebrates. In more extensive experiments with Drosophila melanogaster, vitamin E exerted both life span extending and toxic effects. At 20 micro g/ml, the life span was increased by 16%, although there was no effect at higher or lower concentrations. At 200 micro g/ml, vitamin E protected Drosophila against paraquat toxicity. At this concentration, vitamin E had no effect on longevity in one set of experiments, and shortened the life span in another set. Apparent toxicity of vitamin E was also observed in behavior experiments. We suggest that inactivity of vitamin E that has been reported by some authors is due to antagonistic actions of a toxic effect and a beneficial anti-oxidant action. This complex response to vitamin E will limit its use for clinical and investigative work on ageing.

Aging↗

How to re-energise old mitochondria without shooting yourself in the foot.

In old humans and pathologies associated with mitochondrial mutations, deletions in mitochondrial DNA have been associated with failing function. Investigations have been reported where treatment with a number of micronutrients, such as coenzyme Q10, have been used to re-energise failing tissues. Bioenergy changes in ageing Drosophila have been observed which indicate similar changes in mitochondrial function in old age. Reserves of carbohydrate and fat fall and food intake rises. Biochemical changes include falling mitochondrial enzymes. Mitochondrial DNA contains increased amounts of sequences corresponding to deletions. Both coenzyme Q10 and nicotinamide in large doses successfully reversed bioenergy changes in aged Drosophila. However, only nicotinamide was able to reduce short term mortality and increase life span, whereas coenzyme Q10 increased mortality and reduced life span. Production of reactive oxygen species (ROS) was increased in coenzyme Q10 treated flies, whereas nicotinamide reduced ROS production. It is suggested that ROS production may account for these longevity differences. Large doses of two micronutrients have been successful in reversing the age-associated bioenergy deficit in Drosophila. This response is similar to clinical reports of re-energising tissues where mitochondrial damage has been observed. However, this work highlights a danger for some micronutrients, such as coenzyme Q10, that clinical efficacy may be limited by increased ROS production.

Animals↗