Biomedical subjects
E J Brierley
Publications and source records attributed to E J Brierley.
Role of mitochondrial DNA mutations in disease and aging.
Since Harman in 1972 first proposed a role in the process of aging for the mitochondrial genome, a wealth of evidence has been accumulated to support this theory. We discuss the hereditary mitochondrial DNA disorders, which we believe may give insight into both normal aging and neurodegenerative conditions. We then review the evidence for the role of mitochondrial DNA mutations in both aging and age-related disorders and also discuss new approaches for investigating the mitochondrial genome at a single cell level, by observing the activity of the mitochondrial enzyme cytochrome c oxidase.
Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle.
It has been proposed that one mechanism for nerve and muscle dysfunction with age involves the mitochondria. Mitochondria contain the only DNA outside the nucleus in mammalian cells. Mitochondrial DNA (mtDNA) has a high mutation rate, and low levels of pathogenic mutations have been found in tissues from elderly subjects. However, the role of these mutations in the aging process is uncertain unless a mechanism can be identified that would lead to a biochemical defect. In muscle tissue from normal elderly subjects we show that there are muscle fibers with very low activity of cytochrome c oxidase, suggestive of a mtDNA defect. In these cytochrome c oxidase-deficient fibers we have found very high levels of mutant mtDNA. In addition, different mtDNA mutations are present in different fibers, which explains why there is a low overall incidence of an individual mutation in tissues from elderly subjects. These studies show a direct age-related correlation between a biochemical and genetic defect in normal human tissues and that mtDNA abnormalities are involved in the aging process in human muscle.
Reversal of a mitochondrial DNA defect in human skeletal muscle.
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Mitochondrial involvement in the ageing process. Facts and controversies.
Mitochondria are believed to be involved in human ageing. Whilst it is clear that various mitochondrial DNA mutations do accumulate in human tissues with age, whether or not they interfere with respiratory chain function is uncertain. We question the results of previous studies which have measured respiratory chain function in human skeletal muscle with age. Whilst cytochrome c oxidase deficient fibres are a real finding in skeletal muscle, the contribution of mitochondrial DNA mutations to human ageing is still controversial. Our results show for mitochondria to be involved in ageing then it must be through a more subtle mechanism than a global decline in respiratory chain function.
Normal respiratory chain function in patients with low-tension glaucoma.
OBJECTIVE: To test the hypothesis that low-tension glaucoma has a pathogenesis similar to Leber's hereditary optic neuropathy and results from a defect in the mitochondrial respiratory chain. METHODS: Mitochondrial fractions were prepared from skeletal muscle samples collected from eight subjects with low-tension glaucoma. Their oxidative metabolism was compared with that of age- and sex-matched controls. Skeletal muscle DNA prepared from the subjects with glaucoma was also screened for the 3,460, 11,778, and 14,484 mitochondrial DNA mutations that are associated with Leber's hereditary optic neuropathy. RESULTS: No subject with low-tension glaucoma had a defect in respiratory chain activity or one of three mitochondrial DNA mutations that are commonly associated with Leber's hereditary optic neuropathy. CONCLUSION: Although these results do not exclude the possibility that low-tension glaucoma is caused by an organ-specific defect of mitochondrial function, we have excluded a systemic defect of the mitochondrial respiratory chain.
Effects of physical activity and age on mitochondrial function.
It has been proposed that ageing results from the accumulation of mitochondrial DNA mutations with age which interfere with respiratory chain ATP production. Insufficient ATP production impairs cell function, and tissue dysfunction ensues, leading to morbidity, decline and eventually death. Supporting this theory, mitochondrial DNA mutations accumulate with age and respiratory chain function declines dramatically in human skeletal muscle. However, the extent of decline in respiratory chain function is greater (50%) than anticipated from the low levels of mitochondrial DNA mutations (< 1%) observed in aged muscle. We hypothesized that an age-related reduction in physical activity could be an important factor in this decline and thus studied the influence of chronological age on muscle mitochondria in subjects matched for levels of physical activity. In this carefully selected group, there was little correlation between oxidative metabolism and age. However, several parameters of respiratory chain function did correlate with markers of physical activity (activity score and handgrip strength). Our results suggest that reduced physical activity is a major contribution to the decline in mitochondrial oxidations during ageing. Physical activity ameliorates and may even mask mitochondrial 'ageing' in muscle.
Reduced awareness of hypoglycaemia in the elderly despite an intact counter-regulatory response.
We investigated awareness of hypoglycaemia and its counter-regulatory hormone response in six young (ages 24-49, mean 30 years) and seven elderly (ages 65-80, mean 72 years) healthy non-diabetic subjects. A hyperinsulinaemic glucose clamp was used to control blood glucose level on two separate occasions. During the hypoglycaemic study, blood glucose was lowered in a stepwise manner to plateaus of 3.5, 3.0 and 2.5 mmol/l. A symptom score, visual reaction time test and digit symbol substitution test was completed pre-study, and at the end of each plateau. Pulse rate, blood pressure and counter-regulatory hormone measurements were taken every 15-30 min. The euglycaemic study was identical except that blood glucose remained at the fasting level. During hypoglycaemia, the elderly group had lower symptom scores than the young group (total relative score at glucose 2.5 mmol/l, mean +/- SEM: elderly -1 +/- 2.5, young 23 +/- 6.7, p < 0.01) and fewer individual symptoms despite a similar counter-regulatory hormone response. There was no difference in deterioration of the visual reaction times or digit symbol substitution scores during hypoglycaemia between the age groups. Unlike the young group, the elderly subjects had no tachycardia in response to hypoglycaemia. Their reduced awareness of hypoglycaemia may be due to an impaired end-organ response to counter-regulatory hormones, resulting in fewer symptoms.