Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle

Brierley, Elizabeth J.; Johnson, Margaret; Lightowlers, Robert N.; James, Oliver; Turnbull, Douglass M.

doi:10.1002/ana.410430212

Cited by 270 publications

(173 citation statements)

References 33 publications

(2 reference statements)

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“…complexes I, III, IV, and V)66 than that of mitochondrial enzymes that are entirely nuclear DNA encoded (e.g. complex II) 67. Such a situation would be reflected in muscle biopsies by fibres with an increased activity of SDH, as a compensation for, for example, the reduction in cytochrome oxidase (complex IV) activity 68.…”

Section: Discussionmentioning

confidence: 99%

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging

Barnouin

McPhee

Butler-Browne

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAs muscle capillarization is related to the oxidative capacity of the muscle and the size of muscle fibres, capillary rarefaction may contribute to sarcopenia and functional impairment in older adults. Therefore, it is important to assess how ageing affects muscle capillarization and the interrelationship between fibre capillary supply with the oxidative capacity and size of the fibres.MethodsMuscle biopsies from healthy recreationally active young (22 years; 14 men and 5 women) and older (74 years; 22 men and 6 women) people were assessed for muscle capillarization and the distribution of capillaries with the method of capillary domains. Oxidative capacity of muscle fibres was assessed with quantitative histochemistry for succinate dehydrogenase (SDH) activity.ResultsThere was no significant age‐related reduction in muscle fibre oxidative capacity. Despite 18% type II fibre atrophy (P = 0.019) and 23% fewer capillaries per fibre (P < 0.002) in the old people, there was no significant difference in capillary distribution between young and old people, irrespective of sex. The capillary supply to a fibre was primarily determined by fibre size and only to a small extent by oxidative capacity, irrespective of age and sex. Based on SDH, the maximal oxygen consumption supported by a capillary did not differ significantly between young and old people.ConclusionsThe similar quantitative and qualitative distribution of capillaries within muscle from healthy recreationally active older people and young adults indicates that the age‐related capillary rarefaction, which does occur, nevertheless maintains the coupling between skeletal muscle fibre size and capillarization during healthy ageing.

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Section: Discussionmentioning

confidence: 99%

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging

Barnouin

McPhee

Butler-Browne

et al. 2017

J cachexia sarcopenia muscle

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“…For example, rearranged mtDNAs found in cardiac or skeletal muscle (Brierley et al ., 1998;Bodyak et al ., 2001;Fayet et al ., 2002) commonly segregate to homoplasmy, or to high levels of heteroplasmy, resulting in demonstrable cellular dysfunction, e.g. COX-negative muscle fibre segments.…”

Section: Mtdna Rearrangements and Agingmentioning

confidence: 99%

The mitochondrial theory of aging: dead or alive?

Jacobs

2003

Aging Cell

108

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The mitochondrial theory of aging is based around the idea of a vicious cycle, in which somatic mutation of mtDNA engenders respiratory chain dysfunction, enhancing the production of DNA-damaging oxygen radicals. In turn, this is proposed to result in the accumulation of further mtDNA mutations. Finally, a bioenergetic crisis leads to overt tissue dysfunction and degeneration. A substantial body of circumstantial evidence seems to support this idea. However, the extent of detectable mtDNA mutation is far less than can easily be reconciled to this hypothesis, unless it is assumed that a subset of cells with much higher than average mtDNA mutation load is systematically lost by apoptosis. A rigorous test of the hypothesis remains to be undertaken, but would require a direct manipulation of the rate of mtDNA mutagenesis, to test whether this could alter the kinetics of aging.

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“…The presence of similar 8-oxodG levels at young and intermediate ages suggests that the flux of oxidative damage through mtDNA is maintained essentially constant during most of the life span (in young adults and at middle age), which would lead to a constant rate of accumulation of mtDNA mutations (25)(26)(27)(28)(29)(30)(31)(32). This would agree with the known fact that aging is a progressive phenomenon occurring at roughly the same rate throughout most of the life span of each species.…”

Section: Discussionmentioning

confidence: 99%

Effect of aging on mitochondrial and nuclear DNA oxidative damage in the heart and brain throughout the life-span of the rat

Herrero

Barja

2001

AGE

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The oxygen radical-induced DNA lesion 8-oxo,7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most commonly measured marker of oxidative DNA damage, which is currently considered a main cause of aging. However, a detailed study of the age-related variations of this marker in both mitochondrial (mtDNA) and nuclear (nDNA) DNA of post-mitotic organs throughout the life span has not been previously performed. In this investigation 8-oxodG steady-state levels were simultaneously measured in mtDNA and nDNA in the heart and brain of SpragueDawley rats at up to five different ages covering most of the adult life span, 4, 8, 12,17 and 24 months of age, using exactly the same digestion of DNA to deoxynucleosides and chromatographic procedures for mtDNA and nDNA. 8-oxodG levels were maintained without changes during young and middle age in all cases, but showed statistically significant increases at the older ages studied in the majority of the kinds of DNA investigated. These age-related increases in oxidative damage occurred in brain nDNA at 17 and 24 months of age, in heart nDNA at 24 months of age, and in brain mtDNA at 24 months of age, whereas no significant age-related changes were detected in heart mtDNA. Besides, 8-oxodG levels were various fold higher in mtDNA than in nDNA, both in brain and heart, at all the ages studied. The results show that oxidative damage to DNA is higher in the mtDNA than in the nDNA of postmitotic tissues throughout the whole life span of the rat and that and increase in mtDNA and nDNA oxidative stress occurs in most cases in old animals.

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Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle

Cited by 270 publications

References 33 publications

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging

The mitochondrial theory of aging: dead or alive?

Effect of aging on mitochondrial and nuclear DNA oxidative damage in the heart and brain throughout the life-span of the rat

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