Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain

Abstract

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/micrograms of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.

Oxidative stress in Parkinson’s disease

“…Their existence and importance in living systems was ignored (17). Oxidative stress has been implicated in the pathophysiology of many neurological disorders (18,19).…”

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

“…In AD brain ROS lead to protein oxidation [1,[7][8][9][10][11][12], lipid peroxidation [2,3], DNA and RNA oxidation [18][19][20], and neuronal dysfunction or death. Recent studies indicate that protein oxidation and lipid peroxidation in brain from mild cognitive impairment subjects [21,22], suggesting oxidative stress is an early event in the pathogenesis of AD.…”

Mitochondrial DNA repair in aging and disease

“…Early studies, using HPLC-electrochemical detection of the 8-oxoG, described 16-fold higher levels of 8-oxoG in mtDNA than in nDNA (23). Further studies revealed that 8-oxoG accumulates with age in nDNA and to a greater extent in mtDNA (24,21). However, others reported that the damage in mitochondria was overestimated, and its level is comparable to that of nuclear DNA (25,26).…”