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

TLDR

Oxidative DNA damage accumulates with age and may contribute to neurodegenerative disease risk. We examined age‑related accumulation of oxidative damage to nuclear and mitochondrial DNA in human brain tissue. We measured 8‑hydroxy‑2′‑deoxyguanosine in DNA from three cortical regions and cerebellum of 10 normal adults aged 42–97. Oxidative damage to DNA rises with age in human brain, with mitochondrial DNA showing a markedly steeper increase—overall a 10‑fold higher level than nuclear DNA and a 15‑fold rise in individuals over 70—demonstrating preferential accumulation in mtDNA.

Abstract

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 (OH 8 dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH 8 dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/μg 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 OH 8 dG 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.