OXIDATIVE DAMAGE TO MITOCHONDRIAL-DNA SHOWS MARKED AGE-DEPENDENT INCREASES IN HUMAN BRAIN

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We exa mined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measur ed the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DN A isolated from 3 regions of cerebral cortex and cerebellum from 10 no rmal humans aged 42 to 97 years. The amount of OH8dG, expressed as a r atio of the amount of deoxyguanosine (dG) or as fmol/mug of DNA, incre ased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a s ignificant 10-fold increase in the amount of OH8dG in mtDNA as compare d 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 f irst time that there is a progressive age-related accumulation in oxid ative damage to DNA in human brain, and that the mtDNA is preferential ly affected. It is possible that such damage may contribute to age-dep endent increases in incidence of neurodegenerative diseases.