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 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.
Mecocci
P
P
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
MacGarvey
U
U
Kaufman
A E
AE
Koontz
D
D
Shoffner
J M
JM
Wallace
D C
DC
Beal
M F
MF
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction
D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine