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

Abstract

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.

Effect of time of restriction on the decrease in mitochondrial H2O2 production and oxidative DNA damage in the heart of food‐restricted rats

“…Oxidative DNA damage is specially important for aging. Changes in oxidative DNA damage have been studied during aging (Herrero and Barja, 2001;Kaneko et al, 1996), and in comparative studies (Barja and Herrero, 2000). However, relatively few studies concerning the effect of CR on oxidative DNA damage have been performed, and most of them were developed in non-postmitotic tissues.…”

Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production–DNA damage mechanism?

“…Furthermore, some of the base adducts, like the most commonly measured 8-oxo-7,8-dihydro-2k-deoxyguanosine (8-oxodG), can cause DNA mutations during DNA replication or repair. Similarly to protein oxidative damage, many investigations have found that tissue steady-state levels of 8-oxodG show a moderate increase during aging in brain, heart or liver nuclear (nDNA) or mitochondrial (mtDNA) DNA in rodents and humans (Fraga et al, 1990 ;Mecocci et al, 1993 ;Sohal, Agarwal & Sohal, 1995 ;Asunción et al, 1996;Kaneko, Tahara & Matsuo, 1996;Lezza et al, 1999;Herrero & Barja, 2001), while again such increases were not detected in other cases (Sai et al, 1992;Hirano et al, 1996;Muscari et al, 1996). The occurrence of an increase in oxidative damage to DNA during aging has been recently confirmed using a technique which is thought to minimize the possibility of artefactual DNA oxidation during sample preparation (Hamilton et al, 2001).…”

Vitamin E and Age Alter Liver Mitochondrial Morphometry

“…They suggested that with age, mitochondria undergo morphological adaptations in an effort to meet metabolic demands. A more recent study 16 reported an age effect on oxidative damage of brain mtDNA in the rat, suggesting a flux of free radical damage to DNA, especially in the late stages of life. An increase in mitochondrial size in the aging rat myocardium was reported by Cosmas et al 5 They found that senescence was associated with a shift in mitochondrial size distributions toward a greater percentage of larger organelles, consistent with a decline in physiologic function.…”