Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart

Abstract

The effect of caloric restriction (CR) (40%) on the rates of mitochondrial H2O2 production and oxygen consumption and oxidative damage to nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) was studied for short‐term (6‐wk) and long‐term (1‐year) periods in the heart of young and old rats. Short‐term CR did not change any of the parameters measured. However, long‐term CR significantly decreased the rate of mitochondrial H2O2 generation (by 45%) and significantly lowered oxidative damage to mtDNA (by 30%) without modifying damage to nDNA. The decrease in H2O2 production occurred exclusively at the complex I free radical generator of the respiratory chain. The mechanism allowing that decrease was not a simple decrease in mitochondrial oxygen consumption. Instead, the mitochondria of caloric‐restricted animals released fewer oxygen radicals per unit electron flow in the respiratory chain. This was due to a decrease in the degree of reduction of the complex I generator in caloric‐restricted mitochondria. The results are consistent with the concept that CR decreases the aging rate at least in part by decreasing the rate of mitochondrial oxygen radical generation and then the rate of attack on mtDNA.

Long-lived Ames dwarf mice: Oxidative damage to mitochondrial DNA in heart and brain

“…In agreement with this theory, both long-lived animals and caloric restdcted animals show decreased levels of mitochondrial oxygen radical generation and 8-oxodG in mtDNA in their heart and brain (6,7,21). The results obtained in this report show that 8-oxodG is also diminished in the mitochondda of long-lived Ames dwarf mice.…”

“…After initial homogenization of the organs in a buffer containing 5mM EDTA, mtDNA was isolated by the method of Latorre et al (24) adapted to mammals (6,7). mtDNA digestion to deoxynucleosides and 8-oxodG and dG HPLC analyses were performed as described (25).…”

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

“…Caloric restriction also retards age related diseases, studies of dietary links to Parkinson's disease and Alzheimer's suggest that individuals with a low calorie intake are at reduced risk (Matteson et al, 2002). Caloric restriction was shown to specifically decrease ROS production at complex I of the electron transport chain (Gredilla et al, 2001) giving further strength to the argument that mitochondrial ROS are major contributors to aging and potentially the development of age-onset diseases.…”

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…On a biochemical level, free radicals are implicated in senescence and in mouse studies, DR decreases free-radical production from the mitochondria (Gredilla et al 2001). In worms, insulin/IGF mutants have an increase in free-radical resistance (Gredilla et al 2001;Honda and Honda 1999).…”

“…On a biochemical level, free radicals are implicated in senescence and in mouse studies, DR decreases free-radical production from the mitochondria (Gredilla et al 2001). In worms, insulin/IGF mutants have an increase in free-radical resistance (Gredilla et al 2001;Honda and Honda 1999). Although free radicals have been correlated with senescence, in both mice and worms, there is increasing evidence that they may not be the causative agent (Doonan et al 2008;Ran et al 2007;Van Raamsdonk and Hekimi 2009;Van Remmen et al 2003;Yen et al 2009).…”