Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction

Abstract

Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seems to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters. In addition, old rats also conserve the capacity to respond to 7weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA.

Keywords: %FRL; 8-oxo-7,8-dihydro-2′deoxyguanosine; 8-oxodG; Aging; BER; Complex I; DNA damage; DR; Dietary restriction; IGF; IIS; MFRTA; MetR; Mitochondria; PR; Reactive oxygen species; S-adenosylhomocysteine; S-adenosylmethyonine; SAH; SAM; base excision repair; dietary restriction; insulin-like growth factor; insulin/insulin-like growth factor signaling; methionine restriction; mitochondrial DNA; mitochondrial ROS production; mitochondrial free radical theory of aging; mitochondrial oxygen consumption; mtDNA; mtROSp; mtVO(2); nDNA; nuclear DNA; percentage free radical leak; protein restriction.