Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

Abstract

The main purpose of the present study was to determine whether specific regions of the mouse brain exhibit different age-related changes in oxidative stress, as indicated by glutathione redox state and the level of protein-glutathionyl mixed disulfides. Comparison of 3-and 21-month-old mice indicated an age-related decrease in the ratio of reduced to oxidized glutathione (GSH:GSSG) as well as a prooxidizing shift in the calculated redox potential (ranging from 6 to 15 mV) in the cortex, hippocampus, striatum and cerebellum, whereas there was little change in the brainstem. This pro-oxidizing shift in redox state was due to a modest decrease in GSH content occurring in all the brain regions examined, and elevations in GSSG amount that were most pronounced in the striatum and cerebellum. The regional changes in glutathione redox state were paralleled by increases in the amounts of protein-mixed disulfides. A reduction of caloric intake by 40% for a short period (7 weeks), implemented in relatively old mice (17 months), increased the GSH:GSSG ratio and redox potential at 19 months in the same brain regions that exhibited age-related decreases. The effects of age and caloric restriction were qualitatively similar in C57BL/6 and DBA/2 mice. However, young DBA/2 mice, which do not show extension of life span in response to long-term caloric restriction, had lower GSH:GSSG ratios and higher protein-mixed disulfides than age-matched C57BL/6 mice. The current findings demonstrate that oxidative stress, as reflected by glutathione redox state, increases in the aging brain in regions linked to age-associated losses of function and neurodegenerative diseases.

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

“…Several studies have indicated that a disturbance in the redox state of an organism leads to aging and age-related diseases [35–37]. Due to these unique features, Trx, along with thioredoxin interacting protein (Txnip), has been shown to play very important roles in physiology and its dysregulation could be involved in various diseases [38].…”

Changes in dihydrolipoamide dehydrogenase expression and activity during postnatal development and aging in the rat brain

“…Indeed, the degree of age-associated oxidative stress/damage differs markedly among different regions of the brain , Rebrin, et al, 2007. Furthermore, studies of α-ketoglutarate dehydrogenase complex activity in neurodegenerative diseases have also suggested a dependence on brain region (Klivenyi, et al, 2004).…”

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…Cysteine availability is rate-limiting for glutathione synthesis (Richman and Meister 1975;Suh et al 2004a). In this regard, there is considerable evidence that glutathione synthesis and glutathione tissue levels tend to decline in rodents and humans as they age (Suh et al 2004a;Rebrin and Sohal 2008;Rebrin et al 2007;Droge et al 2006;Sekhar et al 2011;Wang et al 2003;Lean et al 2005). This appears to reflect, in turn, an age-related decline in expression and function of the Nrf2 transcription factor (Suh et al 2004a;Suh et al 2004b;Ungvari et al 2011;Shih and Yen 2007).…”

“…In aging mice, the content of reduced glutathione in the brain's cortex (hippocampus) and striatum is about 20-25 % lower than in young mice, whereas the ratio of reduced to oxidized glutathione is about 50 % as highindicative of a major increase in brain oxidative stress during aging (Rebrin et al 2007). Beginning at 18 months of age, rats were treated with a daily antioxidant cocktail-providing NAC, lipoic acid, and vitamin E; others were employed as controls (Thakurta et al 2014).…”