Diet plays a key role in determining the longevity of the organisms since it has been demonstrated that glucose restriction increases life span whereas a high-glucose diet decreases it. However, the molecular basis of how diet leads to the aging process is currently unknown. We propose that the quantity of glucose that fuels respiration influences reactive oxygen species generation and glutathione levels, and both chemical species impact in the aging process. Herein, we provide evidence that mutation of the gene GSH1 in Saccharomyces cerevisiae diminishes glutathione levels. Moreover, glutathione levels were higher with 0.5% than in 10% glucose in the gsh1Δ and wild-type strains. Interestingly, the chronological life span was lowered in the gsh1Δ strain cultured with 10% glucose but not under dietary restriction. The gsh1Δ strain also showed inhibition of the mitochondrial respiration in 0.5 and 10% glucose but only increased the H O levels under dietary restriction. These results correlate well with the GSH/GSSG ratio, which showed a decrease in gsh1Δ strain cultured with 0.5% glucose. Together, these data indicate that glutathione exhaustion impact negatively both the electron transport chain function and the chronological life span of yeast, the latter occurring when a low threshold level of this antioxidant is reached, independently of the H O levels.
Diet plays a key role in determining the longevity of the organisms since it has been demonstrated that glucose restriction increases lifespan whereas a high-glucose diet decreases it. However, the molecular basis of how diet leads to the aging process is currently unknown. We propose that the quantity of glucose that fuels respiration influences ROS generation and glutathione levels, and both chemical species impact in the aging process. Herein, we provide evidence that mutation of the gene GSH1 diminishes glutathione levels. Moreover, glutathione levels were higher with 0.5% than in 10% glucose in the gsh1Δ and WT strains. Interestingly, the chronological life span (CLS) was lowered in the gsh1Δ strain cultured with 10% glucose but not under dietary restriction. The gsh1Δ strain also showed an inhibition of the mitochondrial respiration in 0.5 and 10% of glucose but only increased the H 2 O 2 levels under dietary restriction. These results correlate well with the GSH/GSSG ratio, which showed a decrease in gsh1Δ strain cultured with 0.5% glucose. Altogether these data indicate that glutathione has a major role in the function of electron transport chain (ETC) and is essential to maintain life span of Saccharomyces cerevisiae in 10% glucose. KeywordsAging; GSH; yeast; glucose concentration; oxidative stress; dietary restriction . CC-BY-ND4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/217125 doi: bioRxiv preprint first posted online Nov. 9, 2017; 3 IntroductionAging is an irreversible process that all the living organisms undergo. It has been postulated that aging leads to the malfunction of multiple cellular processes, which drives to chronic degenerative diseases (Barzilai et al., 2012). Diet is a chief environmental factor that influences the development of chronic degenerative diseases related to aging (Brandhorst et al., 2015;Honma et al., 2012;Prasad et al., 2012;Wei et al., 2017). Accordingly, dietary restriction increases the longevity across a wide range of species and has also been associated with the amelioration of some chronic degenerative diseases (Colman et al., 2009;Colman et al., 2014;Marchal et al., 2012), although it is not entirely clear how the restriction of certain nutrients such as glucose contributes to longevity extension. Saccharomyces cerevisiae is a useful model to elucidate the relationships between nutrient load and aging, as the effects of a high-energy diet and dietary restriction can be mimicked in this yeast by evaluating the effects of glucose concentrations of > 1% w/v or < 0.5% w/v, respectively, on chronological lifespan (CLS), which is the viability of the cell culture in a certain time in a nondividing, quiescent-like condition (Kaeberlein, 2010;Madrigal-Perez et al., 2016;Rockenfeller and Madeo, 2010). High concentrations of glucose decrease CLS by a mechanism related to increased oxidative stress (Barros et al., 2004;Mesquita et al., 2010...
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