Abstract
Inhibition of growth signaling pathways protects against aging and age-related diseases in parallel with reduced oxidative stress. The relationships between growth signaling, oxidative stress and aging remain unclear. Here we report that in Saccharomyces cerevisiae, alterations in growth signaling pathways impact levels of superoxide anions that promote chronological aging and inhibit growth arrest of stationary phase cells in G0/G1. Factors that decrease intracellular superoxide anions in parallel with enhanced longevity and more efficient G0/G1 arrest include genetic inactivation of growth signaling pathways that inhibit Rim15p, which activates oxidative stress responses, and downregulation of these pathways by caloric restriction. Caloric restriction also reduces superoxide anions independently of Rim15p by elevating levels of H₂O₂, which activates superoxide dismutases. In contrast, high glucose or mutations that activate growth signaling accelerate chronological aging in parallel with increased superoxide anions and reduced efficiency of stationary phase G0/G1 arrest. High glucose also activates DNA damage responses and preferentially kills stationary phase cells that fail to arrest growth in G0/G1. These findings suggest that growth signaling promotes chronological aging in budding yeast by elevating superoxide anions that inhibit quiescence and induce DNA replication stress. A similar mechanism likely contributes to aging and age-related diseases in complex eukaryotes.
Highlights
Inhibition of growth signaling by caloric restriction (CR) or mutational inactivation of conserved insulin/IGF-1-like and Target of Rapamycin (TOR) signaling pathways prolongs the lifespans of eukaryotic organisms as diverse as yeasts and humans
To determine whether growth signaling by high glucose might trigger related events and accelerate chronological aging in budding yeast, we examined the effects of increasing the concentration of glucose in medium to 10% from the standard 2%
Growth signaling and superoxide anions in the chronological aging model Our findings reveal that under a variety of experimental conditions, an inverse relationship exists between budding yeast chronological lifespan (CLS) and intracellular levels of O2(summarized in Table 2) that points to O2- accumulating downstream of growth signaling as a primary cause of chronological aging
Summary
Inhibition of growth signaling by caloric restriction (CR) or mutational inactivation of conserved insulin/IGF-1-like and Target of Rapamycin (TOR) signaling pathways prolongs the lifespans of eukaryotic organisms as diverse as yeasts and humans. The lifespan-extending effects of reduced growth signaling occur in parallel with the induction of oxidative stress responses that reduce levels of reactive oxygen species (ROS) and oxidative damage to macromolecules. This is consistent with the longstanding free radical theory of aging, which posits oxidative damage to macromolecules as a primary determinant of lifespan [2]. A number of recent studies have investigated the impact of conserved growth signaling pathways on chronological lifespan (CLS) in the model organism Saccharomyces cerevisiae (budding yeast). Growth arrest in stationary phase mimics the quiescent, postmitotic state that occurs in higher www.impactaging.com
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