Abstract
The non-reducing disaccharide trehalose has been long considered only as a reserve carbohydrate. However, recent studies in yeast suggested that this osmolyte can protect cells and cellular proteins from oxidative damage elicited by exogenously added reactive oxygen species (ROS). Trehalose has been also shown to affect stability, folding, and aggregation of bacterial and firefly proteins heterologously expressed in heat-shocked yeast cells. Our recent investigation of how a lifespan-extending caloric restriction (CR) diet alters the metabolic history of chronologically aging yeast suggested that their longevity is programmed by the level of metabolic capacity – including trehalose biosynthesis and degradation – that yeast cells developed prior to entry into quiescence. To investigate whether trehalose homeostasis in chronologically aging yeast may play a role in longevity extension by CR, in this study we examined how single-gene-deletion mutations affecting trehalose biosynthesis and degradation impact (1) the age-related dynamics of changes in trehalose concentration; (2) yeast chronological lifespan under CR conditions; (3) the chronology of oxidative protein damage, intracellular ROS level and protein aggregation; and (4) the timeline of thermal inactivation of a protein in heat-shocked yeast cells and its subsequent reactivation in yeast returned to low temperature. Our data imply that CR extends yeast chronological lifespan in part by altering a pattern of age-related changes in trehalose concentration. We outline a model for molecular mechanisms underlying the essential role of trehalose in defining yeast longevity by modulating protein folding, misfolding, unfolding, refolding, oxidative damage, solubility, and aggregation throughout lifespan.
Highlights
Growing evidence supports the view that the fundamental mechanisms of aging are conserved across phyla (Kenyon, 2001; Kirkwood, 2008; Fontana et al, 2010; Kenyon, 2010)
To investigate whether trehalose homeostasis in yeast cells may play a role in longevity extension by Caloric restriction (CR), we assessed how singlegene-deletion mutations that in chronologically aging yeast alter www.frontiersin.org trehalose concentrations prior to quiescence and following entry into a quiescent state impact lifespan
We examined the effects of these mutations on the chronology of oxidative protein carbonylation, intracellular reactive oxygen species (ROS), protein aggregation, thermal inactivation of a protein in heat-shocked yeast cells and a subsequent reactivation of this protein in yeast shifted to low temperature
Summary
Growing evidence supports the view that the fundamental mechanisms of aging are conserved across phyla (Kenyon, 2001; Kirkwood, 2008; Fontana et al, 2010; Kenyon, 2010). The identification of single-gene mutations that extend lifespan in yeast, worms, flies, and mice revealed numerous proteins that regulate longevity (Kenyon, 2005, 2011; Fontana et al, 2010; Kaeberlein, 2010) These proteins have been implicated in a wide array of cellular processes including cell cycle, cell growth, stress response, protein folding, apoptosis, autophagy, proteasomal protein degradation, actin organization, signal transduction, nuclear DNA replication, chromatin assembly and maintenance, ribosome biogenesis and translation, lipid and carbohydrate metabolism, oxidative metabolism in mitochondria, NAD+ homeostasis, amino acid biosynthesis and degradation, and ammonium and amino acid uptake (Greer and Brunet, 2008; Guarente et al, 2008; Kenyon, 2010; Masoro and Austad, 2011). A possible essential role of trehalose in regulating yeast longevity has been suggested by other recent www.frontiersin.org
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