Abstract
Dietary restriction (DR) has been shown to increase lifespan in organisms ranging from yeast to mammals. This suggests that the underlying mechanisms may be evolutionarily conserved. Indeed, upstream signalling pathways, such as TOR, are strongly linked to DR-induced longevity in various organisms. However, the downstream effector proteins that ultimately mediate lifespan extension are less clear. To shed light on this, we used a proteomic approach on budding yeast. Our reasoning was that analysis of proteome-wide changes in response to DR might enable the identification of proteins that mediate its physiological effects, including replicative lifespan extension. Of over 2500 proteins we identified by liquid chromatography–mass spectrometry, 183 were significantly altered in expression by at least 3-fold in response to DR. Most of these proteins were mitochondrial and/or had clear links to respiration and metabolism. Indeed, direct analysis of oxygen consumption confirmed that mitochondrial respiration was increased several-fold in response to DR. In addition, several key proteins involved in mating, including Ste2 and Ste6, were down-regulated by DR. Consistent with this, shmoo formation in response to α-factor pheromone was reduced by DR, thus confirming the inhibitory effect of DR on yeast mating. Finally, we found that Hsp26, a member of the conserved small heat shock protein (sHSP) family, was up-regulated by DR and that overexpression of Hsp26 extended yeast replicative lifespan. As overexpression of sHSPs in Caenorhabditis elegans and Drosophila has previously been shown to extend lifespan, our data on yeast Hsp26 suggest that sHSPs may be universally conserved effectors of longevity.
Highlights
Dietary restriction (DR) is the most robust form of environmental manipulation known to increase longevity in a range of organisms [1]
The most common method of performing DR in yeast is through the reduction in glucose from the standard 2% concentration to either 0.5% or 0.05%, with the latter resulting in the largest replicative replicative lifespan extension [6]
To identify proteins that are differentially expressed under DR, S. cerevisiae BY4741 cells were grown under standard (2% glucose) or DR (0.05% glucose) conditions
Summary
Dietary restriction (DR) is the most robust form of environmental manipulation known to increase longevity in a range of organisms [1]. The most common method of performing DR in yeast is through the reduction in glucose from the standard 2% concentration to either 0.5% or 0.05%, with the latter resulting in the largest replicative replicative lifespan extension [6] Such studies in budding yeast have led to the identification of conserved genetic pathways linked to DR’s longevity and healthspan effects, including Ras/PKA, TOR/Sch and sirtuins [1,5,7]. Direct [8] or indirect [9] activation of the yeast sirtuin, Sir, by DR-induced changes in NAD/NADH ratios has been proposed as a longevity-promoting mechanism This idea is controversial, as it has been shown that DR does not increase Sir silencing activity [10,11] and that DR still increases replicative lifespan in sir deletion mutants [12]. Significant progress has been made using various model organisms [1], the key downstream effector proteins that mediate longevity extension by DR remain unclear
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