Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins

Abstract

SummaryCalorie restriction (CR) extends the mean and maximum lifespan of a wide variety of organisms ranging from yeast to mammals, although the molecular mechanisms of action remain unclear. For the budding yeast Saccharomyces cerevisiae reducing glucose in the growth medium extends both the replicative and chronological lifespans (CLS). The conserved NAD + -dependent histone deacetylase, Sir2p, promotes replicative longevity in S. cerevisiae by suppressing recombination within the ribosomal DNA locus and has been proposed to mediate the effects of CR on aging. In this study, we investigated the functional relationships of the yeast Sirtuins (Sir2p, Hst1p, Hst2p, Hst3p and Hst4p) with CLS and CR. SIR2 , HST2 , and HST4 were not major regulators of CLS and were not required for the lifespan extension caused by shifting the glucose concentration from 2 to 0.5% (CR). Deleting HST1 or HST3 moderately shortened CLS, but did not prevent CR from extending lifespan. CR therefore works through a Sirtuin-independent mechanism in the chronological aging system. We also show that low temperature or high osmolarity additively extends CLS when combined with CR, suggesting that these stresses and CR act through separate pathways. The CR effect on CLS was not specific to glucose. Restricting other simple sugars such as galactose or fructose also extended lifespan. Importantly, growth on nonfermentable carbon sources that force yeast to exclusively utilize respiration extended lifespan at nonrestricted concentrations and provided no additional benefit when restricted, suggesting that elevated respiration capacity is an important determinant of chronological longevity.

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

“…7B). Similarly, Sir2p is not required for calorie restriction-mediated chronological life span extension in yeast (66,67). Instead, our results are consistent with other studies that found that blocking sphingolipid synthesis leads to chronological life span extension.…”

“…In yeast, many of these stresses are associated with chronological life span extension (63,66). Consistent with the view that inositol deprivation is a stress provoking growth condition in yeast, we found that wild type cells growing in medium lacking inositol exhibit increased chronological life span (Fig.…”

Different carbon sources affect lifespan and protein redox state during Saccharomyces cerevisiae chronological ageing

“…Respiration induced by caloric restriction or by a non-fermentable carbon source seems to induce good mitochondrial metabolic activity with low ROS leakage from the respiratory chain. Many authors reported that a restricted dietary intake increased the rate of oxygen consumption, thus indicating an increase in mitochondrial respiration [43,44]. Furthermore, an evaluation of the GSH and GSSG levels also suggests that better mitochondrial activity might promote longevity by triggering mechanisms that protect cells against oxidative stress.…”

A genomic analysis of chronological longevity factors in budding yeast

“…[21][22][23][24] Our previous findings suggest that prolonged stationary phase survival of chronologically aging yeast in low glucose results, at least in part, from decreased production of acetic acid. 11 In addition to dietary restriction, inhibition of the target of rapamycin (TOR) kinase and/or deletion of the gene coding for the ribosomal S6 kinase homolog, SCH9, are both known to increase replicative life span and CLS in yeast, [25][26][27][28] as well as the lifespan of C. elegans 29,30 and D. melanogaster.…”