Functional genomic analysis reveals overlapping and distinct features of chronologically long-lived yeast populations

Abstract

Yeast chronological lifespan (CLS) is extended by multiple genetic and environmental manipulations, including caloric restriction (CR). Understanding the common changes in molecular pathways induced by such manipulations could potentially reveal conserved longevity mechanisms. We therefore performed gene expression profiling on several long-lived yeast populations, including an ade4∆ mutant defective in de novo purine (AMP) biosynthesis, and a calorie restricted WT strain. CLS was also extended by isonicotinamide (INAM) or expired media derived from CR cultures. Comparisons between these diverse long-lived conditions revealed a common set of differentially regulated genes, several of which were potential longevity biomarkers. There was also enrichment for genes that function in CLS regulation, including a long-lived adenosine kinase mutant (ado1∆) that links CLS regulation to the methyl cycle and AMP. Genes co-regulated between the CR and ade4∆ conditions were dominated by GO terms related to metabolism of alternative carbon sources, consistent with chronological longevity requiring efficient acetate/acetic acid utilization. Alternatively, treating cells with isonicotinamide (INAM) or the expired CR media resulted in GO terms predominantly related to cell wall remodeling, consistent with improved stress resistance and protection against external insults like acetic acid. Acetic acid therefore has both beneficial and detrimental effects on CLS.

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

“…However, the CLS-extending compound isonicotinamide (INAM) clearly extended CLS of the snf1Δ mutant ( Fig. 1E and G), consistent with INAM changing the stationary-phase gene expression profile differently from CR (24) and indicating that INAM extends CLS through a more Snf1-independent mechanism.…”

“…Expression profiling of cells grown to stationary phase under CR conditions revealed that the genes involved in acetate utilization were upregulated compared to those in nonrestricted (NR) yeast cells (24). Since Snf1 was known to be important for alternative carbon source utilization (25), we hypothesized that it was mediating the CLS extension induced by CR.…”

“…The dependence of CLS extension on CAT8 and ADR1 suggested that expression of their target genes could be enhanced by the CR growth condition. Previous studies implicated acetate and acetic acid utilization as important for proper CLS maintenance (24,46), so we focused quantitative reverse transcription (qRT)-PCR analysis on the expression of several Cat8/Adr1 target genes involved in the conversion of acetate into acetyl coenzyme A (acetyl-CoA). ACH1 encodes a mitochondrial enzyme that produces acetyl-CoA by transferring the CoA moiety of succinyl-CoA onto acetate (47,48).…”

Gene-nutrient interaction markedly influences yeast chronological lifespan

“…Respiration increases with reduction of glucose concentration to 0.5% or lower (“calorie-restricted”) from 2% (“non-restricted”) (Ocampo and others 2012; Pan and others 2011), but the significance of this metabolic change with regard to the many genetic effects on the CLS phenotype is not well understood, for example, there is less organic acid production by cells growing in media with lower glucose (Burtner and others 2009a). Thus, aerobic glycolysis and fermentation of glucose in the log phase of growth, organic acid production and secretion into the media, and its consequent effects on CLS represent an important mechanism of CLS, which can be greatly affected by media conditions and aeration status (Burtner and others 2009a; Murakami and others 2011; Ocampo and others 2012; Wierman and others 2015). Buffering the media (e.g., in the Longo lab media), or washing away the acetic acid in conditioned media, and aging in water can also potentially increase CLS.…”

“…The “acetic acid mechanism” appears to be fairly complex, but it may further be only one of many related or independent mechanisms of CLS. The number of factors that influence CLS is only beginning to be characterized (Matecic and others 2010; Ocampo and others 2012; Wierman and others 2015). …”