Abstract
In mammals, extended periods of fasting leads to the accumulation of blood ketone bodies including acetoacetate. Here we show that similar to the conversion of leucine to acetoacetate in fasting mammals, starvation conditions induced ketone body-like acetic acid generation from leucine in S. cerevisiae. Whereas wild-type and ras2Δ cells accumulated acetic acid, long-lived tor1Δ and sch9Δ mutants rapidly depleted it through a mitochondrial acetate CoA transferase-dependent mechanism, which was essential for lifespan extension. The sch9Δ-dependent utilization of acetic acid also required coenzyme Q biosynthetic genes and promoted the accumulation of intracellular trehalose. These results indicate that Tor-Sch9 deficiency extends longevity by switching cells to an alternative metabolic mode, in which acetic acid can be utilized for the storage of stress resistance carbon sources. These effects are reminiscent of those described for ketone bodies in fasting mammals and raise the possibility that the lifespan extension caused by Tor-S6K inhibition may also involve analogous metabolic changes in higher eukaryotes.
Highlights
The mechanisms underlying the aging process in mammals remain poorly understood
These results suggest that during the early stages of lifespan, as extracellular glucose and other nutrients become depleted, the absence of Tor/Sch9 signaling promotes a metabolic change that utilizes acetic acid, analogous to the generation and use of the ketone bodies, acetoacetic acid and
Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd
Summary
The mechanisms underlying the aging process in mammals remain poorly understood. The budding yeast Saccharomyces cerevisiae has served as a primary model organism to study the mechanisms of aging. Yeast has been responsible for the identification of two of the major pro-aging pathways: the Tor/S6K and the Ras/cAMP/PKA (Longo et al, 1996; Longo 1999; Pedruzzi et al, 2000, 2003; Fabrizio et al, 2001; Kaeberlein et al, 2005; Medvedik et al, 2007; Steffen et al, 2009; McCormick et al, 2011). S. cerevisiae has provided some of the initial links between pro-aging pathways and agedependent genomic instability (McMurray & Gottschling, 2004; Madia et al, 2009).
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