Tor1/Sch9-Regulated Carbon Source Substitution Is as Effective as Calorie Restriction in Life Span Extension

Abstract

The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Δ, tor1Δ, and ras2Δ mutants, was sufficient to reverse chronological life span extension in sch9Δ mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.

Geroconversion: irreversible step to cellular senescence

“…90 The reason is that the same pathways that drive geroconversion and organismal aging also increase glycolisis production. 88,91 Emerging Summary …”

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…In yeast, decreased Ras/ adenylate cyclase and/or Tor/S6K (SCH9) increases lifespan by more than 200%, while providing increased stress resistance against oxidants, genotoxins, and heatshock (Fabrizio et al, 2001(Fabrizio et al, , 2003Longo and Finch, 2003b;Wei et al, 2009). Similarly, in C. elegans, age-1 (PI3K homolog) and daf-2 (insulin/IGF-I receptor homolog) mutations extend the life-span in adult organisms by 65-100% by decreasing AKT-1/AKT-2 signaling, and by activating the transcription factor DAF-16 (FOXO family member), while promoting resistance to oxidative and ER stress (Johnson, 1990;Paradis et al, 1999;Hsu et al, 2003;Henis-Korenblit et al, 2010).…”

Staying alive

“…1 On the other hand, S. cerevisiae that can switch from TCA cycle/respiration to glycolysis during stationary phase exhibit lifespan extension. 267 Thus, decreased TCA cycle use may be advantageous during stationary phase for yeast as well as bacteria. Lymphocytes consume less glucose in a quiescent state compared with actively proliferating lymphocytes, which reflects a decrease in the expression of glucose transporters and in their localization to the plasma membrane.…”