Extension of chronological life span in yeast by decreased TOR pathway signaling

TLDR

Chronological life span in yeast, a model for post‑mitotic tissue aging, is influenced by TOR signaling, which regulates nutrient‑responsive processes and may mediate lifespan extension via calorie restriction. We propose that up‑regulation of a highly conserved starvation‑induced stress response is key to life span extension by decreased TOR signaling in yeast and higher eukaryotes. We developed a high‑throughput assay to determine CLS for ~4800 single‑gene deletion strains and identified long‑lived strains carrying mutations in the conserved TOR pathway. Reducing TOR activity—by amino‑acid removal or pharmacological inhibitors—extends CLS, increases storage carbohydrate accumulation, enhances stress resistance, and induces nuclear relocalization of Msn2.

Abstract

Chronological life span (CLS) in Saccharomyces cerevisiae , defined as the time cells in a stationary phase culture remain viable, has been proposed as a model for the aging of post-mitotic tissues in mammals. We developed a high-throughput assay to determine CLS for ∼4800 single-gene deletion strains of yeast, and identified long-lived strains carrying mutations in the conserved TOR pathway. TOR signaling regulates multiple cellular processes in response to nutrients, especially amino acids, raising the possibility that decreased TOR signaling mediates life span extension by calorie restriction. In support of this possibility, removal of either asparagine or glutamate from the media significantly increased stationary phase survival. Pharmacological inhibition of TOR signaling by methionine sulfoximine or rapamycin also increased CLS. Decreased TOR activity also promoted increased accumulation of storage carbohydrates and enhanced stress resistance and nuclear relocalization of the stress-related transcription factor Msn2. We propose that up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes.