Sir2 and calorie restriction in yeast: a skeptical perspective.

Activation of Sir2-family proteins in response to calorie restriction (CR) has been proposed as an evolutionarily conserved mechanism for life span extension. This idea has been called into question with the discovery that Sir2-family proteins are not required for life span extension from CR in yeast. We present here a historical perspective and critical evaluation of the model that CR acts through Sir2 in yeast, and interpret prior reports in light of more recent discoveries. Several specific cases where the Sir2 model of CR is inconsistent with experimental data are noted. These shortcomings must be considered along with evidence supporting a role for Sir2 in CR in order to fully evaluate the validity of this model.

Pituitary removal in adult mice increases life span.

Dwarf mutations reduce levels of pituitary hormones and increase life span in mice. But because these dwarf mutations confer life-long hormone deficits that alter development and dramatically reduce fecundity, the relevance of these models to normal aging has been questioned. We examined effects of pituitary hormone withdrawal at different ages using hypophysectomy (surgical removal of the pituitary). Hypophysectomy at 1 month of age extended life span significantly (15%), but hypophysectomy at 9 months of age extended life span to the greatest magnitude (21%) of any age we tested. These results demonstrate pituitary hormone withdrawal can extend life span even if these hormones are removed relatively late in life.

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

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 approximately 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.

Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients.

Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.