Date Published: March 25, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Sergio E. Campos, J. Abraham Avelar‐Rivas, Erika Garay, Alejandro Juárez‐Reyes, Alexander DeLuna.
Dietary restriction is arguably the most promising nonpharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other regulatory factors are involved. Here, we measured at the genomewide level the chronological lifespan of Saccharomyces cerevisiae gene deletion strains under two nitrogen source regimens, glutamine (nonrestricted) and γ‐aminobutyric acid (restricted). We identified 473 mutants with diminished or enhanced extension of lifespan. Functional analysis of such dietary restriction genes revealed novel processes underlying longevity by the nitrogen source quality, which also allowed us to generate a prioritized catalogue of transcription factors orchestrating the dietary restriction response. Importantly, deletions of transcription factors Msn2, Msn4, Snf6, Tec1, and Ste12 resulted in diminished lifespan extension and defects in cell cycle arrest upon nutrient starvation, suggesting that regulation of the cell cycle is a major mechanism of chronological longevity. We further show that STE12 overexpression is enough to extend lifespan, linking the pheromone/invasive growth pathway with cell survivorship. Our global picture of the genetic players of longevity by dietary restriction highlights intricate regulatory cross‐talks in aging cells.
Dietary restriction—a reduction in calorie intake without malnutrition, or substitution of the preferred carbon or nitrogen source—extends lifespan in virtually all species studied in the laboratory (Mair & Dillin, 2008). Dietary restriction has been associated with protection against age‐associated disease in mice, including neurodegenerative disorders (Zhu, Guo & Mattson, 1999) and cancer (Yamaza et al., 2010), promoting longer lifespan and healthier aging (Fontana & Partridge, 2015). Importantly, this intervention reduces the mortality rate in nonhuman primates (Colman et al., 2014) and delays the onset of aging‐related physiological changes in humans (Holloszy & Fontana, 2007), making dietary restriction the most promising intervention targeted to extend human lifespan. Yet, we are still missing a global picture of the genetic architecture of such lifespan response, which is needed to grant a deeper understanding of the genotype–phenotype relationship of aging and longevity (Schleit et al., 2013).
“The intrinsic nature of the aging process is essentially one of systems degradation” (Kirkwood, 2008). With a growing number of genetic aging factors in hand, the next great challenge is to understand how the mechanisms of aging and longevity are integrated to one another and to the environment. In this study, we have adapted the chronological aging paradigm in yeast to provide a quantitative and systematic description of how different dietary conditions impacts lifespan. Specifically, we have screened a collection of 3,718 gene deletion strains aged in glutamine—a preferred nitrogen source—or GABA—a nitrogen‐poor condition. Our analysis revealed that nitrogen limitation modifies the lifespan effect of 473 gene deletions (DR genes). To the best of our knowledge, this study yields the most comprehensive phenotypic compendium of genetic players involved in longevity by dietary restriction.
The authors declare that they have no competing interests.