Title: Molecular mechanisms underlying genotype-dependent responses to dietary restriction.
Authors: Schleit, Jennifer; Johnson, Simon C; Bennett, Christopher F; Simko, Marissa; Trongtham, Natalie; Castanza, Anthony; Hsieh, Edward J; Moller, Richard M; Wasko, Brian M; Delaney, Joe R; Sutphin, George L; Carr, Daniel; Murakami, Christopher J; Tocchi, Autumn; Xian, Bo; Chen, Weiyang; Yu, Tao; Goswami, Sarani; Higgins, Sean; Holmberg, Mollie; Jeong, Ki-Soo; Kim, Jin R; Klum, Shannon; Liao, Eric; Lin, Michael S; Lo, Winston; Miller, Hillary; Olsen, Brady; Peng, Zhao J; Pollard, Tom; Pradeep, Prarthana; Pruett, Dillon; Rai, Dilreet; Ros, Vanessa; Singh, Minnie; Spector, Benjamin L; Vander Wende, Helen; An, Elroy H; Fletcher, Marissa; Jelic, Monika; Rabinovitch, Peter S; MacCoss, Michael J; Han, Jing-Dong J; Kennedy, Brian K; Kaeberlein, Matt
Published In Aging Cell, (2013 Dec)
Abstract: Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.
PubMed ID: 23837470
MeSH Terms: Aerobiosis; Animals; Autophagy; Caenorhabditis elegans Proteins/metabolism; Caenorhabditis elegans/cytology; Caenorhabditis elegans/genetics*; Caenorhabditis elegans/physiology*; Caloric Restriction*; Diet*; Genotype; Saccharomyces cerevisiae/cytology; Saccharomyces cerevisiae/genetics*; Unfolded Protein Response/genetics