Molecular mechanisms underlying genotype-dependent responses to dietary restriction

Jennifer Schleit, Simon C Johnson, Christopher F Bennett, Marissa Simko, Natalie Trongtham, Anthony Castanza, Edward J Hsieh, Richard M Moller, Brian M Wasko, Joe R Delaney, George L Sutphin, Daniel Carr, Christopher J Murakami, Autumn Tocchi, Bo Xian, Weiyang Chen, Tao Yu, Sarani Goswami, Sean Higgins, Mollie HolmbergKi-Soo Jeong, Jin R Kim, Shannon Klum, Eric Liao, Michael S Lin, Winston Lo, Hillary Miller, Brady Olsen, Zhao J Peng, Tom Pollard, Prarthana Pradeep, Dillon Pruett, Dilreet Rai, Vanessa Ros, Minnie Singh, Benjamin L Spector, Helen Vander Wende, Elroy H An, Marissa Fletcher, Monika Jelic, Peter S Rabinovitch, Michael J MacCoss, Jing-Dong J Han, Brian K Kennedy, Matt Kaeberlein

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1050-61
Number of pages12
JournalAging Cell
Volume12
Issue number6
DOIs
Publication statusPublished - Dec 2013

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