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Molecular mechanisms underlying genotype-dependent responses to dietary restriction.

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.

SUBMITTER: Schleit J

PROVIDER: S-EPMC3838465 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying genotype-dependent responses to dietary restriction.

Schleit Jennifer J Johnson Simon C SC Bennett Christopher F CF Simko Marissa M Trongtham Natalie N Castanza Anthony A Hsieh Edward J EJ Moller Richard M RM Wasko Brian M BM Delaney Joe R JR Sutphin George L GL Carr Daniel D Murakami Christopher J CJ Tocchi Autumn A Xian Bo B Chen Weiyang W Yu Tao T Goswami Sarani S Higgins Sean S Holmberg Mollie M Jeong Ki-Soo KS Kim Jin R JR Klum Shannon S Liao Eric E Lin Michael S MS Lo Winston W Miller Hillary H Olsen Brady B Peng Zhao J ZJ Pollard Tom T Pradeep Prarthana P Pruett Dillon D Rai Dilreet D Ros Vanessa V Singh Minnie M Spector Benjamin L BL Vander Wende Helen H An Elroy H EH Fletcher Marissa M Jelic Monika M Rabinovitch Peter S PS MacCoss Michael J MJ Han Jing-Dong J JD Kennedy Brian K BK Kaeberlein Matt M

Aging cell 20130811 6

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 ...[more]

PMID: 23837470

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Molecular mechanisms underlying genotype-dependent responses to dietary restriction.

Publications

Molecular mechanisms underlying genotype-dependent responses to dietary restriction.

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